Section 27

NEOPLASMS OF THE HEAD AND NECK

86

HEAD AND NECK CANCER

GARY L. CLAYMAN, MD SCOTT M. LIPPMAN, MD GEORGE E. LARAMORE, MD WAUN KI HONG, MD

The American Cancer Society (ACS) predicted that in 1999 approximately 40,400 new cases of head and neck cancer would be diagnosed in the United States (29,800 with oral cavity and pharyngeal cancer and 10,600 with laryngeal cancer). The same grim reckoning projected 12,300 American deaths in 1999 from this class of cancers.1 These diagnosis and mortality figures correspond to over 4% of all new cancer cases and 2% of all cancer deaths in the United States annually. Nearly identical percentages are reported from Britain, but head and neck cancers have a much greater impact in certain other parts of the world and are among the leading causes of cancer mortality worldwide.2,3 Despite improvements in diagnosis and local management, long-term survival rates in head and neck cancer have not increased significantly over the past 30 years and are among the lowest worldwide of the major cancers. For African Americans, survival rates have decreased. Oropharyngeal cancer, the largest subgroup of head and neck cancers, has a 5-year relative survival rate of only 55% for United States Caucasians and 32% for African Americans.4 Although earlystage head and neck cancers (especially laryngeal and oral cavity) have high cure rates, over 60% of head and neck cancer patients present with advanced disease. Cure rates decrease, of course, in locally advanced cases, whose probability of cure is inversely related to tumor size and even more so to the extent of regional node involvement. Treatment advances have been undermined by the significant percentage of patients initially cured of head and neck squamous cell carcinoma (HNSCC) who go on to develop second primary tumors.5,6 Second primaries are the major threat to long-term survival after successful therapy of early-stage HNSCC. Their high incidence probably results from the same carcinogenic exposure responsible for the initial primarya process called field cancerization (see Biology below). The clinical significance of second primary tumors is that a patient who presents with HNSCC, even in its earliest stage, is a patient for life. In addition to the problem of long-term survival in the face of second primary risk, HNSCC patients also can face tremendous reductions in their quality of life after definitive surgical therapy. Despite

marked advances in reconstructive surgery and rehabilitation, patients who have undergone laryngectomy, glossectomy, or composite resection can have significant residual cosmetic and functional debilities. These compelling problems are responsible for the emerging importance of primary chemotherapy and chemoprevention of HNSCC. New strategies for the management of cancers of the mucous membranes of the upper aerodigestive tract (UADT) are badly needed. A team concept is required. Already, the role of each treatment modality is becoming more clearly defined. New combined-modality approaches (e.g., sequential and synchronous chemoradiotherapy) and advances in organ preservation and chemoprevention are beginning to offer realistic hopes for improvements in HNSCC patients survival rates and quality of life. HNSCC research, both clinical and basic, is becoming a model for research into other epithelial cancers. This chapter reviews both the current status of and future investigative directions for the epidemiology, biology, chemoprevention, diagnosis, and therapy of head and neck cancer. ETIOLOGY AND EPIDEMIOLOGY OVERVIEW The complex process of head and neck carcinogenesis involves dynamic interactions among many factors.711 Approximately 90% of head and neck cancers occur after exposure to known UADT carcinogens. Chief among HNSCC-related carcinogens are tobacco and tobacco-like substances, such as betel leaf. Alcohol use is closely linked to tobacco in this regard and is part of a group of agents that can potentiate tobacco-related carcinogenesis. Other important etiologic factors are viruses, genetic predisposition, occupation, radiation exposure, and diet. The incidence of HNSCC increases with age, and HNSCC patients typically are older than 50.12,13 Several retrospective series report a worse prognosis in younger patients (30 years of age or younger). Other data suggest, however, that the natural history of HNSCC is the same in stage-matched patients regardless of age.14,15 Confounding factors in younger patients include genetic susceptibility and immunologic profile.16 Complicating the issues of HNSCC etiology and epidemiology are carcinomas of the salivary gland and nasopharynx. Both cancers are distinct from head and neck cancers at other sites and, therefore, will be considered separately after a general discussion of etiologic factors in head and neck cancer. TOBACCO AND ALCOHOL EXPOSURE Tobacco initiates a linear doseresponse carcinogenic effect in which duration is more important than the intensity of exposure. The major carcinogenic activity of cigarette

1174 SECTION 27 / Neoplasms of the Head and Neck

smoke resides in the particulate (tar) fraction, which contains a complex mixture of interacting cancer initiators, promoters, and co-carcinogens. Although the risk of bronchogenic carcinoma appears to be less for cigar and pipe smokers, these forms of tobacco use are clearly associated with carcinogenesis of the UADT. The pooling of saliva containing carcinogens in gravity-dependent regions may account for the frequent location of oral SCC along the lateral and ventral surfaces of the tongue and in the floor of the mouth.17 Pipe smokers who have a habitual constant position for the pipe stem may develop carcinoma of the lip at that site, which initiates speculation that physical and thermal trauma may be contributing factors. In heavy smokers, approximately 15 years must pass before the risk approaches that of people who never smoked.8 Tobacco is smoked and chewed in daunting quantities. Estimated 1986 world figures for smoking and smokeless tobacco use were 1 billion and 600 million people, respectively. Smoking rates are rising by 2% per year in developing countries, offsetting a 1.5% annual decrease in developed nations. Smokeless tobacco use is a growing international problem in many parts of the world, including Asia and Africa. Although overall United States rates have not changed in 30 years, dramatic increases in smokeless tobacco use have occurred among younger people, which may account for the recent excess of oral cancer mortality rates in this group.12,13,1821 Striking variations in head and neck cancer sites and incidence are seen among different regions, cultures, and demographic groups, due in large part to differing patterns of tobacco and other substance abuse.1,13,1921 SCC of the oral cavity and hypopharynx accounts for only 3% of all cancers in the United States, where smokers outnumber chewers, but for 50% of all cancers in Bombay, where pano (betel leaf, lime, catechu, and areca nut) is commonly chewed.20 SCC of the hard palate is endemic in other parts of Asia, where reverse chutta (homemade cigar) smokingburning end held in the mouthis common. Oral cancer incidence is highest in Southeast Asia, lip cancer in Newfoundland, and nasopharyngeal cancer in southern China. The male-to-female ratios of HNSCC incidence run the gamut from 12:1 in France to 1:1 in Bangalore, India. In the United States, this ratio has changed from about 4:1 40 years ago to about 2:1 today. The United States rates of head and neck cancer have changed over time as tobacco use habits have shifted. Among American women and nonwhite men, HNSCC incidence and mortality rates have increased over the last 50 years, with the trends most striking for oral cancer (sevenfold increase in women).13 Increased United States tobacco use among women, adolescents, and children portends increasing national death rates from head and neck cancer in the next several decades.18 In addition to causing head and neck cancer, smoking has also been shown to adversely affect radiotherapy.22 Although primary, tobacco is not the only factor in the complex causality equation for these cancers. Alcohol is an important promoter of carcinogenesis and is a contributive factor in at least 75% of UADT cancers.1 It has only a modest independent effect, however.23 Studies attempting to correlate types of alcoholic beverages with specific cancer risks have been conflicting. Most investigators believe that ethanol itself is the important factor.24 The major clinical significance of alcohol consumption is that it potentiates the carcinogenic effect of tobacco at every level of tobacco use, and the causative effect is most striking at the highest levels of exposure to both. The magnitude of the effect is midway between additive and multiplicative. Smoking marijuana appears to confer an even greater risk for HNSCC (but not for lung cancer) than does cigarette smoking.25,26 Marijuana smoke has a four times higher tar burden and 50% higher concentrations of benzopyrene and aromatic hydrocarbons than are present in tobacco smoke. VIRUSES Viruses have been implicated in the pathogenesis of oral, laryngeal, and nasopharyngeal carcinoma (NPC).2729 Seroepidemiologic studies in oral SCC suggest that herpes simplex virus 1 (HSV-1) may act as a mutagen in the development of this cancer. These studies have shown that patients with oral SCC have increased levels of HSV-1 IgA and IgM antibodies that are of prog-

nostic significance.30 Recent laboratory work, however, has raised questions about the importance of HSV-1 in oral carcinogenesis, since HSV-1 gene products appear in oral SCC tissue only in isolated cases.31 If not critical by itself, HSV-1 still may be a cofactor with other viral or chemical agents in causing oral carcinogenesis. More recently, an association between head and neck cancer and human papilloma viruses (HPVs) has been hotly pursued.27,3236 HPVs are a family of at least 65 viral subtypes that have been best studied in cervical carcinogenesis and recently linked to other epithelial cancers. Early studies suggested that the HPV-to-verrucous carcinoma relationship is stronger than that between HPV and other types of oral SCC, but they have not been confirmed. Immunohistochemical analysis of HPV capsid antigen and in situ hybridization and polymerase chain reaction (PCR) studies of HPV DNA suggested the association of HPVs (numbers 6, 11, 16, and 18) with oral carcinogenesis.33,34,36 These uncontrolled small studies generated conflicting results, however, and suggested marked overlap between viral expression in oral SCC and in normal oral mucosa. Laryngeal papillomatosis is associated with HPVs 6 and 11, whereas laryngeal SCC is associated with HPVs 16 and 18. HPV DNA is not limited to lesion sites but is present also in clinically and histologically normal UADT epithelium. New work using PCR probes in controlled studies, coupled with standard epidemiologic analysis data, should provide major insights into the role of HPVs in head and neck carcinogenesis. GENETIC LINKS Levels of aryl hydrocarbon hydroxylase, the enzyme that activates polycyclic aromatic hydrocarbons (the major carcinogens in cigarette smoke), are greater in laryngeal cancer patients than in controls. An association between the development of HNSCC in patients and specific human leukocyte antigens has also been reported. Recent data from several groups suggest that HNSCC patients have increased sensitivity to clastogen-induced chromosome damage when compared with case controls. A multiplicative risk of HNSCC has been reported when analyzing mutagen-induced chromosome damage and carcinogenic exposure.37 Along with environmental factors, genetic factors may become useful components of quantitative risk assessment models.38,39 OCCUPATION Although occupational exposures probably play a minor role overall in the development of HNSCC, they are major risk factors for adenocarcinoma of the sinonasal region.8,40 The most important exposures occur in the environments of nickel refining, woodworking, and leather working. Additionally, thoratrast contrast ingestion has also been related historically to paranasal sinus malignancies. Asbestos exposure may be associated with certain UADT cancers, most notably in the larynx.41 RADIATION A strong association no longer exists between exposure to ionizing radiation and the development of HNSCC. Other than in lip cancer, which, like skin cancer, is associated with ultraviolet-B exposure, only two associations are known to exist between radiation and UADT cancers: paranasal sinus cancers related to radium watch dial painting and thorotrast ingestion and thyroid cancers related to radiotherapy and medical use of radioactive isotopes of iodine (particularly in childhood).42 Therapeutic irradiation of HNSCC does not appear to induce second primary tumors in the aerodigestive tract. Patients with histories of head and neck irradiation in childhood, however, may have an increased incidence of head and neck sarcomas as adults. DIET Considerable epidemiologic evidence suggests that vitamin A and beta-carotene play a protective role in epithelial neoplasia.43 Deficiencies of carotenoids appear to be a risk factor for squamous UADT and lung cancers. It is not known, however, which of the more than 500 carotenoids are protective, what chemical interactions may occur, or what protective role other micronutrients in carotenoid-rich foods may play. Several groups specifically studied the association between dietary vitamin A and/or beta-carotene and risk for oral cancer. Winn and colleagues found that the risk of oral SCC in women was inversely related to the consumption of fresh fruits and vegetables.44 Diets are complex and difficult to assess and validate; in particular, there are often inaccuracies in translating foods into constituent nutrients. Further studies are needed to define sharply the relationship between dietary intake and serum levels of the various carotenoid components. Even in positive studies, it is impossible to determine which of the vast

array of compounds is most beneficial, and controlling for other dietary variables and confounding risk factors has remained a difficult methodologic problem. Further confounding this situation, smoking has been associated with reduced dietary intake and serum levels of carotenoids. Despite their many problems, prospective and retrospective nutritional (serum and dietary) epidemiologic studies, along with basic science research, have provided important clues to the development and prevention of specific cancers. SALIVARY GLAND AND NASOPHARYNGEAL CARCINOMA As stated in the overview, nasopharyngeal and salivary carcinomas, each accounting for 0.2% of all United States cancers, are distinct from those in other head and neck sites.13 Neither has been strongly linked etiologically to tobacco and neither demonstrates the multiple primary or second primary patterns of the other head and neck cancer sites.45 Salivary gland cancer incidence has been stable for the past 25 years in the United States. These tumors are similar to nonmelanoma skin cancers and lip cancer in their epidemiologic association with ultraviolet-B and ionizing radiation exposure.4649 There may also be an association between breast carcinomas and salivary gland malignancies. NPC presents in a younger population than other head and neck cancer sites. Its incidence increases with age and plateaus at 50 to 60 years. In all races, NPC is two- to three-fold more common in males. It is 20 times more common in Asia than in North America, although in the latter it has an increased frequency among Alaskan natives. This carcinomas pattern shows decreasing incidence in a gradient from southern to northern regions of China (30 to 50 per 100,000 personyears down to 2 or 3 per 100,000). Among Chinese in Hong Kong and Singapore, this is the most common cancer in people 15 to 34 years old.50,51 Immigrant studies indicate that incidence differences seemingly associated with ethnicity are really largely associated with environment. Americans with Chinese ancestry have an incidence halfway between those of native Chinese and American whites. These are but a few of the wide variations in NPC incidence produced by geographic, ethnic, and cultural differences.45,50,51 Two major, independent risk factors for NPC are salted fish as a diet standard and the Epstein-Barr virus (EBV).52 Seven studies have used case-control methodology to look at whether eating salted fish correlates with NPC incidence.53 These studies were variously performed in high- and low-risk areas of China. All seven identified salted fish as an independent risk factor (attributable risk of 50%). Even stronger than that of salted fish is the epidemiologic link between EBV and NPC.51,54,55 Regardless of histopathologic subtype (World Health Organization [WHO] I-III), geographic or ethnic setting, sporadic or endemic pattern, premalignant or malignant status, NPC is an EBV-associated malignancy. Types II and III NPC cells have EBV nuclear antigen (EBNA), DNA, and transmissible virus.54,56 The association between EBV and well-differentiated (WHO type I) NPC was recognized only recently with the detection of EBV genome in type I lesions by recombinant DNA technology.57 NPC may be the best example of a virus-related epithelial carcinoma and has served as a model for the study of virus-induced carcinogenesis elsewhere in the body. The fundamental and early role of EBV in the pathogenesis of NPC is suggested by the recent finding of EBV DNA in premalignant nasopharyngeal lesions. The transformation rate of these lesions, however, only 20%, indicates the importance of additional events in nasopharyngeal tumorigenesis. Several serologic associations exist between EBV and types II and III NPC.56,58,59 Elevated IgG response to EBV capsid antigen (EBVCA) is most sensitive, seen in nearly 100% of types II and III NPC, but is the least NPC specific. The IgA EBVCA serologic measure is more specific but less sensitive. The most specific but least sensitive of current serologic tests is IgA response in a diffuse pattern to EBV early antigen (EBVEA)-positive in 40 to 60% of NPC patients and in fewer than 2% of other HNSCC patients and controls.59 These data illustrate that IgA response to both EBVCA and EBVEA is useful for recognizing occult disease in treated patients and for screening high-risk groups. Recent investigations have proposed PCR screening of metastatic unknown primary carcinomas to the neck for EBV capsid DNA as a molecular marker of NPC in the absence of biopsy-confirmed NPC in any primary site.55 In this regard, the management of

CHAPTER 86 / Head and Neck Cancer 1175

unknown primary carcinomas may be altered by contemporary scientific advances. ETIOLOGIC AND EPIDEMIOLOGIC GOALS The ultimate goals of epidemiology and etiology are disease prevention and early detection. Studying incidence patterns and risk factors facilitates research and intervention strategies designed ultimately to reduce cancer mortality. Cancers of the head and neck are a devastating group of diseases for which many etiologic factors are known. The strong relationship of NPC with EBV has important diagnostic and therapeutic implications55 and offers the unique opportunity to develop effective screening for early detection with viral markers in high-risk areas and vaccines for disease prevention.60 Significant efforts should be made toward eliminating, or at least diminishing, the effects of the major known causes of head and neck cancer.61 For example, given the double-barreled multiplicative effect of tobacco and alcohol, substantially reducing the use of either could dramatically reduce rates of HNSCC. Unfortunately, both smoking and drinking have proved so far to be highly resistant to primary prevention (use reduction) approaches.62 Some success has been achieved in getting patients to quit smoking after treatment of primary HNSCC: fear of recurrent disease disposes them to heed the physicians advice. Effective tobacco and alcohol cessation programs are prerequisite to the control and prevention of HNSCC. BIOLOGY CARCINOGENESIS (FIELD CANCERIZATION) Slaughter et al.s classic 1953 report64 on oral cancer proposed that UADT carcinogenesis is a process of field cancerization: the repeated exposure of a regions entire tissue area to carcinogenic insult (e.g., tobacco and alcohol), which increases the tissues risk for developing multiple independent premalignant and malignant foci.5,6466 This concept (also called field carcinogenesis or condemned-mucosa syndrome) may explain the clinical occurrence of multiple primary and second primary tumors in HNSCC. The data indicate that second primaries, whether synchronous or metachronous, generally are of squamous histology, develop at a constant rate (4 to 7% of treated patients per year), are not treatment related, and occur in the aerodigestive field at risk, that is, the head and neck, the upper two-thirds of the esophagus, and the lung.5,6,64 These characteristics of second primaries support the field cancerization hypothesis. Recent data on p53 mutations provide strong molecular support for the field carcinogenesis concept.6769 Despite epidemiologic studies having long associated tobacco and alcohol use with the development of SCC of the head and neck, the molecular targets of these agents remain to be identified. In recent investigations by Brennan et al.,71 significant tobacco and alcohol use was associated with a high frequency of p53 mutations. Their preliminary results suggest that these p53 mutations occur at nonindigenous mutation sites. These findings suggest a role for tobacco in the molecular progression and field carcinogenesis process in head and neck cancer. Despite intensive study, much of the complex fundamental biology of HNSCC remains poorly understood. Like other epithelial neoplasms, UADT carcinogenesis appears to evolve through a complex multi-step process involving certain biomolecular changes that precede premalignant lesions, which, in turn, precede invasive cancer.7173 On the basis of animal studies, epithelial carcinogenesis has been divided into three phases: initiation, promotion, and progression. Although human neoplasia does not fit neatly into this tripartite framework, the framework serves as a useful model for understanding pharmacologic interventions. Pharmacologic interventions at each phase have attendant advantages and disadvantages. Chemopreventions greatest potential is in the promotion and progression phases of carcinogenesis. Occurring within the three-phase model described above, multiple subtle steps of UADT carcinogenesis involve genetic alterations, dysregulated epithelial differentiation, abnormal proliferation, and altered regulatory effects. Although the earliest genetic changes precede the relatively simultaneous occurrences of altered differentiation and proliferation, evolving genetic changes occur as carcinogenesis progresses. One important focus of combined clinical and basic research is to establish specific probes and markers for these carcinogenic

1176 SECTION 27 / Neoplasms of the Head and Neck

steps. These probes would help identify individuals at highest risk of UADT cancer and would act as intermediate end-point markers for early evaluations of the efficacy of chemopreventive agents.74 Genetic Alterations (See also Molecular Biology). The degree of genetic damage reflects a composite of carcinogen exposure and inherent tissue sensitivity. Genomic changes accumulate, presumably in the entire carcinogen-exposed tissue. Clonal malignant foci develop only in specific sites, however, where tumorigenesis is possible. Nonspecific (random) genomic alterations indicated by micronuclei, sister-chromatid exchanges, and aneuploidy can occur in normal, premalignant, and malignant aerodigestive tract tissue.7578 Although the fundamental genetic events associated with UADT cancers have not yet been established, several nonrandom chromosomal alterations (e.g., alterations in chromosomes 1, 3, 6, 7, 8, 9, 10, 11, 13, and 17) have been detected in HNSCC (fresh-tissue and cell-line studies).75,77,79,80 Shortterm cultures of oral premalignant cells and microdisection studies using chromosal marking, loss of heterozygosity (LOH), microsatellite studies have revealed early nonrandom cytogenetic changes as well.81 Carcinogenesis is thought to be regulated fundamentally by the cellular balance between oncogenes and tumor suppressor genes. This dynamic relationship is under intensive study in HNSCC.82,83 Aberrant expressions (amplifications or mutations) of specific families of cellular oncogenes such as myc, ras, neu, bcl, int, ems-1, cyclin D1 and hst are associated with ADT carcinogenesis.8488 Up to one-third of cases of primary HNSCC demonstrate an inactivation of the p16 via multiple mechanisms including methylation, mutation, and translocation.89 The families of ras, neu, int-2, and n-myc oncogenes are amplified in the more advanced stages of oral SCC, and activated oncogenes of these families in vitro alter the response to differentiation agents and promote uncontrolled cellular growth, aneuploidy, and tumorigenicity.85,88 Epidermal growth factor receptor (EGF-R) expression has also been suggested to be amplified in HNSCCs and predictive of aggressive biologic behavior.90 Further studies validating these observations are required. Differentiation Alterations. Dysregulation of differentiation is another hallmark of multi-step carcinogenesis. Human oral and esophageal epithelium is stratified squamous in type. Oral mucosa is noncornified except for the mucosa on the gingiva and dorsal surface of the tongue, which undergo keratinization. Cytokeratins, a family of at least 19 intermediate-sized filaments that range from 40 to 68 kDa, are expressed in different complex patterns that correlate with distinct types of epithelial differentiation and with carcinogenic progression.91,92 The spatial distribution of several cytokeratins, involucrin, transglutaminase I, and other differentiation antigens is also altered in dysplasia and carcinoma.93 Proliferation Alterations. The third major phase of multi-step carcinogenesis is dysregulated proliferation. The transition from normal epithelium to hyperplasia and dysplasia is associated with an increased growth fraction and cells proliferating beyond the basal layer. Older histologic assays have correlated this process with increased frequencies of mitotic figures; more recently, DNA flow cytometry and monoclonal-antibody probes to nuclear antigens (e.g., Ki-67 and proliferating-cell nuclear antigen [PCNA]) have revealed some strong positive correlations in UADT epithelium between abnormal suprabasal proliferation and later carcinogenic stages (severe dysplasia).74,94,95 Altered Regulatory Effects. Epithelial carcinogenesis is associated also with the abnormal expression of cellular factors that regulate growth and development. The importance of these factors is inferred from their differential expression in normal and malignant tissues. For example, high expression of EGF-R is found in a significant fraction of experimental and human SCCs of the UADT.96,97 EGF-R gene activation occurs early in experimental oral carcinogenesis, and foci of cells expressing EGF-R can be found in human premalignant lesions. Similarly, high expression of transforming growth factoralpha (TGF-) has been associated with malignant transformation of a variety of tumors (including oral cancers) and is frequently accompanied by elevated levels of EGF-R in SCC.98,99 The relationship between high TGF- and high EGF-R suggests that an autocrine loop mechanism drives the dysregulation of proliferation.

MOLECULAR BIOLOGY As advances in molecular biology and biotechnology continue at a rapid pace, our understanding of the initiation and progression of carcinogenic processes will follow. The most frequent molecular abnormalities in these cancers, to date, are mutations in the tumor suppressor gene p53, which occur at a rate of approximately 40 to 70%.27,100 Mutations of p53 are present in premalignant areas, including carcinoma in situ or moderate to severe dysplasia, in approximately 20% of cases.101 Inactivation of the tumor suppressor gene p16 may be observed in up to two-thirds of HNSCC, although mutation is not the most frequent mechanism.90 Other genes have been investigated in these cancers, including the tumor suppressor gene Rb, and several oncogenes, such as ras, myc, int-2, bcl-1, cyclin D1, and C-erb/neu; despite these studies, predictors of response to therapy, phenotypic behavior,102 and survival remain elusive.85,102 Biotechnology and scientific advances have also allowed identification of areas of frequent chromosomal loss, termed loss of heterozygosity (LOH). In head and neck cancer, LOH is frequent among chromosomes 3p, 17p, 13q, 11q, 6p, 9p, and 14q.103 These studies may lead to the identification of putative tumor suppressor genes in these malignancies and an understanding of the progression to malignancy. The concepts of multi-step carcinogenesis and field carcinogenesis have now been formulated in molecular biologic terms. The carcinogen-containing environment that initiated tumorigenesis has also affected the nontransformed surrounding tissues. Chromosome labeling and LOH studies have shown that LOH at 9p and abnormalities in chromosome 11 are present in histologically normal mucosa adjacent to tumors, supporting the field hypothesis.103 Once a head and neck cancer has developed, its phenotypic behavior (the ability to invade, metastasize, respond to radiotherapy, and recur) is dependent on complex microenvironmental and biologic systems. Invasive and metastatic capabilities of a tumor depend on degradative enzymes, including collagenases, plasminogen activators (including urokinase), and cathepsin, as well as angiogenic factors, growth factors, cytokines, receptors, cell-surface properties, and motility factors. The tumor milieu is also influenced by nerve fibers, stromal cells, and tumor-associated and tumor-infiltrating lymphocytes. All of these characteristics provide attractive targets for new and more specific therapeutic approaches. IMMUNOLOGY A variety of immunologic abnormalities occur in HNSCC, but precise cause-and-effect relationships between abnormalities and cancer remain unclear.104 Both cellular and humoral immunity have important implications for HNSCC prognosis and therapy. Although multiple and prominent immunologic deficits occur in HNSCC, immunologic therapeutic approaches (interferon [IFN]-, interleukin-2 [IL-2], activated lymphocyte infusion, and plasmapheresis) have yielded only modest response rates and short response durations (see Immunobiologic Therapy in the treatment section). BIOLOGIC GOALS Several nonrandom chromosomal alterations, activated oncogenes, and LOH sites likely for tumor suppressor genes are being actively investigated to develop informative biologic and predictive markers for HNSCC. The recent development of antibody probes for key gene products and molecular probes for gene transcripts should allow future study to identify the timing and sequence of gene alterations during multi-step UADT carcinogenesis. The mechanisms of HNSCC invasion and metastasis are not well established. Recent studies have identified specific membrane proteins, degradative enzymes, and binding sites required for SCC invasion and metastasis (in animal models) and associated with early recurrence (in clinical studies).93 This work opens the way to novel therapeutic approaches for future use of directed monoclonal antibodies/inhibitors to block key binding sites, thus preventing tumor invasion and metastasis. Advances in molecular biology and biotechnology are also expanding our concept of the capabilities for molecular (or gene) therapy.105,106 Novel gene intervention strategies may be applicable for augmenting immune response, delivering a toxic gene or metabolite, alternating chemotherapy or radiation sensitivity, or inducing cell cycle control or cell death. Further studies that demarcate critical molecular events in the HNSCC progression model may be essential for gene therapy prevention strategies.

CHEMOPREVENTION APPROACHES OVERVIEW The control and management of HNSCC are hindered tremendously by poor overall survival rates and the high risk of second primary tumors in early-stage cases. Compounding these issues are severe disfigurements and debilities resulting from definitive local therapy of head and neck tumors. Although tobacco and alcohol cessation is of primary importance, cessation approaches have not succeeded in significantly reducing exposure to these carcinogens.62 Consequently, chemoprevention very recently has come to the forefront of head and neck cancer research efforts.5,38,64,83,107113 In the mid-1970s, Michael Sporn of the National Cancer Institute (NCI) coined the term chemopreventionthe pharmacologic inhibition of carcinogenesis or its reversal in premalignant stages.115 Current HNSCC chemopreventive strategy focuses strongly on retinoids in oral premalignancy and in the adjuvant prevention of second primary tumors. The term retinoid was coined in 1976, also by Dr. Sporn.115 Ultimately, this approach hopes to find effective agents or dietary manipulations with little or no toxicity for use in largely healthy subjects at risk.116,117 Another major focus of this work is on potential biologic markers of intermediate end points.74 ANATOMY OVERVIEW The term cancer of the head and neck describes a diverse collection of cancers of varying histologies arising from a variety of anatomic sites that make up the UADT.118 The UADT consists of a complex mucosa-covered conduit for food and air that extends from the vermilion surface of the lips to the cervical esophagus. In common use, this terminology has been applied primarily to those cancers arising from the mucosal surfaces of the lips, oral cavity, pharynx, larynx, and cervical esophagus. Included in this designation, however, are other important sites, such as the nose and paranasal sinuses, salivary glands (major and minor), thyroid and parathyroid, and melanoma and nonmelanoma skin cancers. Some cancers arising in this region are typically excluded from the generic designation of head and neck cancer. Examples are tumors of the central nervous system, ocular neoplasms, primary tumors of lymphatic origin, and neural and endocrine malignancies. Because of the diversity of sites and tissues of origin, the biology of tumor growth, patterns of metastases, and natural boundaries for tumor extension, the signs and symptoms of disease are quite varied. The anatomy of the region has also dictated that optimal evaluation, diagnosis, and treatment require specific multidisciplinary expertise that frequently crosses traditional training backgrounds. The clinical manifestations of disease are varied and have a significant impact on the cosmetic and functional integrity of the head and neck region. Although the anatomic structures are only millimeters apart, the low metastatic potential and high curability of vocal cord cancers stand in extreme contrast to the early dissemination and grim prognosis of stage-matched pyriform sinus cancers.119124 Clinical differences between cancers in different sites are not explained solely by anatomic factors but by major biologic differences. Regrettably, the relatively small number of head and neck cancer patients (in the United States, 40,000 annual diagnoses of HNSCC) often requires grouping many different types in each HNSCC therapy trial.4 Associated morbidities of disease and treatment involve all of the special senses to varying degrees, notably speech, swallowing, smelling, breathing, and masticationfunctions critically important for social interaction, a good quality of life, and survival. ORAL CAVITY The oral cavity includes the lips, buccal mucosa, anterior tongue, floor of the mouth, hard palate, upper gingiva, and lower gingiva. The tongue occupies a major portion of the oral cavity and is contiguous with the floor of the mouth. The gingival mucosa overlying the mandibular and maxillary alveolar ridges is closely adherent to the underlying periosteum. The hard palate forms the roof of the oral cavity and consists of mucosa overlying the palatine portion of the maxilla extending from the superior alveolar ridge to the junction with the soft palate. PHARYNX The pharynx is a musculomembranous tube extending from the skull base to the level of the sixth cervical vertebra, supported by overlapping constrictor muscles (superior, middle, and inferior) and other muscles arising from the styloid process and skull base.

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The region of the oropharynx consists of a complex three-dimensional musculomembranous conduit communicating with the oral cavity anteriorly, the nasopharynx superiorly, and the hypopharynx/larynx inferiorly. It is divided into four sites of clinical importance: (a) the tonsillar area, which makes up the major portion of the lateral pharyngeal wall and blends with the tongue base, palate, and retromolar trigone; (b) the tongue base; (c) the soft palate; and (d) the posterior pharyngeal wall. Innervation of the pharynx is via the pharyngeal plexus with contributions from the glossopharyngeal (sensory) and vagus nerves (motor and sensory). The hypopharynx is divided into three distinct regions: the pyriform sinuses, the posterior surface of the larynx (postcricoid area), and the inferior, posterior, and lateral pharyngeal walls. The pyriform sinus (a recess) is a paired mucosal cul-de-sac lying lateral to each side of the larynx, bounded superiorly by the pharyngoepiglottic folds and inferiorly by the cricoid cartilage. LARYNX The larynx consists of a mucosally covered cartilaginous framework (thyroid and cricoid cartilages) attached above to the hyoid bone by the thyrohyoid membrane and below to the trachea. The opening to the larynx is continuous with the pharyngeal airway. Unlike the rest of the pharynx, the mucosa of the larynx consists largely of columnar ciliated respiratory-type epithelium, although stratified squamous epithelium is found on the upper posterior epiglottis, aryepiglottic folds, and true vocal cords. Submucosal lymphatics in the upper larynx are extensive, whereas they are sparse in the true vocal cords. The larynx is divided into three anatomic regions: the supraglottic larynx, the glottic larynx, and the subglottic larynx. The supraglottic larynx includes the epiglottis, aryepiglottic folds, laryngeal surface of the arytenoids, false vocal cords, and ventricles. The glottic larynx is derived from the tracheobronchial anlage and consists of both true vocal cords and the mucosa of the anterior and posterior commissures extending 1 cm below the free edge of the vocal folds. The subglottic larynx consists of the region bounded by the vocal cords above and the inferior border of the cricoid cartilage. Lymphatic supply to the subglottic larynx is extensive and bilateral. The infraglottic lymphatics drain to the cervical nodes through the cricothyroid membrane, whereas supraglottic lymphatics drain through the thyrohyoid membrane. NECK Anatomic considerations in the treatment of cancers of the head and neck must include a thorough understanding of the neural, vascular, and lymphatic structures of the neck. Detailed anatomic studies have described the organization of the lymphatic drainage of the UADT. Specific regions of the head and neck and the tumors that arise there have lymphatic drainage, which is consistent and predictable. There are 10 major groups of lymph nodes in the head and neck (Fig. 86.1). Primary and secondary echelons of lymph node drainage have been derived for each major region of the head and neck mucosa. The lip, cheek, and anterior gingiva drain to submandibular and submental lymph node groups. In addition, the cheek and upper lip also drain to inferior parotid nodes, whereas the posterior gingiva and palate drain to the internal jugular chain and lateral retropharyngeal groups. Lymphatic drainage for the tongue can be crossed and drains to the internal jugular, subdigastric, omohyoid, submandibular, and submental nodal groups. Although metastases to the lower neck nodes are infrequent from the oral cavity, generally, the more anterior the tumor location in the tongue, the more likely it is that metastases also will spread to lower jugular nodes. The floor-of-mouth drainage is similar to that of the tongue. The upper portion of the pharynx drains directly to the upper cervical lymph nodes along the internal jugular chain. The oropharynx and tonsil drain through the peripharyngeal space to the midjugular region, particularly to the jugulodigastric nodes. The regions of the hypopharynx and larynx drain primarily along the routes of their vascular supply to either the deep cervical nodes along the midjugular (upper pharynx, larynx) or the deep nodes along the lower jugular and peritracheal region (lower pharynx, larynx). For the purposes of local treatment, the various lymph node groups of the neck have been divided into five levels (Fig. 86.2). Level I includes the submental group of nodes located within the triangle bounded by the anterior belly of the digastric muscles and the hyoid

1178 SECTION 27 / Neoplasms of the Head and Neck

Figure 86.1. Major lymph node groups in the head and neck. These include occipital, mastoid, parotid, submandibular, facial, submental, sublingual, retropharyngeal, anterior cervical, and lateral cervical lymph node groups.

bone and the submandibular group bounded by the digastric muscle and the body of the mandible. Level II nodes consist of the upper jugular lymph nodes located in proximity to the upper third of the internal jugular vein and extending from the skull base to the level of the bifurcation of the carotid artery. The anterior and posterior boundaries are the lateral border of the sternohyoid muscle and the posterior border of the sternocleidomastoid muscle, respectively. Level III nodes include those nodes located adjacent to the middle third of the internal jugular vein from the carotid bifurcation to the omohyoid muscle (level of the cricothyroid notch). Anterior and posterior boundaries are the same as level II. Level IV nodes include the lower jugular group extending from omohyoid muscle to the clavicle below. Level V nodes are those located along the lower half of the spinal accessory nerve and transverse cervical artery. This level is bounded by the anterior border of the trapezius muscle, the posterior border of the sternocleidomastoid muscle, and the clavicle below. PATHOLOGY HISTOLOGY AND PROGNOSIS More than 90% of head and neck cancers of the UADT are SCC.125 Additional information usually reported by the pathologist includes tumor grade or differentiation. Traditionally, tumor grading has been based on criteria developed over 50 years ago by Broder.2,127 Unfortunately, differentiation grade has not been consistently accurate in reflecting the biologic aggressiveness of SCC.2 The difficulty in predicting the behavior of individual tumors, however, is well recognized. Prognosis is influenced by many factors other than grade.127,128 These include tumor size, site, vascularity, lymphatic drainage, and host immune response; the patients age, sex, nutritional status, and performance status; and other, as yet unrecognized variables. The comprehensive histologic evaluation of SCC includes characteristics of tumor-host interactions. Their incorporation into the determination of tumor grade was pioneered by Jakobsson and colleagues.130 Characteristics considered include degree of keratinization, nuclear grade, mitotic rate, inflammatory response, vascular-stromal response, vascular invasion, and pattern of invasion. These characteristics have variably correlated with biologic behavior. Keratinization is the major determinant of Broder grade. Better differentiated tumors that produce more keratin are thought to be less likely

Figure 86.2. Division of lymph nodes by level. A system of five levels of lymph node groups in the lateral neck is used clinically to describe lymph node location. Level I includes submental and submandibular groups. Level II is upper jugular lymph nodes. Level III is middle jugular lymph nodes. Level IV is lower jugular lymph nodes. Level V is posterior cervical lymph nodes. A variably used designation is level VI, for lymph nodes of the anterior cervical compartment.

to metastasize. Nuclear grade assesses nuclear pleomorphism. Enlarged, hyperchromatic nuclei are associated with less differentiated tumors. Nuclear grade accurately predicts the behavior of advanced laryngeal cancers.130 Enlarged nuclear size and staining presumably reflect chromosomal abnormalities and increased DNA content. Numerous studies of DNA content have demonstrated high rates of aneuploidy in squamous cancers that range from 50 to 70%. Aneuploidy has been associated with poor prognosis.131,132 Mitotic rate and labeling index have also been used to reflect proliferative activity, but large-scale studies of head and neck cancers have been lacking. Features reflecting aggressive disease include lymphatic invasion, perineural invasion, lymph node metastases, and penetration of the tumor through the capsule of involved lymph nodes (extracapsular spread). The presence of regional lymph node metastases is the most important determinant of prognosis in head and neck cancer and is associated with a 50% decrease in survival rates as compared with patients without regional metastases. More recently, the histologic pattern of invasion of these cancers was systematically studied. Tumors that invade with thin, finger-like projections or single disassociated cells behave more aggressively regardless of differentiation grade and tend to be associated with vascular and neural invasion.129 The presence of extracapsular spread of tumor in the neck has been directly associated with high rates of distant metastases. These various histologic features play an important role in therapeutic decision making. MOLECULAR PATHOLOGY The head and neck surgical oncologist relies heavily on the histopathologic assessment of surgical margins to ensure total excision of the tumor in patients with head and neck cancer. Currently, surgeons depend on frozen-section analysis of margins to assess these issues. Recently, Sidransky et al. proposed using contemporary molecular techniques to determine whether clonal populations of infiltrating tumor cells harboring mutations of the p53 gene could be detected in histopathologically negative surgical margins and cervical lymph nodes of patients with SCC of the head and neck.133 They found that 38% (5 of 13) of patients had molecular positive margins and approximately 50% had molecular identification of p53

mutations in histopathologically negative lymph nodes. Patients with these molecular positive margins had an increased risk of local recurrence. Using a similar molecular pathologic approach, Koch et al. have applied this strategy to the dilemma of unknown primary HNSCC. In this manner, it may be possible to identify primary sites without necessarily identifying invasive malignancies.134 Although this approach still requires validation, the potential of limiting radiation areas of treatment may significantly reduce the morbidity of radiotherapy in the management of this clinical process. Furthermore, this approach may also allow selection of patients who may be surgically managed in the neck and then clinically observed if neck disease is pathologically diagnosed and confined to a single nodal compartment without extracapsular disease. Although advances in molecular techniques are likely to augment enormously what is now considered standard histopathologic assessment, critical studies will be required to determine the meaning and impact of this new pathologic information and appropriate management steps that result. DIAGNOSIS The identification and appropriate management of premalignant mucosal lesions in the head and neck are important aspects of patient management that have a major impact on overall survival rates. Since stage (extent) of disease at the time of diagnosis is the most important prognostic factor in the treatment of HNSCC, the identification and early treatment of small cancers correlate with excellent survival statistics. Most early premalignant changes or in situ carcinomas of the oral mucosa occur as red (erythroplasia) or white (leukoplakia) patches that should be readily apparent on visual examination. In areas less easily visualized directly, such as the larynx and hypopharynx, early lesions cause such symptoms as chronic hoarseness, chronic sore throat, referred otalgia, or dysphagia. These symptoms demand visualization of the involved structures by direct or indirect laryngoscopy. Appropriate management of leukoplakia and erythroplasia lesions includes a high index of suspicion, particularly in high-risk individuals. Although both lesions are considered premalignant, erythroplasia lesions are of greater clinical concern since approximately half of these lesions contain carcinoma in situ (CIS) or invasive cancer. Additionally, often erythroplasia and leukoplakia may coexist.71,72 Erythroplasia mandates biopsy to rule out invasive cancer. The management of erythroplasia and leukoplakia depends on the location, extent, and histology. The diffuse field effect and multifocal nature of the epithelial carcinogenic process support the need for effective chemoprevention. White lesions can be confused with mucositis; lichen planus; local tissue irritation from mechanical, thermal, or chemical trauma; histoplasmosis; candidiasis; and other infectious processes. Lesions that persist despite the removal of local irritating factors or that are associated with ulceration, vertical growth, induration, a recent change in size, or pain should be biopsied. Topical supravital staining with toluidine blue of suspicious lesions can be helpful in identifying areas to biopsy and in screening high-risk populations. Dysphagia, odynophagia, otalgia (referred), hoarseness, mucosal irregularities and ulceration, pain, weight loss, and the presence of an unexplained neck mass are the common presenting complaints of HNSCC. The predominant symptoms vary with the site: chronic dysphagia or odynophagia (for 6 weeks or even less) demands thorough visualization of the oropharynx, hypopharynx, and esophagus; chronic hoarseness demands visualization of the larynx; chronic, unilateral serous otitis media in an adult is a result of cancer of the nasopharynx until proved otherwise; and unilateral nasal polyps, nasal obstruction, or epistaxis is a common presenting sign of nasal cavity or paranasal sinus neoplasm. A firm or hard unilateral neck mass represents cancer until proved otherwise. More than 80% of the time, such a mass represents neoplasm, and 80% of these neoplasms are due to metastatic spread from an UADT primary. In patients presenting with a suspicious neck mass, a complete head and neck examination usually reveals the primary malignant tumor. If it does not, a thorough search for occult primary cancers both above and below the clavicles is warranted. Technologic advances in fiberoptics and in flexible and rigid endoscopes now provide excellent upper airway visualization that previously required special skills in indirect mir-

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ror examination. Endoscopic evaluation should include the nasopharynx, oropharynx, hypopharynx, larynx, and esophagus. Endoscopic evaluation should be preceded by a barium swallow and chest radiograph. Most commonly, occult primaries responsible for neck metastases occur in the nasopharynx, tongue base, tonsil, or hypopharynx. In the absence of an identifiable mass, directed biopsies of these sites are indicated during endoscopic evaluation. Metastasis to a solitary left supraclavicular lymph node (Virchows node) is occasionally seen with intra-abdominal cancer. Generally, metastatic supraclavicular masses derive from breast, lung, or infradiaphragmatic neoplasms. Nevertheless, thyroid malignancies may also metastasize to this area. Threedimensional imaging with computed tomography (CT) and magnetic resonance imaging (MRI) is frequently used to supplement the clinical evaluation and staging of the primary tumor and regional lymph nodes. Only after a thorough search for a primary tumor has been completed should a neck mass undergo biopsy. We recommend fine-needle aspiration biopsy when this is feasible. If an excisional biopsy is required for the biopsy of a neck mass, the surgeon and patient should be prepared for definitive neck dissection if the mass should prove to be metastatic squamous carcinoma. The introduction of fine-needle aspiration of neck masses has gained wide acceptance in the early evaluation of such masses and frequently supplements the diagnostic workup.55 The potential ramifications of false-negative results are inherently obvious. Accuracy of the cytologic interpretation of the aspirate is directly dependent on the skill and experience of the pathologist. STAGING Staging criteria for cancers arising in the UADT, paranasal sinuses, and salivary glands have been developed by the American Joint Committee on Cancer (AJCC). The criteria undergo regular reevaluation and modification. The stage groupings used for head and neck cancer are based on T (primary tumor), N (regional node), and M (distant metastasis) designations. Because of variations in the growth, behavior, and prognosis of head and neck cancers according to site of origin and extent, differences exist in the staging criteria for each anatomic site and region in the head and neck. Staging criteria for the primary lesion are site specific. However, except for tumors arising in the nasopharynx, there is uniformity in the nodal staging criteria and stage grouping (Tables 86.1, 86.2). Specific details for the nasopharynx will be given in the site-specific section of this chapter. Careful documentation of tumor extent and accurate staging classification are also important for the comparison of the results of different treatment regimens. Accurate evaluation of the results of a given treatment or the efficacy of new treatment strategies requires comparisons with patient groups with tumors of similar extent and behavior. Restaging after treatment or for recurrent cancers must be clearly designated and separate from the primary staging of previously untreated cancers. Postsurgical or pathologic staging is gaining importance in the primary treatment of head and neck cancers because of the increasing use of postoperative radiation therapy and/or adjuvant chemotherapy for patients with specific tumor characteristics, such as histologically proved lymph node metastases, close surgical margins, or extracapsular spread into the soft tissues of the neck.135 TREATMENT GENERAL PRINCIPLES After a histologic diagnosis has been established and tumor extent determined, the selection of appropriate treatment for a specific cancer depends on a complex array of variables, including tumor site, respective morbidity of various treatments, patient performance and nutritional status, concomitant health problems, social and logistic factors, therapy anticipated for potential recurrences or second primaries, and patient preference. These variables are each considered with respect to the established effectiveness of various treatment regimens available (Table 86.3). Several generalizations are useful in therapeutic decision making, but variations on these themes are numerous. Surgical resection and radiation therapy are the mainstays of treatment for most head and neck cancers. For small primary cancers without regional metastases (stage I or II), wide surgical excision alone or curative radiation therapy alone is used. Functional and cosmetic results are usually better

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Table 86.1. Cancer Stage 0 Stage 1 Stage 2 Stage 3 Clinical Tumor Stage and Groupings for Head and Neck Tis T1 T2 T3 T1 T2 T3 T4 Any T Any T N0 N0 N0 N0 N1 N1 N1 Any N N2,3 Any N M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Stage 4

following radiotherapy. Local tumor control rates are generally better with primary surgical resection, but if local recurrences occur after primary radiation therapy, they can often be successfully treated with salvage surgery, resulting in similar overall survival rates. Surgical complication rates are generally increased following radiation. Salvage of surgical recurrences by radiation therapy is less effective than is surgical salvage of radiation failures. For more extensive primary tumors or regional metastases (stage III or IV), planned combinations of pre- or postoperative radiation and complete surgical excision are generally used.136 For selected patients with advanced cancers of specific sites, such as the larynx, treatment approaches with radiation alone, with surgery held in reserve for salvage of recurrences, have been used in attempts to preserve structure and function. Although these organ-preserving techniques have been successful in many patients, they were generally associated with lower overall survival rates.137142 The overall management goals in treating patients with head and neck cancer are to achieve the highest cure rates at the lowest cost in terms of functional and cosmetic morbidity. These goals include early diagnosis, effective rehabilitation, and appropriate palliation when cancers are incurable. The achievement of these goals requires the close interaction and cooperation of a multidisciplinary team of practitioners representing surgery, radiation, chemotherapy, prosthodontics, dentistry, social services, dietetics, physical medicine, pathology, nursing, and sometimes psychiatry. Effective rehabilitation is an important part of the overall treatment of head and neck cancers. Modern advances in surgical reconstruction, microvascular free-tissue transfer, and prosthodontics have significantly improved functional performance.143 Rehabilitation concerns must be addressed at initial treatment planning and carefully integrated with the various treatment modalities used. Pretreatment dental evalu-

ations and speech and swallowing assessments are routine. Needed dental care and/or extractions should be planned prior to chemotherapy or radiation to reduce dental-associated sepsis, mucositis, and osteoradionecrosis. The overall impact of treatment and rehabilitation decisions on a patients quality of life is an important issue that may require use of specialized social or psychiatric support systems for the patient and family. Finally, the prolonged nature of treatment for advanced disease, which may extend over many months, requires consideration of the social and financial effect of treatment decisions on the patient, the family, and the patients employer. Biopsies of primary tumors should not be excisional unless the biopsy procedure is sufficient for definitive treatment and the surgeon performing the excision is responsible for providing curative treatment. Oncologic principles of surgical resection must not be compromised by ill-conceived reconstructive efforts or attempts at modifying the necessary resection in order to minimize functional or cosmetic morbidity. Head and neck cancers are serious threats to life. Temporary preservation of function at the cost of high morbidity and death from recurrent cancer is a poor bargain. Positive surgical margins after tumor resection or gross residual cancer portends inevitable treatment failure. Molecular pathologic staging may identify other patients earlier, where additional therapy may be essential to achieve cure.133 Appropriate management must also include the use of precise modern techniques of conservative surgical resection (e.g., partial laryngectomy and functional neck dissection) that, in selected patients, have cure rates similar to those of more radical techniques.144 RADIOTHERAPY General. Radiation therapy is an effective modality in treating local/regional disease. For early (T1 and T2) lesions, it gives results comparable to those achieved by surgery. For certain tumor sites, such as the larynx, it is preferred over surgery in the treatment of early tumors because it maintains organ function. When lesions are intermediate in size, it is used adjuvantly (following surgical excision) to improve local/regional control. Vikram and colleagues found that the rates of local/regional tumor recurrence were markedly higher if there was a greater than 6-week delay between surgery and postoperative radiotherapy.146 For advanced, inoperable lesions and for lesions arising in certain sites, such as the nasopharynx, radiation therapy may be the only modality that offers a potential for cure. Its therapeutic effectiveness has now been enhanced by the concomitant use of chemotherapy. Ionizing radiation (high-energy photons, electrons, neutrons, charged particles) interacts with matter in subtle ways.146 Tumors can vary dramatically in their ability to repair the DNA damage inflicted by radiation. Hyperthermia and concomitant chemotherapy are methods of reducing this repair ability. HNSCCs are generally characterized as moderately radioresponsive, meaning that fairly large dosages of radiation are required to achieve high probabilities of tumor control. Fortunately, the required dosages are within the tolerance of the various critical structures of the head and neck.

Table 86.2. Clinical Tumor Staging Characteristics for Regional Lymph Nodes and Distant Metastases Regional Lymph Nodes (N) Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension N2a Metastasis in a single ipsilateral lymph node, more than 3 cm, bu not more than 6 cm in greatest dimension N2b Metastasis in multiple ipsilateral lymph nodes, none greater than 6 cm in greatest dimension N2c Metastasis in bilateral or contralateral lymph nodes, none greater than 6 cm in greatest dimension N3 Metastasis in a lymph node greater than 6 cm in greatest dimension Distant Metastases (M) Mx Presence of distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

Table 86.3.

Therapeutic Approaches in Head and Neck Cancer

Established Definitive surgery (S) Definitive radiation therapy (RT) Surgery and planned preoperative or postoperative RT Definitive radiation therapy (RT) with surgery reserved for salvage of recurrence Palliative RT Palliative chemotherapy Investigational Induction chemotherapy and S or RT Induction chemotherapy with curative RT (organ perservation) Concomitant chemoradiotherapy S or RT and adjuvant chemotherapy RT and adjunctive hyperthermia or radiosensitizers Altered fractionation RT Immunobiologic therapy Chemoprevention

The effectiveness of a given dose of radiation depends on the manner in which it is given.146 Over the past 25 years, standard treatment regimens have evolved to treat head and neck cancer. In the United States, the curative standard treatment regimen consists of giving 180 to 200 cGy once a day for 5 days a week to a total dose of 6,500 to 7,400 cGy, whereas in Canada and England, giving a higher daily dose of 220 to 250 cGy once a day for 5 days a week to a total dose of 5,000 to 5,500 cGy is more commonly used. These schemas have evolved empirically to allow regeneration of normal tissues during the course of radiotherapy. Radiation kills the stem cells in the basal layer, and several weeks later the cells in the more superficial layers are not adequately replaced when they are lost through normal physiologic processes. This denudes the epithelium, giving rise to a mucositis reaction that can greatly inhibit a patients ability to swallow solids and liquids. This does not occur immediately but is progressive after several weeks of radiotherapy. Patients must be monitored closely to ensure that this problem is minimized. If a patient becomes too debilitated, then consideration should be given to placement of a feeding tube to ensure adequate nutrition. A similar process occurs in the skin in the treatment portals, giving rise to a sunburn-like desquamation. Certain chemotherapeutic agents (5-fluorouracil, actinomycin D, doxorubicin, methotrexate, mitomycin C, platinum agents, and the taxanes) can potentiate these reactions. Such agents are being used more frequently as part of increasingly more aggressive treatment of head and neck tumors. Although mucositis can delay the delivery and increase the overall treatment time, the major limiting factors for final dose determination are the long-term effects of radiation on normal tissues. The late effects of head and neck irradiation can include thickening or fibrosis of the subcutaneous tissues or fibrosis in the temporomandibular joint (which can cause trismus). In contrast to acute reactions, the magnitude of the late effects is determined more by the total dose given than by the daily fraction size. Salivary gland function and taste perception are altered by radiation.147149 The loss of saliva is significant after about 1,000 cGy is given to the glands; this decreased salivary output may persist for years. Approximately 4,000 to 5,000 cGy cause permanent loss of salivary gland function. Taste loss is significant after 4,000 to 4,500 cGy to the oral cavity. The degree of recovery is dose and volume dependent but it appears that pilocarpine (Saligen) can be helpful in reducing side effects.150,151 The decrease in saliva and changes in its chemical composition cause alterations in the microorganisms inhabiting the mouth, which,

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in turn, can cause a marked increase in the number of caries. Aggressive dental prophylaxis can reduce this problem, and work-up by a dentist with expertise in these problems is mandatory before radiotherapy is initiated. The incidence of osteoradionecrosis can be considerably reduced if the necessary repairs and/or extractions are done pretreatment rather than waiting until problems occur in a heavily irradiated field.152154 A delay of 2 to 3 weeks is required between extractions and the initiation of radiotherapy to allow adequate healing. Technologic Advances. Advances in radiotherapy have been tied to advances in technology. Modern radiotherapy departments use linear accelerators rather than cobalt 60 units, producing sharper field edges and higher dose rates. Megavoltage electron beams are used to treat the posterior neck nodes to tumoricidal dosages without risk of spinal cord damage. Computer-controlled multi-leaf collimators facilitate custom blocking techniques and sequential changes in field geometry as a patient progresses through treatment. This reduces morbidity by lowering the dose to adjacent normal tissues. CT and MRI are used to locate tumors for radiation therapy treatment planning with many departments having dedicated CT simulators. Figure 86.3 shows a reconstructed CT scan with a large tumor of the maxillary, ethmoid, and frontal sinuses outlined on anterior and lateral projections. Information from such scans is inputted into treatment planning computers to design individualized optimal treatment plans. Figure 86.4 shows the isodose distribution from a treatment plan for the tumor shown in Figure 86.3. Two levels are shown. Note how the radiation dose distribution lies deeper in the region of the maxillary and ethmoid sinuses but is pulled anteriorly at a level through the frontal sinus, thus sparing the frontal lobe. Noncoplanar field configurations, often using vertex presentations, are now fairly standard techniques in many radiotherapy centers. Treatment field arrangements are verified immediately using a fluoroscopic simulator. With such techniques, there should be many fewer marginal misses than in the past. Curative Radiotherapy. HNSCCs respond to radiation injury through a loss of reproductive capability, resulting in a clonogenic cell death. This cell-killing ability is essentially an exponential function of the radiation dosage (within the context of a given radiation fractionation schema), and so the dosage required for a given level of tumor control is approximately proportional to the number of clonogenic cells in the tumor.146 Subclinical microscopic disease requires a

Figure 86.3. A large tumor of the maxillary, ethmoid, and frontal sinuses outlined on a CT scan reconstruction showing the patient in anterior and lateral views. This information is used to design radiation therapy treatment fields.

Figure 86.4. Radiation isodose distributions overlying transverse CT scan images at two different levels for the tumor shown in Figure 86.3. Note how the radiation isodoses extend posteriorly to cover the tumor in the maxillary and ethmoid sinus regions but are pulled anteriorly at the superior level, thus sparing the normal brain tissue at this level while adequately treating the frontal sinuses.

dosage of approximately 5,000 cGy, a 1-cm337 tumor requires approximately 6,500 cGy, and large (T3 or T4) tumors require dosages in the range of 7,000 to 7,500 cGy to maximize the chances of achieving tumor control.155,156 Patients with head and neck tumors are generally treated with shrinking-field techniques, wherein the various regions at risk receive dosages commensurate with the tumor mass they are thought to contain. A typical head and neck treatment regimen involves at least three separate alterations in radiation field geometry. Dosages greater than 7,500 cGy may be achieved using interstitial radioactive implants, which allow the delivery of ultra-high dosages to small volumes with the dose levels to critical normal tissues kept within safe limits. Table 86.4 shows representative local control rates and survival data for patients with SCCs of common head and neck sites treated with definitive radiotherapy.156 Although the local/regional control rates are excellent for the small lesions, there is obviously a need for improvement regarding definitive radiation therapy for larger lesions.157 The choice between radiotherapy and surgery as definitive primary treatment is dependent on the interplay among many factors.158 For early lesions of the larynx and the tip of the tongue, the two modalities yield equivalent local/regional control and survival. However, the functional result is better with radiotherapy, and so it is the treatment of choice. For early lesions of the lip or skin cancers of the nose or eyelid, the ultimate cosmetic result is better with radiotherapy. For sites, such as the nasopharynx, that are surgically unapproachable, radiotherapy is the only tenable form of definitive treatment. For early lesions of the tonsil and tongue (base and lateral aspect), the results are equivalent to those of surgery, and informed patient choice should guide the treatment decision. Radiotherapy is also given following diagnosis of SCC metastatic to the cervical lymph nodes from an unknown primary site. The treatment fields encompass the probable sites of tumor origin: nasopharynx, tonsillar fossa, base of tongue, and hypopharynx. The patient survival at 2 to 3 years ranges from 30 to 60%.159 Accelerated and Hyperfractionated Radiotherapy. An area of current clinical interest in radiotherapy is the use of nonstandard fractionation patterns in radiotherapy in an attempt to improve the therapeutic response ratio.160,161 Late radiation effects limit the total amount of radiation that can be safely given in the standard treatment schema. The slowly proliferating normal tissues are the dose-limiting structures for these late effects. Such tissues tend to have large shoulders on their cell survival curves, which indicates an increased ability to repair sublethal radiation damage as compared with that of rapidly proliferating

normal tissues.146 Hence, a logical approach would be to give smaller radiation treatment fractions so as not to exceed the shoulder on the late-effects tissue cell survival curves and then to go to a higher total dose. The assumption is implicit that the tumor will behave like the rapidly proliferating normal tissues in that it will not have a large shoulder on its radiation cell survival curve and so a therapeutic gain will result. To avoid inordinately prolonging the overall treatment time and allowing tumor repopulation kinetics to become the dominant effect, multiple daily fractions must be given.146,162 A sufficient time interval (generally more than 6 hours) must be allowed between treatments to allow for adequate repair of sublethal and potentially lethal damage. Hyperfractionation refers to giving multiple daily doses such that the overall treatment time is about the same as for a course of conventionally fractionated once-a-day radiotherapy.163 Early work using hyperfractionated radiotherapy for head and neck cancer took place at the University of Florida.164 Doses up to 8,011 cGy were given using 120 cGy twice daily with an apparent benefit compared to historic controls. The Radiation Therapy Oncology Group (RTOG) has subsequently conducted a dose-searching study with patients being randomized to receive total doses of 6,720, 7,200, 7,680, or 8,160 cGy using 120 cGy twice daily. A preliminary analysis for 479 patients entered onto the three lower dose arms shows a trend toward improved local/regional control with increasing dose (25% vs. 37% vs. 42%, p = .08) without there being any survival advantage.165 The incidence of grade 4 necrosis was 10.0% on the 6,720-cGy arm, 5.1% on the 7,200-cGy arm, and 13.9% on the 7,680-cGy arm. Data on the 8,160-cGy arm are not yet available. The European Organization for Research and Treatment of Cancer (EORTC) has investigated three daily fractions of 160 cGy each for 10 days, a 3-week break in treatment, followed by a boost to 6,720 cGy with or without misonidazole (a hypoxic cell radiosensitizer), compared with a third arm of standard fraction radiotherapy alone in a total of 523 patients. No significant differences in local or regional control or survival have been reported among the three arms.166 Early mucosal reactions were more severe on the hyperfractionation arms but late effects were equivalent. The EORTC subsequently conducted a phase III clinical trial for patients with oropharyngeal cancer.167 This study compared twice-daily treatments of 115 cGy to a total dose of 8,050 cGy versus a conventional fractionation schema of 200 cGy once a day to a total dose of 7,000 cGy. Eligible patients had stage T12, N01 tumors, with base-of-tongue primaries being excluded. A total of 356 patients were entered between 1980 to 1987. At the 5-year end point, local control was 59% on the hyperfractiona-

Table 86.4. Representative Local Control Rates and Survival for Patients with Squamous Cell Carcinoma of Common Head and Neck Sites Treated with Definitive Radiotherapy
Stage by site Local control (%) Survival* (%)

CHAPTER 86 / Head and Neck Cancer 1183

Oral cavity Oral tongue T1 T2 T3 T4 Floor of mouth T1 T2 T3 T4 Oropharynx Base of tongue T1 T2 T3 T4 Tonsil/tonsillar fossa T1 T2 T3 T4 Soft palate T1 T2 T3 T4 Nasopharynx T1 T2 T3 T4 Hypopharynx Pyriform sinus T1 T2 T3 T4 Larynx Supraglottic T1 T2 T3 T4 Glottis T1 T2 T3 T4

8090 6085 3050 2445 7585 6080 3050 530

7580 4060 2030 1015 7085 5060 1540 520

8095 6075 4065 3050 7595 6080 3570 2030 90100 7585 6070 2535 7085 5060 2045 1535

6585 4055 1520 520 6585 5560 2040 1015 9095 6575 3040 1015 6075 5065 2550 530

6070 4050 3040 1025

3050 2045 1525 520

8090 6080 3570 3060 8595 6575 2035 1530

6590 5065 3555 1540 8095 6085 3560 1030

Local control is for radiation alone. Survival data include surgical salvage for radiation failures. Overlap in the two sets of figures is due to data coming from different patient series, which are a heterogeneous mix of nodal stages, Kmofsky scores, tumor differentiation. *Adapted from Laramore.157

tion arm as compared with 40% on the conventional fractionation arm (p = .02). Subset analysis showed that the improved benefit was confined to patients with T3 tumors, since equivalent results were noted for patients with the smaller T2 lesions. The overall survival difference at 5 years (40 vs. 31%; p = .08) did not achieve statistical significance. Late normal-tissue toxicity was equivalent on the two treatment arms. Accelerated fractionation refers to giving multiple daily doses of such a size that the overall treatment time is shortened relative to that of conventional radiotherapy. The fraction size and the total dose given are generally slightly less than that of conventional radiotherapy. Wang and colleagues have developed a twice-daily schema using 160-cGy

fractions.169,170 The total daily dose is thus 320 cGy, which is too high for the rapidly proliferating normal tissues (e.g., mucosa) to tolerate without a planned interruption in treatment to allow for recovery and repopulation. No randomized trial has been carried out to evaluate it, but historic comparison suggests a possible benefit to its use. Other accelerated fractionation schemes have been used in various pilot studies, but no randomized trials have taken place.170173 Another version of accelerated fractionation that attempts to limit the normaltissue acute reaction is the concomitant boost regimen proposed by Ang et al.175 In this approach, the accelerated portion of the radiation therapy is delivered only during the last phase of treatment when the proliferation rates of both tumor and normal tissues have been accelerated. The volume of tissue that receives the twice-daily treatment is limited to the primary target volume; there are no planned breaks in treatment. A recent meta-analysis evaluating the clinical use of hyperfractionated radiotherapy shows improved local control for head and neck tumor sites,175 but only the EORTC study167 described earlier had a tightly defined set of patient entry criteria. The RTOG has just completed a randomized trial for patients with inoperable tumors comparing three different treatment regimens: conventionally fractionated radiotherapy to 7,000 cGy, twice-daily hyperfractionation at 120 cGy per fraction to 7,960 cGy, and the concomitant boost protocol of Ang et al.175 and Mak et al.176 Preliminary reports indicate that there is better local/regional control using the concomitant boost approach but that there is no early survival advantage. COMBINED SURGERY AND RADIOTHERAPY Very few well-designed randomized trials have compared surgery alone with combined therapy in any disease site. When treatment is surgery or radiotherapy alone, local/regional control rates for stages I and II lesions are in the range of 75 to 90% (depending on disease site). The local/regional control rates with single-modality therapy are much less satisfactory in stages III and IV lesions, for which standard medical practice employs both modalities. Radiotherapy can be given either preoperatively or postoperatively. The aims of preoperative radiotherapy are to sterilize microscopic disease outside the resection field and to shrink the tumor bulk, thus making the surgery easier to perform. Theoretically, preoperative radiotherapy should also reduce the risk of disseminating viable tumor cells at surgery. A dosage of 5,000 cGy over 5 to 5.5 weeks is usually given.176 No significant problems with delayed wound healing occur at this dosage. When radiotherapy is postoperative, the surgical resection bed has a disrupted blood supply. Conventional wisdom says that higher dosages of radiation are needed because of the increased likelihood of hypoxic tumor cells, which are less radiosensitive. Generally, one delivers 5,500 to 6,000 cGy in 180- to 200-cGy fractions in a postoperative setting. Higher dosages are used if the surgical margins are compromised or if there is a high likelihood of the presence of macroscopic residual disease. In particular, Peters et al. have found that at least 6,300 cGy should be given if extracapsular nodal extension is found in the operative specimen.178 Postoperative radiotherapy has the advantage of being given to only those patients thought to be at a significant risk for local/regional tumor recurrence based on a thorough review of the pathologic data. It has the further advantage of not delaying the surgical procedure, which for patients with operable disease is the most important treatment modality. Preoperative radiotherapy and postoperative radiotherapy were compared in a randomized clinical trial by the RTOG. A total of 277 patients with tumors of the oral cavity, oropharynx, supraglottic larynx, or hypopharynx were entered into the study.140 Patients in the preoperative arm received 5,000 cGy followed by surgery in 4 to 6 weeks, whereas patients in the postoperative arm received 6,000 cGy starting 2 to 4 weeks after the surgical resection. A higher percentage of patients in the postoperative arm completed the combined course of therapy within protocol guidelines (74 vs. 56%). The 4-year competing-risk local/regional tumor control was 65% in the postoperative arm versus 48% in the preoperative arm (p = .04). For the subgroup of 194 patients who completed overall treatment within protocol guide-

1184 SECTION 27 / Neoplasms of the Head and Neck

lines, the local/regional control rates were 74% in the postoperative arm and 56% in the preoperative arm. There were no significant differences between the two study arms in complication or survival rates. Although it is generally felt that there is little role for debulking surgery in the treatment of head and neck cancers, there may be situations where a gross total resection followed by high-dose radiotherapy is preferable to treatment with radiation alone. A recent analysis by the Head and Neck Intergroup Study IG 0034 showed that the patients who were excluded because of positive surgical margins exhibited improved local/regional control of tumor as compared with a matched set of patients from the RTOG databases treated with radiotherapy alone.140,178 At 4 years, respective local/regional controls were 44 versus 24% (p = .007). However, there was no difference in survival. This was not a randomized trial, and no analysis was made of quality of life with either treatment. The authors argue for testing the concept in a controlled clinical trial rather than changing traditional resectability criteria. ChemotherapyGeneral. Chemotherapeutic strategies for HNSCC are reviewed in detail under Chemotherapy Approaches below. Systemic approaches to salivary gland tumors, NPC, advanced skin cancer, esthesioneuroblastoma, and other nonsquamous cancers are distinct from head and neck cancers at other sites and, therefore, are discussed separately. NATURAL HISTORY AND TREATMENT BY SITE Oral Cavity. Both tumor growth and treatment significantly compromise speech and deglutition, particularly for those patients in whom cancer involves the tongue, the floor of the mouth, or the mandible. Furthermore, the diversity of potential sites of cancer development in the oral cavity and variations of lymphatic drainage and rates of node metastases lend added complexity to treatment planning.179181 Despite the fact that this region is readily amenable to visual examination and bimanual palpation, more than 50% of patients are diagnosed in advanced stages. The current T staging of oral cavity primaries is presented in Table 86.5. SCCs of the lip are the most common oral cavity cancer. Over 90% occur on the lower lip, usually on the exposed vermilion border, midway between the midline and the oral commissure. Upper lip cancers most commonly are basal cell carcinomas.182 Well-differentiated and verrucous cancers rarely metastasize. Poorly differentiated and spindle cell varieties tend to grow aggressively and metastasize commonly. Perineural infiltration of large nerves is indicative of aggressive disease. Lip. The treatment of lip cancers must consider adequate removal of tissue to encompass the disease and yet provide the patient with a lip that functions in speech, chewing, and oral competence and affords adequate cosmesis.183,184 These goals are achieved equally well with either primary radiation or surgery when the tumors are less than 2 cm in size or are very superficial. Larger lesions are best treated with surgical resection and reconstruction, where there is greater accuracy in evaluating the extent of tumor and nerve or cervical lymphatic involvement.185,186 Frequently, adjacent precancerous changes are present that can be treated with surgery (lip shaving and advancement) to prevent recurrences or the development of second primary tumors.187 For large lesions, primary reconstruction with local and regional flaps avoids defects that result from tissue loss with radiotherapy, provides for future reconstructive and treatment options, and eliminates the risk of osteoradionecrosis of the mandible. Lesions
Table 86.5. Primary Tumor Staging Characteristics for Oral Cavity Carcinoma Tx T0 Tis T1 T2 T3 T4 T4 Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor 2 cm or less in greatest dimension Tumor more than 2 cm but less than 4 cm in greatest dimension Tumor more than 4 cm in greatest dimension (lip) Tumor invades adjacent structures, e.g., through cortical bone, tongue, skin of neck (oral cavity) Tumor invades adjacent structures, e.g., cortical bone, deep tissues (extrinsic muscle of tongue, maxillary sinus, skin)

demonstrating extensive infiltration, bone involvement, or lymphatic metastases are increasingly managed with combined surgery and postoperative radiation. Radiation therapy techniques for management of lip cancers include external irradiation, interstitial implants, and combinations of both. Either the more traditional low dose rate or the newer, high dose rate techniques can be used. Local tumor control rates with irradiation exceed 80%,188190 with determinant survival at 5 years, including surgical salvage, in excess of 95%. Similar tumor control and survival rates are reported with primary surgical excision.191 Confirmed regional metastases decrease the survival rates to 36 to 55%.188,192 Five-year survival rates for patients with carcinomas of the upper lip are lower than for lower lip lesions and range from 40 to 60%.193,194 Involvement of both lips or the lateral commissure is uncommon. The prognosis for commissure lesions is not as good as for cancers of other areas of the lip. Cross reported a 5-year survival rate of 34% for patients with oral commissure carcinoma (Table 86.6).193 Tongue. Tongue cancers account for 25% of oral cavity SCC and most commonly arise in the oral portion or anterior two-thirds of the tongue on the lateral edge or ventral surface. Infiltration of the underlying tongue musculature occurs early. The intrinsic tongue muscles are loosely arranged, interdigitating, and endowed with a rich vascular and lymphatic supply, which may explain the early high rate of regional metastases. Most patients present with T2 or greater lesions. Prognosis is directly related to the degree of infiltration and the presence of regional metastases. The biologic aggressiveness of small (less than 4 cm) tongue cancers is noteworthy and is reflected in higher rates of occult regional metastases than similarly staged lesions arising from other oral sites (Table 86.7). Occult node metastases are present in 30 to 40% of early lesions.195198 Approximately 40% of patients have clinical evidence of node metastases at diagnosis.199 Primary echelon node drainage is to the upper deep cervical lymphatics. Involvement of middle and lower neck nodes (levels III and IV) is not uncommon. Bilateral nodal involvement may be present with cancers of the tip of the tongue or those involving the midline of the tongue. Local/regional recurrence in patients with tongue cancer accounts for 60 to 70% of cancer deaths.200202 Distant metastases account for 15% of deaths and second primaries for 20 to 40%. The management of carcinomas of the tongue has been significantly influenced by a better appreciation of the aggressiveness of small, deeply infiltrative lesions; the high rate of occult lymph node metastases; and an interest in improving treatment without compromising oral function. Although surgical excision has been the mainstay of treatment, combined surgery and adjuvant radiation therapy to include the primary site and regional nodes is commonly used for most advanced (stages III and IV) cancers and is being used increasingly for small stage II cancers that exhibit pathologic indicators of lymph node metastasis or perineural invasion. For stage I cancers, surgical excision is effective and expeditious with good preservation of function. For stage II lesions that are infiltrative, hemiglossectomy achieves excellent tumor control rates and can be combined with modified dissection of neck nodes (supraomohyoid dissections) to provide accurate staging information and determination of the need for adjuvant radiation. Hemiglossectomy may result in some functional morbidity in terms of articulation and deglutition. Because of this, radiation therapy may be used in selected cases. Nevertheless, surgery should remain the mainstay of treatment in oral

Table 86.6. 5-Year Survival Rates for Patients with Carcinoma of the Lip
5-Year survival (%) Investigator Number of patients Determinant Absolute

Schreiner195 Molnar194 Cross193 Jorgensen189 MacKay190

636 2,066 563 869 3,166

74 86 58 97 89

59 76 50 84 65

Table 86.7. by Level*

Level (*positive/ total)

Occult Lymph Node Metastases for Oral Cavity Carcinoma

Floor of mouth (15/57) % Retromolar trigone (7/16) %

CHAPTER 86 / Head and Neck Cancer 1185

Tongue (18/58) %

Gingiva (20/52) %

Buccal (5/9) %

I II III IV V

14 19 16 3 0

16 12 7 2 0

27 21 6 4 2

19 12 6 6 0

44 11 0 0 0

tongue malignancies. For radiation to be as effective as surgery in controlling these cancers, interstitial brachytherapy combined with external radiation is essential. Radiation doses of 80 to 85 Gy are generally given via external megavoltage radiation or in combination with brachytherapy. Interstitial treatment requires precise placement and spacing of implants. Accurate dosimetry is enhanced by using afterloading techniques in which the radioactive source is inserted into previously placed hollow tubes. Tracheostomy at the time of implant should be considered because of the potential development of tongue edema after implantation. Occult or apparent neck disease is usually treated using external radiation or radiation combined with neck dissection.195 The long-term ramifications of radiation therapy for oral cavity malignancies must also be considered, including radiation fibrosis with impaired function of the oral structures (including the tongue), dry mouth, and osteoradionecrosis. Extension of cancer to the floor of the mouth or the mandible may necessitate partial mandibulectomy or segmental mandibular resection. Modern reconstructive techniques with vascularized composite bone and soft-tissue free flaps, titanium metal prostheses, pedicled myocutaneous regional flaps, and free bone grafts have improved the functional and cosmetic results of major mandibular resections. If the neck must be surgically entered to accomplish adequate resection of the primary tumor, a neck dissection should be simultaneously performed. When tumors grossly involve bone, radiation therapy is less effective in these poorly vascularized osseous tissues and requires high doses that are associated with osteoradionecrosis. After local failure of interstitial implants, complication rates for salvage surgical resections are extremely high and are associated with significant morbidity from fistulization, radionecrosis, and failure of primary reconstructive efforts. In many cases, control fistulas and delayed reconstruction with well-vascularized flaps are advantageous. Although the surgical salvage of radiation failures is often successful in early lesions, success drops to less than 50% in advanced lesions. For more advanced primary lesions (stages III and IV), surgery and external radiation are generally used. Radiation has been administered as either planned preoperative or postoperative therapy, although currently we advocate postoperative treatment in most instances. Although no prospective controlled trials have proved the superiority of combined therapy over surgery alone, many studies indicate improved local/regional control rates.6,185,203205 These improvements have generally been offset, in part, by an increased frequency of distant metastases and second primaries. Surgical management generally consists of partial glossectomy and neck dissection, with the mandibular apparatus spared unless directly involved. In instances with limited periosteal invasion, coronal and other partial mandibular resections can be performed that spare mandibular continuity and maximize function. Where tumors extend to the midline or involve the tongue base, subtotal or total glossectomy may be necessary. Modern reconstructive techniques have improved the functional results of these aggressive resections. Provision for temporary tracheostomy and prolonged enteral nutrition should be made. Total glossectomy or sacrifice of both hypoglossal nerves frequently necessitates permanent feeding gastrostomy or jejunostomy. Current experience indicates that total glossectomy can often be accomplished without the need for laryngectomy.206 Tumor resection is more difficult after preoperative radiation therapy unless precise tattooing of intended resection margins is accomplished prior to therapy. Likewise, the rates of surgical complications, fistuliza-

tion, exposed bone, and radionecrosis may be increased with preoperative radiation, although studies have been conflicting. Because of this, most centers have adopted a policy of postoperative radiation. With postoperative radiation, higher doses can be delivered, the extent of disease is precisely defined, the histologic status of the lymph nodes is known, and high-risk areas of close margins or residual cancer can be treated to a high dose. Both ipsilateral and contralateral necks are irradiated, with the dosage determined by the extent of disease. Postoperative radiation should begin within 3 to 6 weeks of resection. Interstitial implants are not used. Close surgical margins require high doses (70 Gy) because of the difficulty in eradicating even small amounts of tumor in the tongue after glossectomy.207 Curative radiation alone with surgical salvage has been shown to be inferior to combined therapy in control of local/regional disease and in the complication rate, even though survival rates are similar with these approaches.140,208 Even with combined therapy, estimated 2year disease-free and overall survival rates for advanced disease are only 51 and 53%, respectively.209 The 5-year survival rates range from 50 to 70% for stages I and II to 15 to 30% for stages III and IV (Table 86.8).200 The management of the neck is of particular interest in patients with tongue cancer because of the high rate of occult node metastases. For lesions T2 or greater in size, rates of occult metastases exceed 40% and some form of neck treatment is generally indicated. When the primary tumor can be adequately excised via a transoral technique, unilateral or bilateral neck dissections should be performed based on the location of the primary disease. Radiotherapy should be used postoperatively if pathologic indicators are recognized. When radiation alone is selected for the treatment of primary tumors with neck node metastases, this treatment is often combined with therapeutic neck dissection.195 Floor of Mouth. Floor-of-mouth cancers occur with a frequency similar to that for tongue cancer. Early spread to adjacent areas (gingiva and periosteum of the mandible) is common. The periosteum is a natural barrier to spread. Fixation of the tongue is a sign of deep invasion. The tumor may extend to or through the myohyoid muscle, which serves as a natural barrier to direct spread below the hyoid bone. Lymph node metastases at presentation are seen in approximately 40% of patients and an additional 20% have occult lymphatic metastases.196 The occult metastatic rate increases with the T stage of the primary: T2 tumors have a 40% and T3 tumors a 70% occult metastasis rate. First-echelon nodes of lymphatic drainage include the submandibular and jugulodigastric lymph nodes (levels I and II). Submental node involvement is unusual. Evaluation for early mandibular involvement is facilitated by palpation since fixation to the mandible indicates periosteal involvement and direct bone invasion is present in 50 to 60% of such tumors. Small cancers (T1, T2) are generally treated effectively by wide resection or radiation therapy. Little morbidity results from surgical resection of superficial lesions. Lateral floor-of-mouth tumors can often be resected transorally and the resection defect closed with the advancement of adjacent mucosa, skin grafts, or secondary intention. Early cancers involving the mandible are best treated surgically because bone involvement compromises radiation efficacy. Surgery remains the mainstay of treatment for early floor-of-mouth malignancies, achieving excellent functional and curative results.

Table 86.8. Overall 5-Year Survival Rates (%) for Patients with Squamous Carcinoma of the Tongue
Stage Investigator N I II III IV

Callery201 Decroix196 Wallner203 OBrien581 Average

*Disease-free survival.

252 602 424 97 (1,375)

75 59 68 73* 69

60 45 50 62* 54

40 25 33 33

20 13 20 18

1186 SECTION 27 / Neoplasms of the Head and Neck

Radiation therapy for small floor-of-mouth cancers usually involves combinations of external radiation and brachytherapy. Decision making concerning primary therapy takes into consideration the expected functional result, management of the neck nodes, and risk of osteoradionecrosis. Radiotherapy for moderate-size (T2) anterior floor-of-mouth lesions and small or deeply invasive cancers must also include treating bilateral first-echelon lymph nodes. Rates of occult nodal metastases range from 30 to 40%. More advanced floor-of-mouth cancers (T3, T4) are generally treated with resection combined with postoperative radiation of the primary and regional nodes. These resections require a transcervical approach and are combined with neck dissection and mandibular resections as needed. Again, mandibular continuity-sparing procedures with cortectomies can often be employed. In these instances, we have found that the radial free forearm (fasciocutaneous) flap offers excellent floor-of-mouth and tongue reconstructive potential. Large surgical defects are reconstructed with skin grafts, local flaps, myocutaneous pedicled regional flaps, and frequently free-tissue transfers. Mandibular reconstruction for segmental defects is performed primarily with composite free-tissue transfers. Doses of radiation therapy for local/regional tumor control are based on actual tumor volume rather than T stage.210 Interstitial doses of 65 to 75 Gy are recommended for early lesions (1 to 3 cm) if brachytherapy alone is used or external-beam radiation of 50 Gy combined with 25 to 30 Gy of interstitial radiation. Postoperative doses are given by external radiation only at doses of 65 Gy over 6 to 7 weeks or preoperative doses of 50 Gy over 6 weeks. No significant differences in overall survival rates have been shown when comparing preoperative and postoperative radiation regimens.140 Treatment results are influenced by the size of the primary tumor, presence of lymph node metastases, degree of mandibular involvement, and adequacy of resection. The 5-year survival rates for localized stages I and II carcinomas of the floor of the mouth range from 60 to 80% (Table 86.9). Cancers that cross the midline or involve the tongue or the mandible are associated with 5-year survival rates of 50 to 60%.141 Survival rates for more advanced lesions (stages III and IV) are less than 50%. Lymph node metastases decrease survival rates to approximately 25%. The major advantage of combined treatment (radiation and surgery) in these patients is improved control of ipsilateral and contralateral neck disease. Because rates of occult nodal disease are high in advanced primary lesions, elective treatment of the neck with radiation or bilateral neck dissections is indicated. Recurrence in the untreated, clinically negative neck is the most frequent site of failure in patients treated only with surgery.211 The debate over performing elective neck dissection versus irradiation remains unresolved. If adequate primary tumor margins are uncertain or if multiple histologically positive lymph node metastases are detected, postoperative radiation to the ipsilateral and contralateral neck is administered. The development of second primary cancers is a major cause of morbidity and death. Fu and colleagues reported that 55 of 153 (36%) patients developed second primaries, of whom 30 died of their second cancer.213 Distant metastases occur in 10 to 15% of patients.212,213 Gingiva and Buccal Mucosa. Gingival cancers occur most commonly (80%) in the lower gingiva posterior to the bicuspid teeth.213 For both sites, trismus is an ominous sign. Clinical staging

Table 86.9. Overall 5-Year Survival Rates (%) in Patients with Squamous Carcinoma of the Floor of Mouth
Stage Investigator N I II III IV

Panje142 Shaha212 Fu213 Average

103 320 153 576

57 88 83 76

60 80 71 70

43 66 43 51

19 32 10 20

criteria are similar to those for other oral sites. Overall, regional metastases occur in approximately 15% of gingival cancers and are rarely associated with buccal cancers.214 Occult metastases occur in 10 to 20% of patients. Exophytic tumors tend to be papillary or verrucous in appearance and can be confused with benign hyperkeratosis. Small, superficial gingival cancers can be effectively treated with surgical resection or radiation therapy with excellent preservation of function.215 Generally, the amount of bone resected for small lesions is minimal and resection can be accomplished transorally. Even larger lesions requiring partial maxillectomy or alveolectomy can be resected without external incision. External-beam irradiation is not as effective in local tumor control once gross bone involvement has occurred. The intermediate (T2 or larger) lesions are best handled surgically; the risk of osteoradionecrosis is thereby avoided. For large lesions (T3 and T4), segmental mandibulectomy or maxillectomy is required and adjuvant radiation is frequently recommended. Elective neck dissection is not indicated unless the en bloc resection of a large primary tumor requires neck exposure. For patients in whom no neck dissection is performed, elective neck irradiation should be considered. Clinically positive neck nodes warrant neck dissection combined with resection of the primary tumor. Buccal carcinomas of early stage (I or II) can be treated equally well with surgery or radiation. Radiation therapy offers the advantage of including the draining lymphatics in the treatment fields but also risks post-treatment fibrosis and trismus. Large primary tumors or tumors with regional metastases are managed surgically, with the need for adjuvant radiation determined by the adequacy of resection and risk of suspected residual disease. Neck dissection is recommended only in cases of clinically positive lymph nodes with buccal cancers, unless neck access is required for surgical excision of the primary. Overall survival rates for gingival and buccal cancers depend on tumor size, bone involvement, and node metastases. The 5-year survival rates for lower gingival lesions do not differ from those for the upper gingiva and range from 78% for stage I to 15% for stage IV disease.216 Surgical results are clearly superior to those of radiation when bone involvement is present. Survival rates (5 year) for stages I and II buccal carcinomas range from 65 to 75%. Determinant survival for stages III and IV disease varies from 20 to 30%.214 For both gingival and buccal mucosal cancers, overall survival rates have improved over recent years as surgical management has replaced radiation therapy as the primary treatment. Retromolar Trigone. Cancers arising in the retromolar trigone (the narrow band of mucosa that lies behind the mandibular molar teeth and covers the ascending ramus) are rarely confined to that gingiva but involve adjacent buccal mucosa, anterior tonsillar pillar, the floor of the mouth, or posterior gingiva. Thus, retromolar trigone cancers that involve the anterior tonsillar pillar behave more like oropharyngeal cancers than like oral cavity primaries. The risk of clinically positive and occult lymph node metastases is higher than with other gingival cancers. The frequent involvement of periosteum mandates partial (rim or marginal) mandibulectomy as part of the surgical management, even for small lesions. Primary radiation therapy is reserved for superficial lesions that cover a large surface area, such as extension to the soft palate or buccal mucosa, and remain mobile. Moderately advanced or deeply invasive lesions are best treated with surgical resection (mandibulectomy and neck dissection), followed by radiation therapy if pathologically indicated, unless the functional or cosmetic result would be unacceptable to the patient. Oropharynx. The clinical staging of oropharyngeal cancers depends primarily on tumor size and is similar to the staging of oral cavity cancers (Table 86.10). Although tumors may arise from any site in the oropharynx, most commonly they arise from the tonsillar area and palatine arch. The most common presenting symptom is chronic sore throat (often unilateral) and referred otalgia. Change in voice, dysphagia, and trismus are late signs. Regional lymphatic metastases occur frequently and are related to the depth of tumor invasion and tumor size. Upper cervical nodes are generally first involved, but lower nodes can become clinically involved with skipping of the upper first-echelon nodes. Bilateral lymphatic metastases can occur, particularly with cancers of the soft palate, tongue base, and midline pharyngeal wall.

Tonsil. These cancers tend to be superficial, better differentiated, and of an earlier stage than other oropharyngeal tumors. The treatment of early tonsillar neoplasms (stages I and II) is usually radiation therapy alone. Transoral wide local excision of small, superficial lesions may be effective but does not address the potential of subclinical lymph node metastasis. Deeply invasive cancers require extensive resections of the pharyngeal wall or mandible.217,218 Radiation for early cancers offers the advantage of treating upperechelon lymph nodes. Treatment is usually unilateral unless extension to the tongue base or midline soft palate is present that warrants treatment of contralateral lymphatics. Ipsilateral treatment portals allow sparing of the contralateral mucosa and salivary glands. Because much of the tumor may be hidden from external-beam photons by the mandible, deeper dose calculation with electron beam therapy is used, which can be combined with a small interstitial implant if invasion of adjacent tongue is present. Early cancers of the tonsillar pillar are less effectively treated with radiation alone than are cancers confined to the tonsillar fossa.219 Radical radiotherapy to lymph nodes controls approximately 90% of limited nodal disease (N1) if the primary tumor is controlled, but nodal failure increases to more than 20% if failure occurs at the primary tumor site. Overall 5-year survival rates for patients with advanced primary tumors or regional metastases are generally less than 25% with single-modality therapy.219222 Combinations of surgery and radiation therapy offer improved rates of local and regional tumor control, which, in some studies, has translated into improved survival.137,219,223 Similar tumor control and survival rates have been reported for stage III (T3N0) patients without nodal metastases who are treated with radiation alone or combined surgery and radiation or surgery alone (Table 86.11).224,225 In general, preoperative or postoperative radiation for advanced (stage III or IV) cancers of the tonsillar fossa is recommended, combined with resection to include the tonsillar fossa and regional nodes. In some instances, advances in surgical approaches may allow for sparing of the mandible, but composite resection of the pharynx, mandible, and neck remains a frequent surgical approach. Postoperative rather than preoperative radiation is currently preferred because it allows more accurate assessment of surgical margins, local extent of disease, and degree of lymphatic involvement and is associated with lower rates of surgical complications. Tongue Base. Base-of-the-tongue cancer poses a more difficult therapeutic problem than do tonsillar carcinomas. The 5-year survival rates are lower, metastases are more common, early diagnosis is less common, and treatment morbidity is greater. Because of the functional difficulties from wide local excision, even of small tongue-base cancers, most early (T1, T2) tumors are treated with definitive radiation. Three-quarters of patients are first seen with stage III or IV disease, primarily because of the early development of regional metastases, even with T1 or T2 tumors. Understaging of the primary tumor is frequent because these cancers tend to be diffusely infiltrative beyond their clinical appearance. This may account for similarities in local tumor control rates for both early and advanced lesions. The poor outcome is largely attributable to late diagnosis.226 The staging of tongue-base carcinomas is principally dependent on primary tumor size and the extent of regional metastases. Lymph node involvement is present in approximately 60% of patients with small (T1, T2) primaries227 and is the major determinant of prognosis. Overall 5-year survival rates range from 11 to 45%.228,229 The 5-year

CHAPTER 86 / Head and Neck Cancer 1187

Table 86.11. 3-Year Survival Rates (%) in Patients with Squamous Carcinoma of the Tonsil
Stage Investigator N N I II III IV

Perez226 Dasmahapatra138 Amornarn225 Mizono220

218 174 185 171

76 83 100 92

40 72 73 77

42 23 52 56

25 15 21 29

3 yr 5 yr 5 yr 5-year determinant

Table 86.10. Primary Tumor Staging Characteristics for Cancer of the Oropharynx Tx T0 Tis T1 T2 T3 T4 Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor < 2 cm in greatest dimension Tumor > 2 cm but not more than 4 cm in greatest dimension Tumor > 4 cm in greatest dimension Tumor invades adjacent structures, e.g., through cortical bone, soft tissue of neck, deep muscle of tongue

survival rates decrease from over 60% for N0 patients to less than 30% for N1 patients.37,228,230 The results of radiation therapy alone as definitive treatment for small primary tumors (T1, T2) are better for exophytic than for deeply invasive tumors.227 Radiation alone is generally reserved for those patients without clinical node metastases but can be combined with salvage neck dissection for patients with clinically positive nodes that persist after the completion of radiation. Local recurrence is more frequent after radiation alone in most series,227,228,231 and salvage of local failure with subsequent surgery is poor. In selected patients, interstitial radiation therapy has been used to treat residual palpable disease after external-beam radiation in anticipation of better local control. The use of brachytherapy is associated with high rates of softtissue necrosis and osteoradionecrosis, however.232,233 The results of supplemental interstitial therapy appear to be highly dependent on the dose and technique, with the best results reported with extensive percutaneous lateral cervical loop implants to include treatment of the lateral oropharyngeal wall and pharyngoepiglottic fold.234 The acute morbidity with implantation techniques is severe and results in massive tongue edema that necessitates tracheostomy in all patients. The use of either twice-daily, hyperfractionated radiotherapy or concomitant chemotherapy and radiotherapy appears to result in improved tumor control without many of the complications associated with implants for the larger tumors.235,236 Surgical management of small primary tongue-base tumors (T1) achieves results similar to those from radiation alone. In most cases, primary tumors are moderately advanced and require transcervical resection via mandibulotomy or lateral pharyngotomy approaches, combined with elective or therapeutic neck dissection. Local tumor control rates are superior to those with radiation alone,227,228 but regional control is poor if clinically positive nodes are present. Elective neck dissection can serve an important role as a staging procedure, thereby providing a rationale for adjuvant radiation therapy. To date, no prospective randomized trial data are available that compare surgery alone with combined surgery with either pre- or postoperative radiation. Survival rates do not differ substantially by stage of disease for patients with tongue-base cancers, except for those with stage IV disease (Table 86.12). Soft Palate and Pharyngeal Wall. These cancers are less common than other oropharyngeal neoplasms. Most soft palate cancers occur on the anterior surface of the palate and tend to be superficial. Regional metastases are uncommon, although lateral extension to the tonsillar area results in an increased rate of lymph node involvement and lesions close to the midline result in bilateral or contralateral neck metastases in 15% of patients. Occult node metastases are estimated to occur in 16% of patients.237 Posterior wall lesions tend to be superficial with less tumor bulk than similarly staged lesions elsewhere in the oropharynx. Tumor extension to the tongue base decreases survival and increases the rate of metastases, which are often bilateral. Advanced lesions with deep invasion have ready access to the prevertebral space, infratemporal fossa, and skull base and can be associated with extensive submucosal spread with clinical skip areas. Radiation alone as curative treatment is preferred in most cases, even for T3 or T4 primary tumors.238 Resection of all but the smallest soft palate lesions is associated with significant functional disability. The rates of occult regional metastases are difficult to determine

Table 86.12.

Overall Survival Rates (%) in Patients with Squamous Carcinoma of the Tongue Base According to T Class and Tumor Stage
T class Stage T3 T4 I II III IV Rate

Investigator

T1

T2

Weber228 Barrs229

173 119

100 63

58 56

38 31

20

100 68

72 55

50 55

30 11

5 yr 3 yr

because elective irradiation of bilateral nodal groups is included as part of primary treatment and must include the retropharyngeal lymphatics. Clinically positive lymph nodes at presentation occur in 30% of patients. Small primary tumors with positive nodes can be effectively treated with definitive radiation to the primary tumor and neck. Neck dissections should be initiated if disease in the neck persists for 6 weeks following the completion of external-beam therapy. Extensive pharyngeal wall cancers or palate cancers with extension to the tonsil and those cases with advanced regional metastases are usually treated with combined surgical resection and postoperative radiation. Overall 5-year survival rates for soft palate and facial pillar cancers are 60 to 70% and range from 80 to 90% for T1 or T2 lesions to 30 to 60% for stages III and IV lesions.227 Local/regional recurrence is the most frequent cause of failure.239 Hypopharynx. The hypopharynx represents one of the most lethal sites of SCC. Lymph node metastases are clinically evident at time of diagnosis in 70 to 80% of patients119,120,240 and are indicative of advanced disease. Bilateral and contralateral lymph node metastases occur in 10 to 20% of cases, particularly if tumors cross the midline of the hypopharynx. Primary tumor extension beyond the hypopharynx is common.241,242 Hypopharyngeal cancers are characterized by a propensity to spread submucosally to involve the oropharynx or esophagus. Ulcerated, deep infiltration and skip areas are common. This leads to difficulties in adequately assessing the margins of the tumor and contributes to poor local tumor control, even with the addition of adjuvant radiation.242 The majority (over 75%) of hypopharyngeal cancers arise in the pyriform sinus, whereas 20% occur in the posterior pharyngeal wall. Postcricoid cancers are rare (less than 5%). Posterior pharyngeal wall cancers tend to grow superficially and only involve the prevertebral fascia in advanced lesions. Pyriform cancers spread early to other contiguous structures, such as the larynx, postcricoid area, thyroid gland, and thyroid and cricoid cartilages. Most pyriform sinus cancers arise along the medial wall followed by the lateral wall of the sinus. The postcricoid mucosa is contiguous with the apex of the pyriform, and the tumor can spread circumferentially to involve the entire lower hypopharynx. Because of the locale of hypopharyngeal cancers and their growth patterns and proximity to the larynx, surgical management generally entails partial or total pharyngectomy combined with laryngectomy.123 The staging of hypopharyngeal cancer is based both on the subsite of the pharynx involved and the size of the tumor, the presence of vocal cord fixation, and the extent of lymph node metastases (Table 86.13). Distant metastases at the time of diagnosis are rare. Staging evaluation is critical for treatment planning and must include endoscopic evaluation to determine precisely the tumor margins, extent of invasion of adjacent structures, and presence of second primary tumors or skip areas.243 Determination of the precise site of origin and inferior extent of a tumor can be difficult with large tumors or with those obstructing the esophageal inlet. Because of the necessity to remove the larynx as part of the surgical treatment of most hypopharyngeal cancers, radiation therapy alone as treatment has been extensively investigated.244 Retrospective analyses have consistently demonstrated that survival rates are lower and local/regional failure rates higher with radiation alone as compared with surgery or surgery and radiotherapy.120,142,241,242,245,246 However, for small (T1) cancers of the hypopharynx, and, in particular, for superficial posterior pharyngeal wall lesions, radiation therapy alone has been used effectively, with surgery reserved for salvage.247,248 Radiation therapy offers the advantage of treating bilateral occult lymph node disease, including retropharyngeal nodes, which are frequently involved when cancer arises from the posterior pharyngeal

wall.249 Small cancers of the hypopharynx can be treated equally effectively with surgical resection, often with sparing of the larynx for posterior wall lesions or with supraglottic laryngectomy for superficial cancers of the medial or lateral pyriform when the apex mucosa is tumor-free. Most patients, however, present with advanced primary tumors (T2T4) and positive lymph nodes. In such patients, local control rates with radiation alone decrease to 50% and salvage surgery is rarely successful. Thus, surgical management has become the mainstay of treatment for most hypopharyngeal cancers. Resections may entail partial pharyngectomy, pharyngolaryngectomy, or total pharyngectomy combined with neck dissection. Tumors arising in the lower laryngopharynx or postcricoid mucosa often spread to involve the esophagus. Distal submucosal spread in the esophagus can be extensive and require partial or total esophagectomy. Reconstruction with transposition of the stomach (gastric pullup) or jejunal free graft is currently recommended.250252 Following the advent of total laryngopharyngectomy and postoperative radiation therapy, disease recurrence more commonly occurs in distant sites (i.e., the lung). Treatment approaches with combined preoperative or postoperative radiation have improved the control of lymph node disease, but survival rates have not improved substantially over those with surgery alone because of the increased rates of distant metastases. Postoperative radiation is currently preferred to preoperative radiation because of its lower local recurrence rates, fewer complications, and less difficulty in accurately assessing tumor margins.242 The clear superiority of combined surgery and radiation over surgery alone has not been established.124,241,242,253 Although several studies demonstrate improved survival with combined therapy,120,245 direct comparisons with surgery alone are difficult because of differences in patient selection factors, tumor extent, and degree of lymph node involvement. Well-designed, randomized trials to compare surgery alone with combined therapy have not been performed. The presence of lymph node metastases, extracapsular lymph node involvement, and direct extension of the primary tumor into the soft tissues of the neck are major negative prognostic factors. Overall 5year survival rates range from 10 to 30% for posterior pharyngeal wall cancers,247,248,254256 and from 20 to 40% for pyriform sinus cancers (Table 86.14).119,120,124,142,245,246 Local/regional recurrence continues to account for the greatest number of deaths from disease.124,257 Distant metastases are rarely evident at the time of presentation. The development of distant metastases may appear many years after primary therapy and seems to correlate with extent of regional lymph node involvement.120,258 The rates of distant metastases range from 20 to 50%120,124 and increase with the extent of lymph node metastatic disease. In a recent study by the EORTC, induction chemotherapy and radiation therapy were used for stages II and III hypopharyngeal canTable 86.13. Primary Tumor Staging Characteristics for Carcinoma of the Hypopharynx Tx T0 Tis T1 T2 T3 T4 Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor limited to one subsite of the hypopharynx and less than 2 cm in size More than one subsite or involving an adjacent site or between 24 cm in size without fixation of the larynx More than 4 cm in size or with fixation of larynx Tumor invades adjacent structures of the neck such as the soft tissues, prevertebral fascia, esophagus, thyroid or cricoid cartilage, thyroid gland, etc.

cers. In these randomized trials, which compared laryngeal preservation with combination chemotherapy and radiation therapy with surgery with postoperative radiation therapy, survival (including surgical salvage) remained equal. Approximately 30% of patients with stage III disease can preserve their larynx. Larynx. Because of the prominent role the larynx plays in speech communication, swallowing, respiration, and protection of the lower airway, the treatment of cancer of the larynx presents formidable functional consequences in addition to the intrinsic threat to life posed by these cancers. Unique to this particular site of head and neck cancer, quality-of-life issues have been incorporated into treatment decision making more extensively than for other cancer sites.259 Cancer of the larynx is generally diagnosed at an earlier stage of development than are other head and neck sites, primarily owing to the early manifestation of symptoms. As a result, cure rates are generally higher than for other sites. The three laryngeal subdivisions (see Anatomy above) form the basis for classifying cancers arising at the different sites within the larynx and have clinical importance in the embryologic development, vascular and lymphatic anatomy and the patterns of tumor growth in the larynx, and in the frequency of metastases. The characteristics used in the clinical staging of primary tumors arising in each of these major subdivisions differ (Table 86.15). Considerable attention has been devoted to anatomic studies of the vascular and lymphatic compartments of the larynx.260263 These studies have formed the basis for defining natural anatomic barriers to cancer spread within the larynx and have contributed to the development of precise surgical techniques for partial laryngeal resections for small cancers. The true vocal cords present an effective apparent boundary between supraglottic and subglottic lymphatic spread within the larynx. This separation breaks down with tumors involving the anterior or posterior commissures and with deep invasive tumors that extend vertically across the true and false vocal cords (transglottic cancers). Normally, the internal perichondrium of the thyroid cartilage also presents an effective barrier to cancer spread. However, cancer involvement of the anterior commissure or transglottic extension is associated with invasion of the thyroid cartilage in 40 to 60% of cases.264,265 Early diagnosis is critical for achieving high survival rates and larynx preservation.266 Most cancers that are diagnosed at an early stage of development arise in the glottic larynx. This is so because minimal changes in the mass of the vibrating vocal cord due to tumor growth result in changes in its vibrating characteristics evident as dysphonia or hoarseness. Supraglottic cancers are usually more advanced than glottic cancers at the time of diagnosis because they do not generally produce early symptoms of hoarseness. Rather, the earliest symptoms of a supraglottic cancer are usually sore throat, dysphagia, referred otalgia, or the development of a neck mass representing regional metastasis. Airway compromise may be an early symptom with subglottic cancer. Modern clinical evaluation of laryngeal cancers includes indirect mirror-assisted or fiberoptic laryngoscopy, direct laryngoscopy, CT, and MRI scanning of the larynx and neck, as well as videostroboscopic analysis. These radiologic assessments are of value in assessing direct extension to the pre-epiglottic and paraglottic spaces of the larynx, detecting cartilage invasion, and evaluating the soft tissues and lymph nodes of the neck. These studies have replaced conventional

CHAPTER 86 / Head and Neck Cancer 1189

Table 86.15. the Larynx Primary Tumor Staging Characteristics for Carcinoma of

Supraglottis T1 Tumor limited to one subsite, normal vocal cord mobility T2 Tumor invades more than one subsite, normal vocal cord mobility T3 Tumor limited to larynx with vocal cord fixation and/or invades postcricoid area, medial wall of pyriform sinus or pre-epiglottic tissues T4 Tumor invades thyroid cartilage and/or extends to tissues beyond larynx, e.g., oropharynx, soft tissue of neck Glottis T1 T2 T3 T4 Tumor limited to vocal cord(s) with normal mobility Tumor extends to supraglottis and/or subglottis and/or impaired vocal cord mobility Tumor limited to larynx with vocal cord fixation Tumor invades thyroid cartilage and/or extends to tissues beyond larynx

Subglottis T1 Tumor limited to the subglottis T2 Tumor extends to vocal cord(s) with normal or impaired mobility T3 Tumor limited to larynx with vocal cord fixation T4 Tumor invades cricoid or thyroid cartilage and/or extends to tissues beyond the larynx

Table 86.14. Overall 5-Year Survival Rate (%) in Patients with Squamous Carcinoma of the Hypopharynx
Stage Investigator (n) I II III IV Overall

Dubois246 Bataini120 Razack247 Carpenter242 Pingree143

(457) (384) (120) (162) (1,208)

60 36 77 100

47 33 63 66 35*

23 24 25 51

8 10 5 0 23*

16 19 28 47 25

*Stages I and II combined; III and IV combined.

tomography and contrast laryngograms. The precise evaluation of tumor extent demands direct laryngoscopy under anesthesia. With large obstructive tumors, this may necessitate prior tracheostomy. In some patients with large obstructive lesions, debulking the tumor mass at the time of direct laryngoscopy can obviate the need for tracheostomy and thereby reduce the potential risk of tumor seeding of the tracheostomy site. Even with precise clinical evaluation, inaccurate estimation of tumor extent (usually underestimation) occurs in 30 to 40% of cases.267 Most often this involves failure to identify invasion of the laryngeal cartilage framework. Nevertheless, with clinical examination confirming normal vocal cord function and the absence of anterior commissure involvement, there is no clear role for radiologic imaging of the larynx. Supraglottic primary tumors account for 25 to 50% of all laryngeal cancers.268,269 A knowledge of the laryngeal compartments aids in understanding the spread and staging of supraglottic and glottic cancers. The staging of supraglottic cancers is based on the subsite or region of the supraglottis involved in the cancer. Subsites include the false vocal cords, arytenoids, lingual and laryngeal surfaces of the epiglottis, and aryepiglottic folds. The epiglottis itself is also subdivided into the region extending above the plane of the hyoid and that below the hyoid. Suprahyoid epiglottic tumors tend to have a better prognosis than infrahyoid cancers with the exception of those invading the aryepiglottic fold (marginal area) to involve the pyriform sinus. Early cancers (T1 and T2) involve one or more subsites but have normal vocal cord motion. Those cancers that cause fixation of the vocal cord or involve the postcricoid region, medial wall of the pyriform sinus, or pre-epiglottic space are staged T3. Those that extend beyond the larynx or invade thyroid cartilage are staged T4. Glottic carcinomas are also staged according to the subsites involved. Cancers limited to the true vocal cords are T1 (T1aone vocal cord involved, T1bboth vocal cords involved) and those with extension to the false cord above or the subglottis below are staged T2. Vocal cord fixations are classified T3, whereas those with cartilage involvement or extension outside the larynx are T4. Subglottic cancers that are limited to the subglottic region (T1) or to the subglottis and true vocal cords (T2) are early cancers. Fixation of the vocal cord (T3) and cartilage invasion or extension outside the larynx (T4) are associated with a worse prognosis. The nodal classification for staging is the same as for other HNSCC sites. Curative radiotherapy is generally the treatment of choice for early-stage laryngeal lesions. It is for the moderately advanced lesions that one must consider the trade-offs between definitive radiotherapy with salvage surgery held in reserve and a surgical approach. The

1190 SECTION 27 / Neoplasms of the Head and Neck

patient must be brought into the decision-making process when the various treatment options are being formulated. A treatment algorithm for premalignant and early glottic malignancies is shown in Figure 86.5. Obviously, examination under anesthesia and biopsy is the gold standard in the assessment of early lesions, with radiographic imaging reserved for assessment of the paraglottic space when decreased cord mobility is noted and thyroid cartilage if an infiltrative lesion of the anterior commissure is noted. Certainly, radiation therapy remains the management of choice in early glottic cancers. Nevertheless, in some instances, patients may choose conservative laryngeal surgery, including endoscopic laser excision of localized lesions or partial laryngeal surgery; both require frozen-section analysis of margins if the patient and tumor factors support such an approach. Additionally, in some instances, conservative laryngeal surgical salvage may be attempted in those 10 to 20% of cases where external-beam therapy has been unsuccessful in stages I and II cancers. The design of the radiation portals must be tailored to the individual patient, but some general comments can be made. In general, supraglottic tumors have access to a richer lymphatic drainage than do tumors of the glottic larynx and so radiation fields tend to be larger in order to treat the larger volume at risk for metastatic disease.270 Typically, one treats the primary tumor volume and regions at risk for subclinical metastatic disease to 5,000 cGy and then reduces the field size to areas of gross disease and delivers an additional 2,000 to 2,400 cGy. The spinal cord is shielded at 4,500 cGy and megavoltage electron beams are used to treat the posterior cervical nodes to higher doses as required. Because of the V shape of the anterior neck, wedge-compensating filters are often required to ensure uniform radiation dose distributions. If the anterior supraclavicular fossa is at risk for micrometastatic disease, it is treated to 5,000 cGy using an anterior field suitably matched to the upper neck fields. Early-stage (T1-2N0) glottic lesions are generally treated with relatively small fields localized to the primary tumor. Tumors of the subglottic larynx can spread to the upper paratracheal nodes and to the nodes in the cervical chain, and radiation fields for this disease must, therefore, include the upper mediastinum.271 The treatment of more advanced laryngeal cancers (T3 and T4) has historically included surgery with or without radiation therapy. Prospective randomized studies have shown convincingly that chemotherapy and radiation therapy (including surgical salvage) are equally effective in the long-term survival of patients with T3 laryngeal cancers as compared to surgery with or without radiation therapy.

It is important to note that approximately 60% of patients may preserve their larynx, and thus a significantly better quality of life is preserved.259,272 Speech communication profiles are clearly better in patients treated with organ-sparing approaches, and they suffer no deterioration of swallowing function.273 However, local control is poorer for patients with T4 lesions. Current standard of care argues that laryngeal preservation protocols be considered in treating such patients. A treatment algorithm for advanced glottic cancers is shown in Figure 86.6. Many surgical procedures for laryngeal carcinoma involve the creation of a tracheal stoma. This area is sometimes at significant risk for tumor recurrence, which is most likely associated with peritracheal metastases that erode into the peristomal area. For this reason, bilateral peritracheal dissections should be performed in T4 glottic cancers and radiation therapy provided postoperatively if metastases to this echelon of nodes are found pathologically. Once a stomal recurrence has developed, the prognosis is very grave regardless of whether it is treated with surgery or radiotherapy. Sisson and colleagues report on a series of 28 patients with stomal recurrences treated with one or more surgical resections.275 The 5-year survival was only 17%. Schneider and colleagues report on patients with tracheal recurrences treated with radiotherapy; good palliation of local pain and/or bleeding was achieved, but the 2-year survival was only 6%.276 Given the poor results with salvage therapy, it is clearly better to prevent stomal recurrence in the first place. If risk factors for stomal recurrence are present (Table 86.16), then the tracheal stoma should be irradiated as part of the initial management. Supraglottic. Important factors in selecting therapy for supraglottic cancers are tumor location and pre-epiglottic extension. Tumors limited to the suprahyoid epiglottis are amenable to radiation with fields that encompass neck regions at risk for lymphatic metastases. Additionally, some proponents of limited surgical interventions recommend endoscopic laser excision with observation of the neck for N1 disease. An algorithm for early supraglottic cancers is shown in Figure 86.7. Tumors involving the aryepiglottic folds, pyriform sinuses, or infrahyoid epiglottis tend to be more aggressive, are deeply infiltrative, and frequently involve the pre-epiglottic space. Radiation alone is less effective than surgery, resulting in more frequent local recurrences that require surgical salvage. Often these recurrences are difficult to detect early enough to allow salvage by laryngeal conservation surgery and, therefore, require salvage total laryngectomy. Persistent postradiation edema of the supraglottic larynx is not uncommon and contributes to difficulty in detecting recurrence, which occurs in 40 to 50%.276278

Early Glottic Lesions History & Physical Exam Superficial lesions (T1 & T2) normal cord mobility EUA with biopsy Dysplasia CIS Invasive cancers *Surgery XRT T2 with decreased mobility T2 with decreased mobility High resolution CT of larynx O Paraglottic space involvement O Paraglottic space involvement

Observe, smoking cessation + anti-reflux treatment & re-evaluate Re-evaluate 2-3 months

Suspension with stripping

O Invasion Re-evaluate 2-3 months

O Microinvasion *Surgery XRT

EUA with biopsy

*Surgery

XRT

Figure 86.5.

Treatment algorithm for premalignant and early glottic malignancies.

T3 or T4 Glottic Lesions
Table 86.16.

CHAPTER 86 / Head and Neck Cancer 1191

Risk Factors for Tracheal Stomal Recurrence

High resolution CT scan of the larynx Thyroid cartilage involvement No EUA with biopsy Laryngeal preservation protocol XRT Chemo + XRT Yes EUA with biopsy Surgery

Extensive primary lesion (T3 or T4) Subglottic tumor extension Preliminary emergency tracheostomy for airway obstruction Inadequate tumor margins on the pathologic specimen Tumor involvement of the paratracheal lymphatics Large, fixed nodes or multiple involved cervical nodes Perineural or venous invasion by tumor

Post-op XRT if pathologic indicators

Figure 86.6.

Treatment algorithm for advanced glottic cancers.

Pre-epiglottic extension of cancer carries a poor prognosis. However, these situations can be managed effectively with horizontal supraglottic laryngectomy, which allows preservation of the voice. Indeed, even advanced tumors with extension of cancer to the valleculae and tongue base can often be treated by supraglottic laryngectomy with results equal to those of total laryngectomy. Very superficial tumors of the suprahyoid epiglottis can also be treated with simple epiglottectomy. Because supraglottic laryngectomy is associated with variable degrees of postoperative aspiration, adequate pulmonary status is a prerequisite for this surgery, as is intact mobility of the true vocal cords.

In every patient undergoing supraglottic laryngectomy, preoperative permission must be obtained for total laryngectomy in case the surgical findings dictate that more extensive surgery is needed to extirpate the cancer. Approximately 20% of patients require prolonged tracheostomy, and this is usually related to edema secondary to postoperative radiation. The rates of persistent swallowing difficulties are low, however, and the need for completion laryngectomy for persistent aspiration ranges only from 0 to 5%.279281 The frequency of neck node metastases is high with T2 or greater tumors. Treatment of the clinically negative neck may be accomplished with surgery or radiation. Surgical approaches should include removal of bilateral primary nodal groups at risk (levels II, III, IV) for occult disease. For N0 disease, most authors advocate elective modified radical dissection or selective dissection of nodal groups.282284 Others argue that neck dissection can be delayed until clinically evident metastases occur.285,286 For T1 and T2 lesions, most authors demonstrate overall cure rates of 68 to 73%283,287 with determinate 3year survival rates of 80 to 85%268,282,288 when elective neck dissection is included. Most recurrences occur in the neck, and this argues for prophylactic neck treatment. Radiation is also effective for early lesions. Local control rates for patients with supraglottic tumors treated with radiation alone range from 68 to 94% and survival rates from 50 to 89%. The latter set of survival figures is comparable to those for planned surgery and adjuvant radiotherapy, which range from 46 to 90%. Although the figures are comparable for T1 and T2 lesions, there is a trend favoring the com-

Early Supraglottic Cancers History & Physical Exam T1 and T2 Superficial lesions (T1 & T2) with normal cord mobility EUA with biopsy *Surgery: supraglottic laryngectomy or endoscopic laser excisions XRT Bulky lesions without deep invasion T2 with decreased mobility

High resolution CT of larynx and neck a) Pre-epiglottic space extension b) Paraglottic space involvement c) Hypopharyngeal extension d) Thyroid cartilage intact EUA with biopsy XRT O Recurrences Surgical Salvage *Surgery XRT LP studies

O Recurrence Surgical salvage

EUA with biopsy *Surgery

O Recurrences

Surgical Salvage

Figure 86.7.

Treatment for early supraglottic cancers.

1192 SECTION 27 / Neoplasms of the Head and Neck

bined approach for larger lesions. Nonrandomized series from different institutions are not strictly comparable since unstated patient selection factors are generally involved. For example, the excellent local control results by Goepfert and colleagues for T3 and T4 lesions are for a selected set of tumors that were exophytic in nature.290 Survival rates tend to run lower than local control rates for supraglottic tumors because of deaths from second primaries and other intercurrent diseases. Cure rates range from 73 to 75%290292 and increase to 80 to 85% with the addition of surgical salvage.293295 Most recurrences are local and preservation of voice is successful in 65 to 70% of patients when salvage surgery is included.295,296 The treatment of more advanced supraglottic cancers (T3, T4) remains controversial. Laryngeal preservation remains a focus on this population as well, however. A patient management algorithm is shown in Figure 86.8. In cases with clinically evident regional metastases, combined surgery and postoperative radiation are usually recommended since this treatment approach is associated with better local control rates297 and better control rates for neck disease in both the ipsilateral and contralateral neck.298 Approximately 50% of patients have clinically palpable lymph nodes at the time of diagnosis and 20 to 25% have bilateral nodal involvement. In the clinically negative neck, elective neck dissection shows cancer metastases in 15 to 30% of patients. Failure to control disease in the neck is a major cause of mortality in advanced supraglottic cancers. In most reports, radiation alone for the control of supraglottic cancers with N2 or N3 nodes is clearly inferior to combined therapy. Therefore, in instances where T1T3 lesions of the supraglottis are associated with N2 or N3 disease, neck dissection should be performed when the primaries are treated by radiation therapy. Although the issue of optimal initial management for the patient with N0 disease has not been settled, an individualized approach has been recommended in which bilateral selective node dissections are performed. Postoperative radiation is reserved for patients with proven regional metastases.280,299 Overall 5-year survival rates for supraglottic cancers range from 40 to 50% (Table 86.17).295,300 Local failures occur in approximately 10% of patients and regional failures in 15 to 20%. Rates of distant

Supraglottic Cancers

History and Physical Exam

T3 and T4 lesions

High resolution CT of larynx and neck Thyroid cartilage intact (a) Thyroid cartilage destruction (b) Tumor significantly extending to oropharynx or hypopharynx

EUA with biopsy *Surgery Chemo + XRT LP Studies

EUA with biopsy

Surgery

metastases range from 11 to 18%,270,295,301,302 with rates approaching 30% in patients with stage IV disease.295 Second primaries (20 to 25% of failures) are a major cause of death.295,300 Intercurrent illness accounts for up to 20% of deaths.300,303 Glottic. The treatment of glottic cancer is greatly influenced by the secondary goal of voice preservation. Mobility of the vocal cords is a critical factor in selecting treatment. For small cancers (T1, T2) with mobile vocal cords, radiation therapy alone for cure achieves excellent local control rates (T1, 85 to 95%; T2, 65 to 75%) and overall survival rates similar to those for surgical resection.304,305 Voice quality, although often impaired by radiation, is generally better than that following surgical resection.306,307 Local control rates are 10 to 15% better with primary surgery, but local recurrences after definitive radiation can often be salvaged by subsequent surgery, and this combined approach results in overall survival figures comparable to those with primary surgery. Tumor involvement of the anterior commissure or arytenoids may be associated with higher local recurrence rates with radiation alone, but this may historically have been related to understaging. As with supraglottic cancers, careful clinical tumor staging is necessary since underestimation of tumor extent is common. The irradiate and watch treatment strategy is predicated on close follow-up in order to detect recurrences when they are still salvageable by surgery. Delay in the diagnosis of recurrent glottic cancers after radiation is more frequent than with supraglottic cancers284 and often requires total laryngectomy for cure. Thus, unreliable patients, or patients who are difficult to examine, may be more suitable for primary surgical treatment. Survival figures in radiotherapy series are comparable to local control figures, reflecting the effectiveness of surgical salvage and the fact that few patients with early-stage glottic cancer die of their disease. The 5-year survival rates for T1 lesions range from 80 to 95% with either primary surgery or radiation (Table 86.18). Rates for T2 lesions are generally in the range of 70 to 80%, but these rates are decreased 10 to 15% (local control rates drop 20 to 25%) when the mobility of the vocal cords is impaired308 or transglottic spread is present.309 Lesions with impairment due to invasion of muscle behave more like T3 cancers and have a poorer response to radiation alone.303,310313 Transglottic cancers and those with subglottic extension have higher rates of regional metastases and often require total laryngectomy for cure. In selected patients with these more advanced lesions or impaired vocal cord mobility, extended hemilaryngectomy, or more extensive subtotal laryngectomy with resection of a major portion of the cricoid cartilage, can achieve excellent cure rates.314,315 Voice quality is diminished with these extensive procedures, and chronic aspiration or permanent tracheostomy may result. Additionally, these procedures are technically challenging and experience dependent. However, if proper patient selection is accomplished, these procedures can be well tolerated. Although further study is required, hemilaryngectomy with postoperative radiation therapy has been advocated for some patients with close or involved surgical margins.316 Management of advanced T3 glottic cancers has historically consisted of total laryngectomy with or without postoperative radiation therapy. Although older series show suboptimal control rates (2035%) and survival rates (1050%) for unselected sets of T3 and T4 tumors treated with radiation alone, it is now recognized that with proper selection radiotherapy, control rates for T3 lesions can approach 80%.317 In patients without regional metastases, local tumor control rates with surgery alone are excellent. Significant increases in local control with the addition of radiation therapy have not been clearly demonstrated. However, in patients with regional metastases, overall prognosis is poor and recurrence in the neck is a major problem when surgery is used

XRT

Table 86.17. Overall 5-Year Survival Rates (%) for Patients with Squamous Carcinoma of the Supraglottic Larynx
O Recurrences
Investigator N I II Stage III IV

Surgical salvage

Figure 86.8.

Patient management algorithm.

Fu299 Goepfert290

173 241

64 100

80 68

35 59

10 32

Table 86.18. Overall 5-Year Survival Rates (%) for Patients with Squamous Carcinoma of the Glottic Larynx
Stage Investigator N I II III IV

CHAPTER 86 / Head and Neck Cancer 1193

Kelly313 Kaplan312 Yuen320 Skolnick322

148 283 192 264

82 96 82

79 88 70

65 80 53

57* 63 20

alone. Better regional tumor control rates are achieved with the addition of adjuvant radiation therapy, and this justifies its use in these advanced cases.289 Because rates of occult regional metastases approach 30% in patients with advanced glottic (T3, T4) cancers, elective modified or selective node dissections for staging purposes are recommended when surgery is performed for primary disease. Demonstration of histologically positive nodal metastases has been used as an indication for postoperative radiation. Surgery alone is curative in 50 to 80% of patients without nodal metastases138,291,311,318,319 and decreases to less than 40% if metastases are present.309,320,321 Considerable controversy surrounds the use of definitive radiation with surgical salvage in patients with advanced (T3N0, T4N0) but localized glottic cancers.138,322 A very large, long-term British study demonstrated that salvage laryngectomy was possible in less than 50% of patients who suffered tumor recurrence after definitive radiation.324 The radiation-alone concept, however, presumes equal overall survivorship as compared with primary laryngectomy, with associated low complication rates. Overall survival rates range from 50 to 55%139,320 with larynx preservation in 60 to 70% of these patients.309,320 High complication rates, however, have been reported with late surgical salvage of radiation failures.320 The overall patterns are confusing and based entirely on retrospective series. The resolution of this controversy in management will require carefully designed prospective studies that include assessments not only of survival but also of voice and quality-of-life issues and complication rates. A subset of laryngeal cancers that warrant special consideration are those that involve both the glottic and supraglottic regions (transglottic). These cancers are usually advanced and are associated with a high incidence (30 to 50%) of regional metastases,309,324 extralaryngeal spread, and vocal cord fixation. Although clinical understaging is common, occasionally these cancers are quite superficial and amenable to conservation surgical techniques. Most patients, however, require total laryngectomy. In a careful review of 152 cases of transglottic carcinomas, Mittal reported a 55% cure rate with combined therapy as compared with a 5-year survival of 8% with radiation alone.310 Subglottic. Primary subglottic carcinomas account for less than 5% of laryngeal cancers. Limited data may support the use of primary radiotherapy for early-stage (T1, T2) lesions. However, these lesions are usually advanced at diagnosis and require surgery (laryngectomy) and bilateral peritracheal lymph node dissections since regional metastases occur in about 20% of these patients.325 Many reported series contain glottic primaries with subglottic extension and confuse these analyses. Surgical treatment generally requires total laryngectomy combined with resection of adjacent soft tissues (thyroid gland, strap muscles, peritracheal lymph nodes). Five-year survival rates of 36% for radiation therapy and 42% for surgery205 have been reported. Also, cure rates as high as 70% have been reported in a small number of patients treated with combined therapy.325 The addition of adjuvant radiation offers the advantage of improved regional control rates and treatment of peritracheal and upper mediastinal lymph nodes. Histologically positive lymph nodes can be found in 65% of cases. The risk of stomal recurrence increases substantially with cancers that involve the subglottic larynx, particularly if prior tracheostomy was necessary for impending airway obstruction.326 Early aggressive treatment (often within 24 hours) has been recommended for patients requiring tracheostomy for subglottic extension of laryngeal cancers.327 Patterns of failure for glottic carcinoma differ somewhat from other laryngeal sites. Local failures are uncommon with primary sur-

gical therapy and account for fewer than 10% of recurrences. However, after primary radiation therapy for local glottic primaries, recurrences account for 10 to 50% of failures.139,323 Regional nodal recurrences are seen in 15 to 30% of patients with advanced disease who are treated with surgery alone.319 This contrasts to supraglottic cancers where regional recurrences are a major site of failure. It previously was thought that distant metastases from laryngeal cancers were uncommon, accounting for less than 10% of failures. Distant spread is approximately four times more common with supraglottic than with glottic cancers.122 Rates of distant metastases associated with glottic cancer have increased, however, with the use of combined therapy and have been reported in approximately 20% of patients with advanced disease.139 Rates appear to be directly related to the extent of nodal disease, with reported rates as high as 40 to 50% of failures attributed to distant metastases in patients with N2 or N3 disease. Carcinoma in Situ. A special issue relates to the treatment of CIS of the vocal cords.328,330 This disease often can be managed with vocal cord stripping, but if enough serial sections are examined, foci of invasive carcinoma are often found. Pane and Fletcher report on a series of 79 patients with CIS and seven patients with leukoplakia/atypical hyperplasia who were treated with radiotherapy.331 Patients were staged as either T1 or T2 using the same criteria as for invasive tumors. Local control rates were the same as for invasive lesions: 89% for T1 and 74% for T2. However, only 2 of 12 failures were on the initially involved cord, suggesting that most were not true recurrences but rather new disease developing in dysplastic epithelium. Furthermore, it took about 5 years for 80% of the failures to develop, which further suggests a second process. Most of the failures after primary radiotherapy tend to be invasive, whereas failures after vocal cord stripping tend to be equally divided between CIS and invasive disease. Very superficial cancers limited to the free edge of the vocal cord or CIS can be effectively treated by limited excision by conventional means, or with laser excision, with excellent voice preservation.331,332 More extensive disease requires cordectomy or vertical hemilaryngectomy.333 Numerous methods have been devised for reconstructing the vocal cords after conservation surgery, although, in fact, they are probably not necessary if proper patient selection is pursued. Voice results, in general, are inferior to that with radiation therapy alone for early lesions. The patient with CIS, however, by inference has diffuse premalignant mucosal findings and certainly should be targeted for novel prevention strategies due to the likelihood of later developing invasive disease. PARANASAL SINUS AND NASAL CAVITY Paranasal sinus and nasal cavity tumors represent 0.2% of all human cancers. Roughly two-thirds occur in the maxillary sinus and one-third in the ethmoid sinus. Frontal and sphenoid sinus cancers are rare0.3% of sinus tumors. These cancers are associated epidemiologically with occupational exposures (woodworking, nickel refining), inhaling noxious fumes (dioxane, nitrosamine), and tobacco (see Epidemiology above). Although 80% of paranasal sinus cancers are squamous cell, a variety of other cell types exist and are increasing in frequency relative to SCC.125 These tumors notoriously present at a late stage; over 80% have bony involvement at diagnosis by radiographic or clinical examination. This fact relates to their vague and often protean symptoms: sinusitis is the most common. The natural history is characterized by local invasion into adjacent structures: base of the skull and orbit. Nodal and distant metastases are staged according to standard AJCC criteria for HNSCC, but primary tumor staging systems exist only for tumors of the maxillary and ethmoid sinuses. Esthesioneuroblastomas have their own staging system. The complex anatomy of the paranasal sinuses and nasal cavity and their proximity to the orbit and skull base pose major problems in staging and treatment planning. The maxillary sinus can be visualized as a pyramidal chamber, which is bordered inferiorly by the alveolar ridge and palate, medially by the nasal cavity, and laterally by the cheek. This tumor can invade superiorly to the orbit, inferiorly into the alveolar ridge impinging on the superior alveolar nerve, and posteriorly involving the trunk of the maxillary branch of the trigeminal

1194 SECTION 27 / Neoplasms of the Head and Neck

nerve and extending into the skull base. Invasion superiorly into the orbit may frequently compromise ocular integrity. The ethmoid sinus is a complex of air cells between the medial walls of the orbits. The sphenoid sinus is a deep midline structure. Lateral wall invasion commonly results in an abducens paralysis but can also cause facial paresthesias and numbness in the first and second divisions of the trigeminal nerve, as well as ocular palsies. Invasion superiorly into the cribriform plate often occurs. The treatment of tumors of the paranasal and nasal cavity has traditionally been linked to advances in surgical excision along with muscle preservation or reconstitution for effective prosthesis. Early reports indicated poor results with 5-year survivors of 20 to 40%. With the advance of craniofacial resections and improved diagnostic imaging over the last two decades, some improved success has been experienced in the treatment of extensive sinus malignancies.332 Traditional surgical therapy of paranasal/nasal sinus tumors consists of resection with free surgical margins for low-grade lesions. High-grade malignancies frequently require combined surgery and radiation therapy. The total maxillectomy involves transection of the malar bone from the zygomatic process of the frontal bone, transection of the hard palate, and separation of the maxilla from the pterygoid plates. Reconstruction requires skin grafting and maxillofacial prosthetic obturation. Single-modality therapy is effective in early-stage disease. Radiation of the cervical or retropharyngeal lymph nodes is limited to the presence of positive nodes, advanced lesions, or perineurally invasive malignancies. Results of pre- versus postsurgical radiation are mixed. Wang found a 58% 3-year disease-free survival with preoperative radiation versus a 36% 3-year disease-free survival with postoperative radiotherapy.293 However, Jesse found no difference between the two groups.336 A recent series suggests that in patients with resectable tumors, survival rates are better in patients treated with surgery and postoperative radiotherapy.336 Radiotherapy data are mixed, with 5year survivals ranging from 0 to 50%. In maxillary sinus tumors without bone invasion, surgery or radiation is equally effective. Once bone invasion has occurred, however, combination radiation and surgery is the suggested therapy. An exception is seen in a study that achieved a 3-year disease-free survival of 40% and a 5-year disease-free survival of 35%, in a group of 20 patients of whom 18 had T4 lesions, using megavoltage beams, meticulous technique, and effective doses.337,338 Additionally, the Japanese experience with chemotherapy and radiation therapy in conjunction with necrotomy and debridement also suggests that advances in organ preservation may be possible in this arena. SCC of the nasal vestibule, a distinct type of skin cancer, is related more to tobacco use than to sunlight exposure and presents a difficult management problem. Nasal vestibule cancers have a distinctly more aggressive natural history with a worse prognosis than skin cancers of other sites and, therefore, require more immediate evaluation and treatment.339 Unexpected deep extension may occur in the nasal vestibule itself, upper lip, and other midface regions.340 Radiation is now the favored approach for patients without regional node disease because recurrence rates and survival data appear equivalent to those seen with surgery, the cosmetic outcome is much better than with surgery, and the morbidity is low.341 Furthermore, many of the radiation failures can be salvaged surgically. In patients without clinical neck node involvement, either surgery or radiotherapy yields 10 to 20% recurrence overall and only a 3% recurrence rate after primary single-modality therapy of lesions smaller than 2 cm.342 Large lesions, or those infiltrating the upper lip, may be treated with external-beam radiation combined with radioactive implants or paired wedged beam radiation. Regional neck node involvement is uncommon (6%) at presentation and confers a poor prognosis with a high (over 50%) recurrence rate despite aggressive local therapy (surgery and radiotherapy). SALIVARY GLAND Anatomy. Tumors can arise not only in the major glands but also in the small foci of salivary gland tissue scattered throughout the upper respiratory and digestive tracts. The most common sites of minor salivary gland tumors are the palate, base of the tongue, and buccal mucosa.343345 The majority of salivary gland

tumors arise in the parotid glands, and about 80% of these are benign. Tumors arising in the submandibular, submaxillary, or minor salivary glands are much more likely to be malignant. The largest salivary glands are the parotids, which lie anterior to the external auditory canals. The facial nerve passes through the parotid and divides it into superficial and deep lobes. About 80% of the parotid gland lies in the superficial lobe and 20% lies within the deep lobe. The internal carotid artery, the internal jugular vein, the cervical sympathetic chain, and cranial nerves IX, X, XI, and XII are in close proximity to the deep lobe of the parotid. The parotids lymphatic drainage is to the parotid and upper jugular nodes. These nodal groups then drain into the nodes at the angle of the mandible, the subdigastric nodes, or the upper portion of the posterior cervical chain. Depending on histology, these nodes may be involved. Certain histologies, such as adenoid cystic carcinoma, tend to invade major nerve sheaths: the facial nerve and the auricular-temporal branch of cranial nerve V In . general, the presence of a parotid mass warrants surgical excision since progression of even benign neoplasms may place the facial nerve at risk. Fine-needle aspiration may, however, be used when inflammatory or infectious etiologies are strongly considered. The second largest glands are the submaxillary (submandibular) glands, located in the submaxillary triangle of the neck, which lies just anterior and inferior to the angle of the mandible. Certain tumors of the submandibular glands may invade along nerve sheaths or perineural lymphatics to spread to the mandible or the base of the skull. The sublingual glands are the smallest of the major salivary glands and are located deep in the floor of the mouth. Histopathology. Benign lesions account for about 80% of tumors arising in the parotid glands, 50% in the submandibular glands, and 25% in minor salivary glands. Tumors of the sublingual glands are almost always malignant. A list of such tumors is given in Table 86.19. The basic histologic classification of malignant salivary tumors was developed by Foote and Frazell (Table 86.20).347 Mucoepidermoid carcinomas constitute about 26%, 21%, and 10%, respectively, of malignant salivary gland tumors of the palatal, parotid, and sublingual glands.347 They are the most common malignant tumor of the parotid.348 Well-differentiated tumors are characterized by a slow growth rate, a low recurrence rate after complete surgical excision (about 15%), and rare metastatic potential. High-grade tumors are more aggressive; the local recurrence rate after surgery alone approaches 60%.347 About 50% of patients with high-grade mucoepidermoid carcinoma present with regional metastasis, and 30% develop distant metastasis.349 Acinic cell carcinomas are usually well differentiated and account for about 13% of the cancers arising in the parotid glands. Lymph node metastasis occurs in about 15% of cases.347 Local recurrences and distant metastases may occur many years after treatment.125,350 Adenoid cystic carcinomas (cylindromas) account for approximately 10% of parotid gland cancers and approximately 60% of malignant neoplasms arising in the submandibular or minor salivary glands.347,351353 An outstanding feature of this neoplasm is its propensity to invade major nerves and to spread along the perineural sheath. This must be taken into account in designing treatment. Although these tumors often follow an indolent course, as many as 40% of patients ultimately develop regional and/or distant metastasis.354,355

Table 86.19.

Benign Tumors of the Salivary Glands

Adenomas Pleomorphic adenoma Monomorphic adenoma Warthins tumor (adenolymphoma) Sebaceous lymphadenoma Oncocytoma Myoepithelioma Vascular tumors Hemangiomas Lymphangiomas

Table 86.20.

Malignant Tumors of the Salivary Glands

CHAPTER 86 / Head and Neck Cancer 1195

Table 86.21. T-Staging System and Stage Grouping for Tumors of the Major Salivary Glands
T-Stage classification Stage grouping

Mucoepidermoid carcinoma Low grade High grade Acinic cell carcinoma Adenoid custic carcinoma Adenocarcinoma Malignant mixed tumors (carcinoma ex-pleomorphic adenoma) Squamous cell carcinoma

T1 T2 T3

< or = 2 cm > 2 cm but < or = 4 cm > 4 cm but < or = 6 cm and/or having extraparenchymal extension T2 N1 M0 > 6 cm and/or invades VII nerve or base of skull

Stage I Stage II Stage III

T1 T2 T3 T1

N0 N0 N0 N1

M0 M0 M0 M0

Adenocarcinomas account for 10% of parotid gland cancers but they are common tumors of the minor salivary glands. The majority of them are high grade. About 36% of patients either present with or subsequently develop regional lymph nodes, and therefore the draining lymphatics need to be addressed in treatment strategies for adenocarcinomas.349 Distant metastases (bone and lungs) are common. Carcinoma, ex pleomorphic adenoma, arises from pre-existing benign pleomorphic adenoma. The risk of malignant transformation increases with time: 1.6% for adenomas of less than 5 years duration and 9.4% for adenomas present for more than 15 years.356 True malignant mixed tumors are very rare, constituting about 2 to 5% of all malignant salivary gland tumors, and are aggressive tumors; the neck nodes become involved in about 25% of patients. Primary SCC of the salivary gland is rare, accounting for less than 3% of all parotid neoplasms. However, given the rich lymphatic network that permeates the parotids, SCCs of the skin of the forehead, temple, or ear may metastasize to this region. Such primary sites must be excluded before the diagnosis of primary SCC of the parotid can be made. About 50% of patients with primary SCC of the parotid ultimately develop positive regional nodes, and, again, the draining lymphatics should be addressed by surgery and usually postoperative radiation therapy. The presentation of malignant salivary gland tumors is variable, depending on site and histology. Facial nerve paralysis is uncommon and generally indicates a malignant lesion. Tumors of the deep lobe of the parotid may produce dysphagia, otalgia, or trismus. When the parapharyngeal space is invaded, there may be cranial nerve IX, X, XI, or XII involvement. The usual presentation of a submandibular gland tumor is painless swelling below the mandible. Staging. Recently, the AJCC and the UICC agreed to changes in the staging system for salivary gland tumors to bring the two schema into agreement. T-stage criteria are reproduced in Table 86.21, along with stage groupings. The N- and M-stage criteria are the same as for the more common HNSCCs. Treatment. The treatment of benign salivary gland tumors is primarily surgical. However, there may be a role for postoperative radiation in high-risk situations. If microscopic disease remains overlying the facial nerve or a recurrence has developed, postoperative radiation may be effective in preventing subsequent recurrences.357 These tumors must be followed for extended periods because of the late recurrence and spontaneous transformation.125 Surgery is the primary form of treatment for patients with resectable salivary gland cancer. Early-stage (T1/T1), low-grade mucoepidermoid cancers should be treated with local excision with free surgical margins. Such tumors arising in the parotid are treated with parotidectomy with preservation of the facial nerve. Early-stage, high-grade tumors of all other histologies are treated with surgical resection plus dissection of the regional lymph nodes. Such tumors arising in the parotid require parotidectomy with facial nerve preservation unless the nerve is clinically involved with disease. Patients with clinically positive neck nodes should have a neck dissection on the involved side. For many years, salivary gland tumors were thought to be resistant to conventional photon irradiation, but now it is recognized that this treatment can be highly effective when given in a postoperative setting to eradicate subclinical disease. Postoperative radiotherapy is indicated358 when (a) the tumor is high grade (any histology, except low-grade mucoepidermoid carcinoma or acinic cell carcinomas) or is metastatic SCC, regardless of the surgical margins; (b) the surgical margins are close or microscopically positive (which often may include tumors involving the deep lobe of the

T4

Stage IV

T3 N1, N2, N3 T4 Any N Any T N2, N3 Any T Any N

M0 M0 M0 M1

parotid gland), regardless of the grade; (c) resection has been performed for recurrent disease, regardless of the histology or margin status; (d) the tumor has invaded skin, bone, nerve, or extraparotid tissue; (e) regional nodes are confirmed as positive on neck dissection; or (f) there is gross residual or unresectable disease. In the past, patients with T3 or T4 parotid disease required radical parotidectomy with sacrifice of the facial nerve. Now, unless the facial nerve is circumferentially encompassed by tumor, nerve-sparing surgery may be used followed by radiotherapy. Dosages given to the primary resection site are in the range of 5,500 to 6,500 cGy, depending on the postsurgical tumor status. In the case of low-grade mucoepidermoid carcinomas and acinic cell carcinomas, it is generally not necessary to treat the neck nodes in the N0 neck. For other histologies, the neck nodal drainage is generally treated to dosages in the range of 5,000 cGy. In the case of adenoid cystic carcinomas, the radiation fields must include the courses of the adjacent cranial nerves because perineural spread is common. The results of treatment depend on both histology and site. In a series from M.D. Anderson Cancer Center, 5-year survivals were 100% for 11 patients with acinic cell carcinoma, 95% for 20 patients with adenoid cystic carcinoma, 90% for 10 patients with low-grade mucoepidermoid carcinoma, 82% for 20 patients with high-grade mucoepidermoid carcinoma, 70% for 30 patients with adenocarcinoma, and 59% for 16 patients with malignant mixed tumor. In a retrospective review of 407 patients treated at Princess Margaret Hospital, primary parotid disease was controlled by surgery alone in 24% of cases and by surgery and radiotherapy in 74% of cases.359 In a surgical series of submandibular tumors,360 8 of 17 patients with adenoid cystic histology were free of disease after 5 years compared with only 3 of 17 with mucoepidermoid histology. Minor salivary gland tumors arising in the paranasal sinuses often present in an advanced stage. Goepfert and colleagues found a 2-year local control rate of 47% (9 of 19) in patients treated with surgery alone compared with 76% (26 of 34) in patients treated with surgery and postoperative radiotherapy.362 For patients with large, inoperable salivary gland cancers, fastneutron radiotherapy is an alternative. A randomized clinical trial was performed comparing neutron irradiation and photon irradiation in patients with large, inoperable lesions.362 After only 32 patients had been entered, the trial was closed early for ethical reasons. The tumor clearance rate at the primary site was 85% for the neutron group versus 33% for the photon group (p = .01); the clearance rate in the neck for patients with clinically positive nodes was 86% for neutrons versus 25% for photons. Actuarial projections showed the 2-year survival at 62% for the neutron group, compared with 25% for the photon group (p = .10). Ten-year data on this study continue to show improved local/regional control on the neutron arm (56 vs. 17%, p = .009) but no difference in survival.208 This appears to be due to distant metastases, which ultimately became of greater importance on the neutron arm owing to a reduction in deaths attributable to local disease. A review

1196 SECTION 27 / Neoplasms of the Head and Neck

of the published data on nonrandomized trials shows a local control rate of 67% for 309 patients treated with neutrons as compared with 26% for 298 patients treated with conventional photon radiation.363 Fast neutron radiotherapy is of particular interest in situations where the surgical alternative would entail sacrifice of the facial nerve. An analysis of the University of Washington experience by Buchholz et al.365 showed no difference in either local/regional control or survival for patients treated postoperatively with neutrons after surgery that left behind gross residual disease versus a comparable group of patients treated with neutron radiotherapy alone. For patients with adenoid cystic tumors less than 4 cm in size, it was found that the local/regional control rates with fast neutron radiotherapy were about 75% for both major and minor salivary gland.365,366 Neutron radiotherapy also appears to be an effective treatment for large, multiply recurrent pleomorphic adenomas, although the follow-up period is too short to make a definitive statement in this regard.367 Control of local/regional disease is only a part of the problem. Table 86.22 shows the incidence of distant metastasis from a series of parotid tumors as a function of histology.368 This ranges from a low of 8% for mucoepidermoid tumors to a high of 42% for adenoid cystic tumors. Although early-stage, low-grade tumors have high cure rates with surgery/radiotherapy, standard local therapy is not so successful in locally or regionally advanced metastatic or high-grade disease. Therefore, a moderate amount of phase II chemotherapeutic study has been conducted in search of effective systemic therapy for these difficult cases.369 Whereas adenoid cystic carcinoma is a slow-growing neoplasm, the mucoepidermoid subtype appears to grow faster and more closely resemble HNSCC in its biologic and clinical behavior. The singleagent response patterns reflect these differences. Paralleling results in HNSCC, methotrexate has yielded a 36% response rate in mucoepidermoid cancer. In salivary gland cancers of other histologies, however, methotrexate has produced only a 6% response rate. In contrast to methotrexate, doxorubicin is relatively inactive in mucoepidermoid carcinoma and HNSCC but active in other salivary gland histologic subtypes.370 These suggestions must be interpreted with great caution since they are based in large part on retrospective data and very small patient numbers. Furthermore, response rates do not correlate well with survival, with the more chemoresistant but slow-growing adenoid cystic subtype having the longest survival. Several single-agent studies have been conducted in salivary gland cancers. Promising results have been achieved with cisplatin, methotrexate, doxorubicin, and 5-fluorouracil. Tannock and Sutherland conducted a single-institution review of results with noncisplatin single agents in adenoid cystic cancer.372 Although achieving one of the lowest response rates (29%), compared with other single-agent or combination trials, it also revealed the longest median survival rate (nearly 2 years). More recently, regimens including cisplatin have been tested. Cisplatin alone or in combination has been evaluated in over 130 patients and has yielded response rates in the range of 17 to 100%. Studies have evaluated single-agent cisplatin, mainly in adenoid cystic carcinomas, and yielded conflicting results.371382 The combination of cyclophosphamide, doxorubicin (Adriamycin), and cisplatin is the most extensively studied regimen.372 A recent study with a dose-intensive cisplatin-based regimen combining all four drugs active in this disease produced high toxicity without an improvement in response or survival over single-agent cisplatin or other combinations.378 Hor-

Table 86.22. Distant Metastasis Rates in Parotid Carcinomas by Histology

Histologic type No. with metastases/total (%)

Mucoepidermoid Acinic cell Adenoid cystic Malignant mixed tumor Adenocarcinoma Squamous cell

14/184 (8) 2/14 (14) 22/53 (42) 3/14 (21) 25/91 (27) 2/13 (15)

monal therapy (based on supportive preclinical work) appears to have limited activity.383 The taxanes are the most promising new agents under study in salivary gland tumors. NASOPHARYNGEAL CARCINOMA In the United States, NPC accounts for 2% of all HNSCCs (see Epidemiology above). Its unusual epidemiologic and natural history features include a remarkable tendency toward early regional and distant dissemination. NPC also is extremely sensitive to radiotherapy and cytotoxic chemotherapy. Natural History. In the adult, the nasopharynx is a chamber that is approximately cuboidal in shape and 4 cm on an edge. Anteriorly, it is bounded by the choana of the nasal cavity, superiorly by the base of the skull, and inferiorly by the soft palate, and its posterior wall is the mucosa that overlies the superior constrictor muscles of the pharynx and the C1 and C2 vertebral bodies. The lateral walls contain the eustachian tube orifices. The epithelium of the superior lateral walls contains pseudostratified columnar cells and occasional goblet cells, whereas the inferior lateral and posterior walls are stratified squamous in nature. The region is richly endowed with lymphatics that drain to the retropharyngeal and deep cervical nodes. Malignant neoplasms of the nasopharynx are primarily epithelial, with the presence of keratin associated with a poorer prognosis. WHO recognizes three histopathologic types of NPC: type 1, differentiated SCC (of varying degrees); type 2, nonkeratinizing carcinoma; and type 3, undifferentiated or lymphoepithelial carcinoma.384 Mixed patterns are common. About 75% of NPC are type 1 or 2 (or predominantly one or both of these types). The term lymphoepithelial carcinoma (type 3) is used when numerous infiltrating lymphocytes are seen. About one-third of patients present with a neck mass without other complaints and about 70 to 75% of patients have enlarged neck nodes at presentation. Other common complaints are epistaxis, nasal stuffiness, headache, or hearing loss (generally unilateral). The tumor can spread laterally and superiorly to cause bony destruction of the base of the skull. Frequently, there are cranial nerve findings, with the sixth nerve being most commonly involved.50 There are two principal cranial nerve syndromes associated with NPC: the retroparotidian syndrome, involving the 9th, 10th, 11th, and 12th cranial nerves, and the petrosphenoidal syndrome, involving the third, fourth, fifth, and sixth cranial nerves (and occasionally the second cranial nerve via extension through the foramen lacerum into the middle cranial fossa). Evaluation of the nasopharynx should consist of direct visualization with either a mirror or a fiberoptic scope. A CT and/or MRI scan is important in evaluating base-of-skull involvement and the possible presence of occult involved lymph nodes. Staging. The most recent revision of the AJCC/UICC staging system recognizes the uniqueness of NPC among other head and neck tumors. Both the criteria for T and N staging have been revised as has the stage grouping. These are summarized in Table 86.23. Treatment. Standard treatment for NPC is radiotherapy for early and locally advanced disease. Surgical resection even for earlystage disease is technically difficult because of the anatomic location of the primary tumor and the frequent bilateral cervical and retropharyngeal node involvement. The role of the surgeon is limited to obtaining tissue for diagnosis and occasionally to resecting residual adenopathy after definitive radiotherapy. Fortunately, these tumors tend to be fairly radiosensitive and even large lymph nodes often respond to moderate doses of radiotherapy.385 Prior to initiating therapy, a dental consultation is advised since it is necessary to irradiate the parotid glands bilaterally, and the resulting xerostomia predisposes to serious oral problems. The initial radiation fields encompass the adjacent base of the skull and the nasopharynx itself. The fields are bilaterally directed and include the retropharyngeal drainage and the anterior and posterior cervical chains. A dose of 4,500 cGy is given using megavoltage photons, and then the fields are reduced to spare the spinal cord and an additional 500 cGy given. Megavoltage electrons are used to bring the posterior cervical nodes to this same dose. The fields are then reduced in size and an additional 2,000 to 2,200 cGy given to the nasopharyngeal primary. Regions of positive cervical adenopathy are also boosted with megavoltage photons and/or electrons to total doses of 6,500 to 7,500 cGy depending on the original size of the node and its response

to the first phase of therapy.386 In selected patients, the boost dose to the nasopharynx itself can be given with an intracavitary implant.387 Critical normal structures in the treatment region include the cervical cord, the brain stem, the optic nerves, and orbital contents. Proper shielding and limiting the delivered dose to these structures are necessary to avoid untoward complications. An anterior supraclavicular field is generally matched to the initial large lateral fields and approximately 5,000 cGy given to treat submicroscopic disease in this area. Treatment results are related to both stage and histopathology, but many series do not adequately document outcome as a function of these variables. Huang combines the above-listed T1, T2, and T3 stages into his T1/T2 categories.389 For a clinically negative neck, he reports a 5-year survival of 65%. For groups corresponding to T4N0N2 and T4N3, he finds respective 5-year survivals of 41.3% and 23%. Vikram and colleagues note a 5-year local/regional control rate for early T-stage N0 patients of 65%.390 Scanlon and colleagues show a clear worsening of prognosis with increasing cervical adenopathy with 5-year survivals of 67%, 24%, and 14% when the patient has no clinical adenopathy, unilateral adenopathy, or bilateral adenopathy.391 It is important to note that these series were treated prior to routine CT/MRI scanning, which would have the tendency to increase the clinical stage of the neck disease. A clear correlation exists between the degree of cervical adenopathy and the subsequent development of distant metastases, with patients with bilateral adenopathy having a 5-year actuarial risk of approximately 80% of developing distant metastases. Common sites of distant metastases are the lung, bone, and liver. In selected cases, a failure at the primary site alone can be salvaged using a combination of external-beam radiotherapy and an intracavitary implant.391 However, the morbidity associated with this may be substantial. Although effective in early stages, standard radiotherapy (despite achieving high complete response rates) produces 5-year survivals in stage III disease of only 10 to 45% and in stage IV disease of 0 to 30%.187 Despite major differences between NPC and other HNSCCs, many chemotherapy studies have included NPC patients, which confounds study results. Chemotherapeutic strategies in NPC now treat this disease as a distinct entity. With the exception of parts of China, the problem of small patient numbers is obviously even greater in NPC trials than in many other HNSCC trials. Early United States reports of chemotherapy in NPC were singleinstitution retrospective surveys of recurrent or metastatic NPC patients treated over a many-year period with a variety of agents. Active single agents include cisplatin, bleomycin, methotrexate, 5-fluorouracil, doxorubicin, and Vinca alkaloids. IFN has very limited activity, with response rates of less than 10%. Retrospective surveys from the early 1980s reported 40 to 70% response rates (less than 20% complete responses) with a variety of cisplatin- and noncisplatinbased combination regimens in recurrent disease. More recent series with intensive cisplatin-based regimens in recurrent disease have reported higher and more durable complete response rates.392

CHAPTER 86 / Head and Neck Cancer 1197

The use of combined-modality treatments (sequential chemotherapy and radiotherapy) is under active study in advanced NPC. Neoadjuvant series have reported 70 to 90% response rates (2040% complete) with cisplatin- and noncisplatin-based regimens. Results of a large series from Taiwan treating 1,206 patients with a variety of chemotherapeutic agents given with split-course radiotherapy suggested that the combined-modality approach was more effective than radiotherapy alone in historic controls.394 At least seven small, single-arm sequential-therapy studies have been reported, all but one with cisplatin-based regimens.394397 Tannock and colleagues reported the largest series of 49 consecutive patients treated with methotrexate, cisplatin, and 3-day continuousinfusion bleomycin followed by radiotherapy.398 The overall response rate was high, but complete response was low: 22% (8 of 36) in patients with measurable nodal disease. After radiotherapy, the complete response rate jumped to 82%. This group compared its results with 140 stage-matched historic controls and reported no differences in disease-free or overall survival. Furthermore, there was no apparent reduction in distant metastases in the chemotherapy group. This study was not confirmed by three similar series.384,398,399 Although complete response rates were equivalent in the combined-modality and radiotherapy groups, the disease-free and median survivals of the combined-modality group were higher. Two phase III trials using neoadjuvant chemotherapy have reported conflicting results. One international trial tested epirubicin, cisplatin, and bleomycin for three cycles in 399 patients in addition to standard radiotherapy.400 This showed an increase in the 3-year disease-free survival from 4 to 31% (p, .02) with the neoadjuvant treatment. Advanced-stage patients with N2 or N3 disease were in this trial. Another trial from Hong Kong tested three cycles of neoadjuvant cisplatin and 5-fluorouracil followed by radiation followed by four more cycles of cisplatin and 5-fluorouracil chemotherapy.401 With a median follow-up time of 29 months, the experimental arm and the radiotherapy-alone arm showed respective 2-year overall survivals of 80% and 81% and respective disease-free survivals of 68% and 72% (differences not statistically significant). The use of concomitant chemotherapy and radiotherapy is more promising. A phase III trial from Taiwan compared neoadjuvant versus concomitant chemotherapy along with radiotherapy.402 Although only 68 patients were entered, the actuarial disease-free survival at 5 years favored the concomitant arm (65 vs. 41%), with the difference being primarily due to a reduced rate of distant metastases. In the United States, an intergroup cooperative study (IG0099) tested radiotherapy alone versus experimental arm that used concomitant cisplatin given every weeks during radiotherapy followed by three courses of adjuvant cisplatin and 5-fluorouracil chemotherapy.403 A total of 147 evaluable patients with stages III and IV tumors were entered into this study. At 3 years, there was improved progression-free survival (69 vs. 24%, p, .001), improved over-

Table 86.23.

TNM Classification and Stage Grouping of the Nasopharynx

TNM classification Stage grouping

T1 T2

T3 T4

Confined to nasopharynx Extends to oropharynx and/or nasal fossa T2ano parapharyngeal extension T2bparapharyngeal extension Invades bony structures and/or paranasal sinuses Invades skull, cranial nerve, orbit, or hypopharynx

Stage 0

Tis

N0

M0

Stage I Stage II A Stage II B

N0

No regional lymph nodes

Stage III

N1 N2 N3

Unilateral lymph node(s) less than 6 cm, above SCF Bilateral lymph nodes(s) less than 6 cm, above SCF N3A Lymph nodes greater than 6 cm N3B Lymph nodes extending to SCF

Stage IV A Stage IV B Stage IV C

T1 T2a T2b T1 T2a, b T3 T1 T2a, b T4 Any T Any T

N0 N0 N0 N1 N1 N0, N1, N2 N2 N2 N0, N1, N2 N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

1198 SECTION 27 / Neoplasms of the Head and Neck

all survival (76 vs. 46%, p = .005), and reduced distant metastases (13 vs. 35%, p = .002) on the experimental arm (the p value for distant metastases was calculated by us using Fishers exact test). ADVANCED SKIN CANCER Although the skin of the head and neck accounts for less than 10% of the bodys surface area, 70 to 80% of cutaneous malignancies occur in this region. As a result of greater sun exposure in occupational and recreational activities and the depleted ozone layer (with increased ultraviolet-B exposure), the incidence of skin cancer seems to be increasing, and the initial age at presentation to be decreasing.404 About 3,000 yearly deaths are attributable to nonmelanoma cutaneous malignancies; morbidity occurs in a manyfold greater number of people, however, in terms of medical costs, cosmetic deformity, and loss of function. About 1,000,000 new nonmelanoma skin cancers are projected annually in the United States. Treatment is protracted because of the recurrent nature of the disease, the need for repeated reconstructive efforts, and the propensity of second primary skin cancers to occur. Most early lesions are successfully controlled on the first attempt with conservative local therapy. But advanced skin cancer of the head and neck is not controlled easily, and its frequently devastating physical consequences can have tremendous influence on a patients psychological well-being. Phase II study of systemic therapy in advanced SCC of the skin tested isotretinoin plus IFN- produced a major response rate of 68%, primarily limited to advanced local and regional disease.405,406 Smaller series of cytotoxic chemotherapy combinations in similar patient populations report overall response rates in the 60 to 70% range.407,408 SARCOMAS Sarcomas arising from bone or extraskeletal soft tissues of the head and neck are rare. The most commonly encountered include osteogenic sarcoma, malignant fibrous histiocytoma, rhabdomyosarcoma, fibrosarcoma, synovial sarcoma, angiosarcoma, and chondrosarcoma. Complete excision is the mainstay of treatment, with radiation or chemotherapy playing a less well-defined role in most head and neck sarcomas, with the exception of rhabdomyosarcoma.409 Osteogenic sarcoma is the most common malignant neoplasm of bone, although it is rare in the oral and facial bones. Less than 10% of all osteogenic sarcomas occur in the skull, with most of them in the mandible or maxilla. Among American children, osteogenic sarcoma is the most frequent primary malignant tumor of the jaw. Craniofacial osteogenic sarcomas tend to have a better prognosis than those arising in long bones, with the best survival seen for tumors of the maxilla. Overall 5-year survival approximates 35%.410 Approximately 10% of chondrosarcomas occur in head and neck sites,411 the most common of which are the jaws, paranasal sinuses, and larynx. Chondrosarcomas of the larynx deserve special note because they tend to be low-grade, well-differentiated sarcomas with low metastatic capability. Successful management usually consists of complete surgical excision, which can often spare functional and cosmetic structures. With advances in craniofacial surgery, complete surgical excision of skull-base and maxillary chondrosarcomas should ultimately improve overall tumor control rates. Survival rates for chondrosarcoma are directly related to resectability, site, and tumor grade. The 5-year survival rate for low-grade, completely resected tumors ranges from 70 to 90%, and overall survival rates range from 0 to 50% for unresectable or high-grade tumors.411413 Rhabdomyosarcoma is the most common soft-tissue sarcoma in children, and in the head and neck it presents most frequently in the orbit, sometimes by invasion from the adjacent nasal cavity or pterygoid musculature. Other sites of involvement include the nasopharynx, ear, paranasal sinuses, and soft tissues of the oral cavity and neck. Histologically, the embryonal variety is the most common. Of prognostic importance in rhabdomyosarcomas of the head and neck is the site of origin. Orbital sites have the most favorable and parameningeal sites have the least favorable prognosis. Five-year survival rates for these sites of childhood rhabdomyosarcoma are 89%, 55%, and 47%, respectively.409 The parameningeal group consists of sites at high risk for meningeal spread of tumor and includes the infratemporal fossa, ear, nasopharynx, nasal cavity, and paranasal sinuses. Prior to the mid1960s, surgical excision was the mainstay of therapy, with survival

rates of less than 20% and with more than 80% of patients developing metastatic disease within 1 year of diagnosis.414 Chemotherapy and radiation had achieved 5-year survival rates of 83% for localized, completely resected disease; 70% for grossly resected disease with microscopic residual; and 52% for patients with gross residual disease.158 Based on these results, chemotherapy and radiation therapy have emerged as the preferred therapy for rhabdomyosarcoma of the head and neck with surgery reserved for residual or recurrent disease. Malignant fibrous histiocytoma is the most common soft-tissue sarcoma in adults, but only 3 to 10% are found in the head and neck.415 The paranasal sinuses are the most common head and neck site of origin, followed by craniofacial bones, larynx, soft tissues of the neck, and oral cavity. Those tumors arising in the sinonasal tract or facial bones tend to be very aggressive, with high rates of local recurrence and distant metastases (25 to 30%). Regional node metastases are rare. The 2year survival rates range from 30 to 40%.415 Lymphomas can arise in any structure in the head and neck region, and they must enter into the differential diagnosis of every neoplasm. SMALL CELL UNDIFFERENTIATED CANCER A variety of small cell neoplasms that occur in the head and neck pose particular diagnostic problems for the pathologist. They probably derive from cells of embryonic neuroectodermal or neuroendocrine origin. In general, these tumors tend to behave aggressively. Some are unique to the head and neck, such as esthesioneuroblastoma, but others, such as neuroendocrine carcinoma, carcinoids, and Merkel cell carcinoma, have counterparts that occur at sites outside the head and neck. Differentiation of distinct entities frequently requires electron microscopy, special stains (PAS, Grimelius), or immunohistochemical stains for keratin, neuronspecific enolase, and polypeptide hormones, such as calcitonin, somatostatin, or adrenocorticotropic hormone. Some tumors may have a mixed histologic appearance with evidence of squamous or glandular differentiation. ESTHESIONEUROBLASTOMA Esthesioneuroblastoma (olfactory neuroblastoma) is an uncommon tumor (3% of nasal tumors) arising from the olfactory epithelium of the superior nasal cavity and cribriform plate.416148 A bimodal age distribution exists and the etiology is not known. Intracranial spread through the natural foramina of the cribriform plate is common. The type and extent of primary therapy depend on the tumor size and location. Generally, early-stage disease is treated with a single-modality approach, such as complete surgical excision, usually with craniofacial resection techniques that encompass the entire cribriform plate and ethmoid complex. Adjuvant radiation is used for extensive tumors or when microscopic residual disease is suspected. Despite aggressive local therapy, this tumor has a high propensity for multiple local recurrences. The distant metastasis rate is 10 to 20%. Overall survival correlates with stage with a 3-year survival of 50% in stage C (Kadish system) after surgery and radiotherapy. Chemotherapy has been increasingly integrated into the management of stage C disease and in recurrent/metastatic disease. Although the data are limited, drug response patterns are similar to those for the lung and other small cell cancers; cyclophosphamide, Vinca alkaloids, doxorubicin, cisplatin, and epipodophyllotoxins appear to be active.419 The most frequently reported regimen, cyclophosphamide/vincristine (with or without doxorubicin), produces overall response rates of 50 to 70%. A retrospective series recently reported significantly improved survival with multi-modality therapy (including primary chemotherapy) over local therapy alone for stage C disease.420 No improvement in diseasefree survival was noted, however, despite multi-agent chemotherapy and craniofacial resection. In an attempt to increase disease-free survival, high-dose chemotherapy and autologous bone marrow transplant were investigated.421 The series included eight heavily pretreated patients, five with esthesioneuroblastoma and three with sinonasal undifferentiated carcinoma. Prolonged disease-free survival (17 to 60 months) was reported in four patients. NEUROENDOCRINE CARCINOMA The most common sites of origin for neuroendocrine carcinoma in the head and neck are the larynx and paranasal sinuses, although similar cancers have been reported in the trachea and parotid gland.422,423 Although biochemical evidence of hormone production is common, paraneoplastic syndromes are rare. The prognosis is directly related to the site of origin and degree of his-

tologic differentiation. Five-year survival rates of 70% for paranasal sinus sites have been reported as compared with less than 20% for laryngeal neuroendocrine tumors.422 Biologic behavior also varies according to histologic spectrum, from low-grade, well-differentiated carcinoid-type tumors to intermediate-grade or moderately differentiated neuroendocrine carcinoma to highly aggressive undifferentiated carcinomas. A particularly virulent entity of undifferentiated carcinoma has been described in the sinonasal tract.424 The management of low-grade tumors consists of conservative resection, often combined with radiation. Because of the rapid occurrence of distant metastases with small cell carcinomas or undifferentiated tumors, chemotherapy combined with radiation therapy or surgery is under study. MERKEL CELL CARCINOMA Merkel cell carcinomas arise from Merkel cells located in the basal layer of the epidermis and occur most commonly as a primary neuroendocrine carcinoma of the skin. Merkel cells are tactile cells of neuroectodermal origin and histologically show ultrastructural neurosecretory granules and immunohistochemical staining for neuron-specific enolase. The skin of the head and neck is a common site of origin. These tumors generally are seen in elderly patients. Although previously viewed as fairly indolent cancers of the skin, these adnexal malignancies are biologically aggressive, with an 80% rate of regional metastases and 50% rate of distant dissemination.425 Overall 5-year survival rates are less than 20%. Wide local excision and regional node dissections are effective in controlling localized disease, often in conjunction with radiation therapy. Adjuvant radiation is indicated for large tumors, tumors with close surgical margins, or lymphatic invasion. Because of the propensity for distant metastases and evidence that these cancers are quite sensitive to chemotherapy,426428 this modality may be explored. CHEMOTHERAPY APPROACHES IN HNSCC OVERVIEW The role of chemotherapy in the primary treatment of locally advanced head and neck cancer has become established in certain clinical settings. These include the definitive treatment of NPC403 and in organ preservation protocols for laryngeal429 and hypopharyngeal tumors.430 Chemotherapy also plays a role in the palliation of recurrent disease. Research into breast, lung, prostate, and colon cancers benefits from large, relatively homogeneous study groups. HNSCC research, on the other hand, suffers from great disease heterogeneity and a low incidence in the United States, factors contributing to confusion and conflicting reports regarding chemotherapy outcome (response and survival) and underscoring the importance of large multicenter randomized chemotherapy trials. Large-scale studies of laryngeal and nasopharyngeal cancers are demonstrating the importance of multicenter studies of specific HNSCC sites.429 PROGNOSTIC FACTORS Prognostic factors for chemotherapy response generally accepted as standard include performance status, nutritional status, degree of tumor differentiation, tumor burden (size of primary tumor, resectability, and extent of regional nodal metastases), disease stage, and primary cancer site.132,209,431433 In head and neck cancer, however, correlative results are conflicting, and it is difficult in most cases to say which of these standard factors has significant effects on response. One clear exception relates to site: undifferentiated nasopharyngeal cancer is the most responsive and adenoid cystic salivary gland cancer the least responsive to chemotherapy. Recent work looking for additional prognostic factors in HNSCC has focused on immunologic studies, tumor DNA content, p53, thymidylate synthase, glutathione Stransferase, and GADD153.3,131,257,434436 Chemotherapy Response. Comparing the results of HNSCC chemotherapy trials can be difficult because of inconsistent standards for response determination.433 Confusion regarding tumor measurements can arise as a result of superinfection from ulcerative lesions or, in studies in recurrent disease, from scarring after local therapy. The timing of response determination also varies. Clinical response determinations 4 to 6 weeks after therapy often describe persistent nonmalignant abnormalities (e.g., fibrosis, edema) that resolve after longer follow-up. This is a problem with bulky tumors treated with chemoradiotherapy.

CHAPTER 86 / Head and Neck Cancer 1199

Complete response to chemotherapy is of overwhelming importance to a patients survival outlook. Response reporting in primary HNSCC trials differentiates between responses at primary sites and those at regional sites. Pathologic documentation of primary-site clinical complete response is critical, and the number and depth of biopsies must be rigorously defined. There is disagreement, however, as to the comparative importance of histologic and clinical complete responses.437439 Much of the discrepancy in this area of research may relate to a lack of thoroughness in clinical staging and a lack of uniform specifications for the number and depth of postchemotherapy biopsies. Although critical in screening for new drug activity, partial responses generally do not increase survival in primary or recurrent disease. Toxicities. Chemotherapy-related toxicities frequently encountered in HNSCC are reviewed briefly in the following discussions of each agent. They are classic toxicities seen with the use of these agents in other cancers.440 Toxicities that are not well established or that are unique to drugs not currently in common use are not mentioned here but only in the applicable discussion of each drug. The most frequent and dose-limiting toxicities with current chemotherapeutic approaches in HNSCC have been reviewed recently441 and fall into three areas: myelosuppression, mucositis, and the legendary toxicities associated with cisplatin. Myelosuppression is a well-known side effect of chemotherapy, and its mitigation by hematopoietic growth factors is well established. Mucositis is a major limiting acute toxicity in the chemotherapy of HNSCC. This is very relevant to two approaches for controlling advanced HNSCC-concomitant chemoradiotherapy and chemical/ pharmacologic modulation of 5-fluorouracil- are severely limited by this toxic effect. How best to mitigate mucositis is not clear. Several strategies to limit therapy-induced mucositis in HNSCC are under study, but no proven standard approach currently exists.407,442445 In a randomized study, sucralfate rinses decreased mucositis associated with cisplatin and 5-fluorouracil.445 Antimicrobial mouthwashes containing amphotericin B, polymyxin B, and tobramycin have been reported to limit radiation-induced oral mucositis by selectively decreasing colonization of the oral cavity by fungi and aerobic gramnegative bacteria. A novel approach for reducing drug-induced mucositis is the use of circadian infusion schedules of anticancer therapy.407 Two other approaches that have yielded promising results include the use of filgrastin (G-CSF) and cryotherapy. Although recently approved for radiation-induced xerostomia, to date amifostine has produced mixed results in the control of mucositis.446 Perhaps the most promising new approach to control mucositis is the use of growth factors such as keratinocyte growth factor.447 Problems with cisplatin toxicities (renal, otologic, neurologic, and gastrointestinal) may be solved largely by substituting carboplatin, a platinum analogue.448 Nevertheless, cisplatin will remain a leading agent against HNSCC when management is hampered by myelosuppression. The availability of specific serotonin receptor antagonists (e.g., ondansetron and gramsetron) greatly enhances control of the major acute problem of cisplatin-induced nausea and vomiting. Preclinical data and suggestive results of single-arm clinical trials have pointed to other ways to control cisplatin toxicity. One such new strategy is the use of a heterogeneous group of agents called chemoprotectors, a group that includes thiol-containing compounds (e.g., sodium diethyldithiocarbamate, sodium thiosulfate, and amifostine, or WR-2721) and probenecid.449,450 Preclinical Screening. Preclinical drug screening for active new agents and combinations is of highest priority. Many groups are developing panels of HNSCC cell lines for this research, and these lines are as heterogeneous as the diseases themselves. The establishment of panels of site-specific HNSCC cell lines may be important for future chemosensitivity studies. However, different cell lines from the same HNSCC may have different chemosensitivity patterns.451 In addition to drug screening, the in vitro work has allowed the study of chemical modulation of active drugs. This work has shown that leucovorin, hydroxyurea, IFN- and methotrexate potentiate 5fluorouracil cytotoxicity. In vitro interactions between chemotherapy

1200 SECTION 27 / Neoplasms of the Head and Neck

(e.g., hydroxyurea, 5-fluorouracil) and irradiation and between chemotherapy (cisplatin, 5-fluorouracil) and hyperthermia have also led to clinical trials. In vivo (xenograft) work has identified promising new drugs/schedules, such as gemcitabine and thymidylate synthase inhibitor tomudex.452454 CHEMOTHERAPY OF RECURRENT HNSCC Clinical testing of new cytotoxic agents traditionally has been conducted first in patients with recurrent disease, followed by testing in combined-modality treatments in patients with potentially curable disease. The majority of patients included in the following discussion have recurrent disease and constitute the principal study group; a minority have metastatic or advanced unresectable disease. We refer to this patient group generically as recurrent, although many studies discussed under this rubric include the minority cases also. Chemotherapy has had no impact on overall survival in recurrent HNSCC. The purely clinical, noninvestigational goal of chemotherapy in recurrent disease has been to achieve palliation, unlike the goal of primary chemotherapy trials, which is to cure locally advanced, untreated cancer. The overall prognosis in recurrent HNSCC is dismal (median survival of 4 to 6 months). Lumped diagnostically under HNSCC is a diverse group of cancers with markedly variable natural histories (fully discussed in the Biology section above) and, therefore, markedly variable responses to chemotherapy. Important diversities also occur in HNSCC relapse patterns: at the primary site, in regional nodes, and at distant sites after definitive local therapy. These and many other diversities make it extremely difficult to interpret results of chemotherapy trials in cancers of this region. Many chemotherapy studies encompass all guises of recurrent HNSCC. They run the gamut from minimal, resectable disease seen locally after radiation therapy to bulky regional and distant disease occurring after surgery, radiotherapy, and even primary and/or salvage chemotherapy. Often, these last salvage patients are excluded from further chemotherapy trials because of their extremely poor prognosis. Other poor-risk patients, such as those with unresectable disease resistant to neoadjuvant chemotherapy or with short disease-free intervals or persistent disease after primary therapy, are included in many trials. Although patients with advanced resectable disease should be included in trials of primary therapy,455 the varying definition of resectable among different head and neck surgeons can place these patients in recurrent trials. Single-Agent Trials. Response rates of different trials with the same agent have varied markedly due to HNSCCs great heterogeneity and because of differences in trial designs. Pooled results indicate that eight drugs show single-agent response rates of 15% or higher and remission durations of 3 to 5 months (Table 86.24). The five longest studied of these agents are methotrexate, cisplatin, bleomycin, 5-fluorouracil, and carboplatin. The three newer agents in this group are paclitaxel, docetaxel, and ifosfamide. Methotrexate, according to many oncologists, is the standard palliative therapy for recurrent or metastatic HNSCC.456,457 The standard dose and schedule for palliation are 40 mg/m2/w intravenously or intramuscularly,458 with dose escalations to 60 mg/m2/w until mild toxicity or any tumor response is achieved. This methotrexate dose and schedule are relatively nontoxic, inexpensive, and convenient, features that are critical to palliative therapy. Preclinical work and early single-arm HNSCC clinical studies suggested a dose-response effect with high-dose methotrexate plus delayed leucovorin. However, five randomized trials of standard-dose methotrexate versus high-dose (up to 100-fold increases) methotrexate plus delayed leucovorin failed to show superiority. Pooled response rates for the two arms (high dose vs. low dose) from all of the five randomized studies are nearly identical. The issue of high-dose methotrexate has been readdressed, however. A randomized, placebo-controlled trial of standard-dose methotrexate with leucovorin or without it revealed that even delayed leucovorin (given 24 hours after high-dose methotrexate) suppressed not only toxicity but also antitumor activity.459 This study indicates the

need for further work in optimizing methotrexate/leucovorin doses and schedules. The methotrexate analogues trimetrexate, piritrexim, and edatrexate have been studied in HNSCC and may have pharmacologic advantages and less renal toxicity.440,460463 In preclinical studies, some lack of cross-resistance between these analogues and methotrexate has been observed. The dose-limiting toxicity of piritrexim is myelosuppression and mucositis is the major problem with edatrexate. Recent clinical data, including multicenter phase II and III trials of edatrexate, have been disappointing.462 Cisplatin is an important component of combinations of chemotherapeutic drugs for HNSCC.464466 Most studies have given cisplatin in an intermittent standard-dose bolus schedule (80 to 120 mg/m2 every 3 to 4 weeks). Altered drug schedules designed to enhance therapeutic index in HNSCC have been tested. A small randomized comparison of schedules showed no difference in activity between bolus cisplatin at 120 mg/m2/d and the less toxic schedule of 20 mg/m2/d for 5 days.467 Cisplatin given as a continuous infusion in HNSCC has pharmacokinetic advantages and activity equivalent to those at the same dose given in boluses.468,469 The dose-response relationship between cisplatin and HNSCC has been studied by several groups but remains unproved. Single-arm studies of regional and high-dose (150 to 200 mg/m2) systemic cisplatin have produced single-agent response rates of over 70% and definite objective responses in patients failing standard-dose cisplatin.470 The only randomized HNSCC trial, however, tested a lower highdose regimen and failed to confirm cisplatins dose-response effect.471 This trial, which directly compared 120 mg/m2 with 60 mg/m2 via intravenous bolus, was stopped early because of very similar response rates between the two arms (16.1% and 17.8%, respectively) and identical median survivals (34 weeks). Driven by the major activity and legendary toxicities of cisplatin, analogue development has moved faster with this drug than with other drugs. Carboplatin is a second-generation platinum complex with activity equivalent to and toxicity less than those of cisplatin.448,472 Bolus carboplatin has pharmacokinetic and toxicity profiles similar to those of continuous-infusion cisplatin and has significantly less renal, otologic, neurologic, and gastrointestinal (nausea/vomiting) toxicity than bolus cisplatin. Reversible myelosuppression (primarily thrombocytopenia) is the dose-limiting toxicity for carboplatin. Single-agent studies of carboplatin given monthly in bolus (400 mg/m2) or fractionated (80 mg/m2/d for 5 days) schedules produced objective response rates of 20 to 30% in recurrent and metastatic HNSCC.473475 These single-arm data were confirmed in a cooperative group randomized phase II trial of two second-generation platinum complexes: carboplatin (response rate 24%) and iproplatin (response 12%).476 In contrast to the proved activity of carboplatin, this and other trials of iproplatin in recurrent HNSCC have been uniformly disappointing, with overall response rates of less than 10% and major toxicity (myelosuppression, nausea/vomiting). In an attempt to increase platinum dose intensity in a number of solid tumors, researchers have studied the combined use of carboplatin and cisplatin. This approach may allow higher serum platinum levels by varying the types and thereby lowering the intensities of platinum toxicities. Single-arm studies, however, have not shown increased response.477 Bleomycin has been studied extensively as a single agent and in combinations in HNSCC. Its spectrum of toxicity is distinctive. Dose
Table 86.24.
Agent

Single-Agent Activity in Recurrent Head and Neck Cancer

Response (%)

Methotrexate Bleomycin Cisplatin Carboplatin 5-Fluorouracil Paclitaxel Docetaxel Ifosfamide

31 21 28 26 15 38 38 26

intensity is directly associated with mucositis, and total cumulative dosage is directly associated with skin toxicity and with the most feared side effect, pulmonary fibrosis. Bleomycins lack of myelosuppression, even with prolonged continuous infusion, promotes its use in combinations. Continuous-infusion regimens produce less pulmonary toxicity but are not clearly more active clinically than intermittentbolus schedules in HNSCC.478480 5-Fluorouracil has limited single-agent activity in HNSCC (see Table 86.24). It has been given in varying doses as an intravenous bolus daily (for 5 days), weekly, or every 3 or 4 weeks. The dose-limiting toxicity of bolus administration is myelosuppression; prolonged administration is limited by mucositis, diarrhea, and cutaneous erythema. Schedule dependency of 5-fluorouracil treatment has received little study in HNSCC, although long-term continuous low-dose infusion (e.g., 6 weeks) is effective palliation for recurrent disease.481 Continuous-infusion regimens were designed initially to reduce myelosuppression and seem to have enhanced activity.482 Despite 5-fluorouracils modest single-agent activity in HNSCC, preclinical studies indicating its synergistic interaction with radiation and its enhanced cytotoxicity with chemical modulators (e.g., leucovorin) have led to active recent study of this agent in HNSCC.483 Analogues of 5-fluorouracil and bleomycin, used systemically, in HNSCC, have shown no therapeutic advantages over the parent compounds.482,485 Oral 5-fluorouracilbased approaches are under study.485 Randomized trials have compared different single agents in recurrent HNSCC. Two phase III studies have directly compared cisplatin and methotrexate (randomized, two-arm design). In the first of these studies, Hong and colleagues gave cisplatin at 50 mg/m2 on days 1 and 8 every month versus methotrexate at 40 to 60 mg/m2 per week.487 Both arms produced similar response rates, 28.6% and 23.5%, respectively. Similar findings were observed in the second phase III trial.487 Three agents that more recently have shown activity in recurrent head and neck cancer are ifosfamide, paclitaxel, and docetaxel.488 Ifosfamide has been tested in a wide range of doses (from 5 to 17 g/m2/cycle) and fractionation schedules, producing an overall major response rate of 32% in a total of over 200 patients reported from several series.489,490 The taxanes are the newest class of established active agents in head and neck cancer.491496 The best study is a recently completed Eastern Cooperative Oncology Group (ECOG) phase II trial of paclitaxel (Taxol) at a dose of 250 mg/m2 over 24 hours with G-CSF in 30 patients.493 This study reported an impressive 40% major response rate, 9.2-month median survival, and 33% 1-year survival, which are even more noteworthy coming from a multicenter cooperative group study. The major toxicity was neutropenia that lasted a mean duration of approximately 2 days. Other infusion schedules are under active study, from weekly short infusion to more prolonged continuous infusions.497 Similar activity with docetaxel has been reported.488 Topotecan, gemcitabine,498 vinorelbine,499 and irinotecan500 are newer agents undergoing study in the head and neck. General classes of drugs with limited single-agent activity include the anthracyclines, Vinca alkaloids, mitomycin (and analogues), and nitrosoureas.501 The major role for anthracyclines in head and neck cancer appears to be in the therapy of nonsquamous cancers (salivary gland cancer, NPC, small cell carcinoma, sarcoma, and esthesioneuroblastoma). Following is a partial list of drugs that are inactive in recurrent HNSCC or do not appear to have advantages over parent compounds in single-agent trials: PCNU, bisantrene, hexamethylmeTable 86.25.
Author

CHAPTER 86 / Head and Neck Cancer 1201

lamine, mitoguazone, m-AMSA, aclacinomycin, doxorubicin, epirubicin, mitoxantrone, tallysomycin S10b, vindesine, dibromodulcitol, triazinate, gallium nitrate, 6-thioguanine, triazofurin, homoharringtonine, porfiromycin, mitozolomide, and lomustine.456,502504 Multi-agent Trials. Nearly all possible combinations and combination doses/schedules of methotrexate, cisplatin, bleomycin, and 5-fluorouracil and other agents listed in Table 86.24 have been tried in numerous single-arm studies in recurrent HNSCC. Results have covered a wide range of response rates, including generally low complete response rates, in heterogeneous subsets of patients. In the late 1970s, work focused on cisplatin-bleomycin combinations, which appeared from single-arm studies to be more active than noncisplatin combinations.455,456,465 The highest complete response rate to a high-dose cisplatin-bleomycin combination strategy in recurrent disease was 24%.505 The cisplatin/5-fluorouracil regimen in HNSCC was an important advance launched by preclinical studies indicating synergy between these drugs and by concern over bleomycins pulmonary toxicity. Pioneering clinical work by investigators at Wayne State in the early 1980s yielded major objective response rates of 78% (27% complete responses) in recurrent disease.506,507 Lower response rates have been reported by other centers, however.502,508,509 Enthusiasm for this combination in recurrent disease is further diminished by the negative long-term results510 and recent results of randomized trials comparing cisplatin/5-fluorouracil with other combinations and even single agents (Tables 86.25, 86.26). Several phase II and III trials (over 300 reported patients) of the less toxic carboplatin/5-fluorouracil regimen report response rates similar to cisplatin/5-fluorouracil.475,511,512 Other cisplatin combinations (e.g., with etoposide or cytarabine) have produced mixed results in HNSCC.513516 There is a high level of enthusiasm currently for integrating the newer agents into combination chemotherapy. Results of such approaches have been encouraging. A recent phase II trial of paclitaxel (175 mg/m2 in a 3-hour infusion on day 1), ifosfamide (1,000 mg/m2 in a 2-hour infusion on days 1 through 3), and cisplatin (60 mg/m2 on day 1, repeated every 3 to 4 weeks) achieved positive results in recurrent HNSCC.518 Response and toxicity were assessable in 52 patients. Survival was assessable in 53 patients (57% with local/regional recurrence alone and 43% with distant metastasis, with or without local/regional recurrence). Based on a 17.7-month median follow-up of all patients, this trial achieved an overall response rate of 58% (30/52); complete response rate of 47% (9/52) (including six complete responses lasting a median 15.7+ months), and median survival of 8.8 months (95% confidence interval [CI] 8.1 to 17.5 months). The relatively well-tolerated toxicity included transient grades 3 to 4 neutropenia in 90% of patients (the most frequent moderate-to-severe toxicity), neutropenic fever in 27%, grade 3 peripheral neuropathy in three patients (none had grade 4), and grade 3 mucositis in only one patient (none had grade 4). There were no deaths due to toxicity.517 More recently, the above regimen was modified by the substitution of carboplatin for cisplatin. This regimen produced less neuropathy, gastrointestinal toxicity, and fatigue and similar overall and complete response and survival rates in recurrent disease in comparison with the TIP regimen.518 Concomitant Chemoradiotherapy for Recurrent Disease. A very novel approach in the recurrent-disease setting is represented by a phase I study of concomitant chemoradiotherapy with paclitaxel, 5-flu-

Randomized Trials of Chemotherapy in Recurrent Head and Neck Cancer: Single Agents vs. Multiple Agents
Agents No. patients % Response (complete) Median survival (mo)

Morton525 Jacobs521 Liverpool524

PIB vs. PB PIF vs. PF PIM vs. PF/PM

31/22 vs. 38 83/83 vs. 79 50/50 vs. 50/50

13(3)/14(0) vs. 24(5) 17(4)/13(2) vs. 32(6)* 29(2)/12(0) vs. 24(6); 22(0)

3.7/2.8 vs. 3.8 5.0/6.1 vs. 5.5 2.7/8.7 vs. 5.3/6.7

*Pf vs. P, p = .035; PF vs. F, p = .005. Taken from interim report, not available in final report. P = cisplatin; F = 5-fluorouracil; M = methotrexate; B = bleomycin; C = cyclophosphamide; I = leucovorin. Italics = single agents.

1202 SECTION 27 / Neoplasms of the Head and Neck

Table 86.26. Agent(s)
Author

Randomized Trials of Cisplatin/5-Fluorouracil vs. Other

No. Agents % Response (complete) Survival

Recurrent 40 Kish528 104 Jacobs521 Liverpool524 200

p = NS PF vs. PF (bolus) 72(22) vs. 20(10)* p = NS PF vs. P/F 32(6) vs. 17(4)/13(2) p = NS PF vs. P/M/PM 24(6) vs. 29(2)/12(0)/22(0) p = NS

*Significant difference (p < .01). PF vs. P, p = .035; PF vs. F, p = .005. P = cisplatin; F = 5-fluorouracil; NS = not significant (p > .05).

orouracil, and hydroxyurea with granulocyte colony-stimulating factor support. This regimen was administered to 55 patients who had either failed to respond to prior radiotherapy (n = 25) or surgery, a coexistent or prior second malignancy, or unresectable or metastatic disease and less than a 10% probability of 2-year survival.519 Twenty such patients were treated at the recommended phase II dose level of hydroxyurea (500 mg orally twice daily for 11 doses), 5-fluorouracil (600 mg/m2/d by continuous infusion for 5 days), and paclitaxel (20 mg/m2/d by continuous infusion for 5 days), with twice-daily radiotherapy. Dose-limiting toxicities consisted of myelosuppression, mucositis, dermatitis, and diarrhea. Paclitaxel concentrations of >10 nmol/L were achieved in the plasma of 65% of patients. Complete responses were achieved in 70% of assessable patients. This study showed (1) the feasibility of adding infusional paclitaxel and hyperfractionated radiotherapy to 5-fluorouracil, hydroxyurea and concomitant radiotherapy and (2) the achievement of radiosensitizing levels of paclitaxel in most patients. Based on the regimens high local/regional control rate, further investigation in previously untreated patients is justified. RANDOMIZED STUDIES Only 2 of the 12 trials comparing multi- and single-agent (methotrexate in seven trials and cisplatin in five) therapies produced significant differences in response, and the overall single- and multi-agent median survivals are similar at 5 to 6 months (see Table 86.25). Jacobs and colleagues reported a three-arm comparative trial of cisplatin and 5-fluorouracil as single agents and in combination.521 Although no major survival differences occurred, the response rate was highest in the cisplatin/infusional 5-fluorouracil combination (see Table 86.25). The Southwest Oncology Group (SWOG) reported a three-arm randomized phase III study comparing cisplatin/5-fluorouracil, carboplatin (300 mg/m2)/5-fluorouracil, and single-agent methotrexate in recurrent HNSCC.521 The response rate and toxicity of cisplatin/5-fluorouracil were significantly greater than they were in the methotrexate arm. The carboplatin/5-fluorouracil arm did not differ significantly from the two other arms in response or toxicity. Median survival was poor and not significantly different among the three groups. Interpretation of these results is clouded by atypical toxicity patterns. Moderate to severe myelosuppression (leukopenia) was significantly more frequent in the cisplatin arm, suggesting suboptimal dosing of carboplatin. Five studies compared single-agent cisplatin with cisplatin combinations. Despite promising single-arm studies, cisplatin combinations have not performed better than cisplatin alone in phase III trials (see Table 86.25). Multi-agent survival rates are equivalent to those with single-agent cisplatin.522524 Two phase III trials compared cisplatin-based combinations and similar regimens without cisplatin.525,526 These trials reported significant increases in response rates with the cisplatin regimen but no survival differences. A randomized trial designed to test the schedule dependency of 5fluorouracil in the cisplatin/5-fluorouracil combination compared cisplatin (100 mg/m2) bolus plus 5-fluorouracil given by continuous infusion (1,000 mg/m2/d for 4 days) with the same bolus dose of cisplatin plus 5-fluorouracil as a bolus (600 mg/m2 on day 1 and day 8).331 The continuous-infusion regimen produced a higher response rate of 72% (22% complete) compared with the bolus-group response rate of 20%

(10% complete) (p , .01). Despite the lower total dose, the bolus arm was associated with greater toxicity (myelosuppression). The interpretation of this study is clouded by the bolus 5-fluorouracil arms unusual day 1 and 8 schedule and more than four-fold lower total dose of 5-fluorouracil. Furthermore, single-arm trials of different schedules (e.g., cisplatin and 5-fluorouracil given as daily intravenous bolus for 5 days)528,529 or different sequences,530 produced response rates comparable to those, in similar-risk patients, of the standard regimen of cisplatin plus continuous-infusion 5-fluorouracil. Single-arm clinical trials of methotrexate pretreatment and 5-fluorouracil in advanced and recurrent HNSCC yielded mixed results: response rates ranging from 16 to 94%.531,532 However, three randomized studies differing somewhat in design and results clearly indicate that the methotrexate/5-fluorouracil sequence, predicted by preclinical studies to be active, does not produce a response or survival advantage over simultaneous administration or the reverse sequence (Table 86.27).533,534 The only completed randomized trial of a taxane combination in recurrent disease was recently reported by ECOG. Based on singleagent activity of paclitaxel (discussed above), this study evaluated high-dose paclitaxel + G-CSF + cisplatin versus low-dose paclitaxel + cisplatin. A total of 210 patients were entered, 199 of which were analyzable (101 in the high-dose and 98 in the low-dose arms). This trial was designed to assess a potential dose-response effect of paclitaxel and the activity of paclitaxel plus cisplatin in this population. Primary end points were event-free and overall survival. No survival advantage was associated with high-dose paclitaxel, suggesting that there was no paclitaxel dose-response effect. This may be due to the mechanism of action of paclitaxel, which has the ability to cause microtubular aggregation at only 10 m serum concentration (readily achieved by lower doses). Myelosuppression and infection were the most frequent toxicities, which was expected with the 24-hour paclitaxel infusion schedule. This regimen was poorly tolerated. Grade 4 neutropenia was more frequent in the low-dose arm (71.1%) than in the high-dose arm (60.9%). Approximately 40% of patients withdrew from treatment because of toxicity. Still, median survival was 7.3 months and the 1year survival rate was nearly 30%, which suggests that paclitaxel and cisplatin may be more efficacious than cisplatin and 5-fluorouracil in this setting. These investigators concluded that the true response rate probably was higher but that the large number of patients taken off study early for reasons of toxicity caused a lowering of the rate. The low- and high-dose paclitaxel (plus cisplatin) regimens of this trial had similar toxicity profiles. Both arms experienced substantial rates of severe myelosuppression leading to life-threatening infection, due to the 24-hour infusion schedule of paclitaxel. This also has been reported in regard to other studies in this setting.535 These toxicity results of a multicenter trial make this infusion schedule unrecommendable for treating recurrent/metastatic disease. As no doseresponse effect was observed, there is no evident need for the more expensive high-dose regimen (including growth factor support). The encouraging median and overall survival data justify further testing of paclitaxel and cisplatin in this population. Although these and previously reported cisplatin and 5-fluorouracil objective-response results are similar, the toxicity-related dropout rate of the current trial may have adversely affected response and survival outcomes. CONCLUSIONS All of the data on traditional agents for recurrent, unresectable, and metastatic disease fail to show that multi-agent therapy is more effective than single-agent therapy. Although combination chemotherapy for recurrent or metastatic HNSCC may produce higher
Table 86.27. Randomized Trials of Sequential Methotrexate-5-Fluorouracil
Author No. Chemotherapy % Response (complete) Median survival (mo)

Browman534,535 Browman460

79 113

M-F* vs. MF M-F vs. MF

38(5) vs. 62(12) 47(5) vs. 45(10)

19 vs. 18 34 vs. 33

*1-hr sequential methotrexate-5-fluorouracil. Simultaneous. All patients (advanced plus recurrent).

response rates than single agents, none of the 12 randomized combination trials (including those comparing cisplatin/5-fluorouracil) produced improved survival over single-agent treatment (see Tables 86.25 and 86.26). Single-agent and combination chemotherapy can provide effective palliation for these patients. The choice of regimen was based on the important balance between efficacy and toxicity (quality of life), which must be considered on a case-by-case basis. The development of new, more active drugs and combinations must assume high priority. Although the combination of cisplatin and infusion 5-fluorouracil had generally been the regimen of choice for palliation in patients able to tolerate the increased toxicity, the results of large series with long follow-up510 and of recent phase III trials indicate no advantage over other combinations (in response or survival) or over less toxic single-agent therapy (in survival). There are promising new active cytotoxic agents, including taxanes and ifosfamide, and novel approaches, such as gene targeting/therapy. REGIONAL CYTOTOXIC THERAPY Preclinical data support regional therapy in HNSCC, as do the predominantly local/regional tumor spread and a relatively selective access to tumor blood supply.536543 High total-body clearance and low regional exchange rates are the major pharmacokinetic factors that allow optimization of regional drug delivery. Total-body clearance for drugs active in HNSCC is highest for floxuridine (FUDR) and lowest for methotrexate, with cisplatin at the low end.541 Although not ideal for regional therapy from a pharmacokinetic perspective, cisplatin is active and achieves an estimated fourfold greater intratumoral drug concentration when given intra-arterially (i.e., regionally) rather than intravenously. Single-arm clinical and pharmacokinetic studies of regional therapy in HNSCC have reported low regional exchange rates, increased intratumoral drug levels, enhanced toxicity in the infused area (mucositis, alopecia), reduced systemic toxicity, and modest increases in response rates (complete and partial) without apparent survival benefit over the systemic route.544 Although the future of regional drug therapy in HNSCC is uncertain, newer microcatheters and catheter placement techniques that have reduced morbidity have led to a renewed interest in intra-arterial therapy. A phase I study using a highly selective intra-arterial infusion of high-dose cisplatin with concurrent intravenous thiosulfate (used to neutralize systemic cisplatin) in locally advanced and recurrent disease was recently reported.545 The MTD was 150 mg/m2/w and the overall response rates were 86% (complete, 41%) in 22 stage III or IV disease patients and 62% (complete, 25%) in 16 recurrent-disease patients. This encouraging phase I work led to a phase II trial integrating this regimen with concurrent radiotherapy in 25 patients with locally advanced disease.546 Although only 18 of the 25 patients were evaluable, all evaluable patients achieved a complete response and 13 were alive and disease-free at a median follow-up of 16 months. These results appear superior to historic results with systemic therapy and previous intra-arterial therapy trials. Future phase III trials will be required to determine whether this approach is superior in terms of survival to systemic chemotherapy. IMMUNOBIOLOGIC THERAPY Immunotherapeutic approaches to head and neck cancer have been disappointing, including early studies of bacille Calmette-Gurin (BCG), thymosin, Corynebacterium parvum, and levamisole,547552 and more recent studies of cytokines, differentiation agents, and plasma exchange.54,82,112,355,553557,559562 The most studied approach in this disease has involved IFN-based combinations, producing limited activity and poorly tolerated toxicity.440,563570 GENE THERAPY/TARGETING Active communication between bench and bedside is necessary to alter our understanding and produce progress toward the management of patients afflicted with head and neck squamous cancers. Without question, gene therapy has provided an example of the ability to translate basic to clinical studies. Preclinical analysis of gene transfer strategies for this malignancy showed that the adenoviral vector delivery of the wild-type p53 gene reduced tumor growth in xenographic mouse models independent of the endogenous p53 genotype of these cancers.105,571 A single-institution dose-escalating phase I trial in squamous carcinoma of the head and neck with Ad5CM p53 demonstrated dose-dependent biodistribution of unmodified vector in plasma and urine following intratumoral injections. Antitumor activity of direct injected tumors and tolerance

CHAPTER 86 / Head and Neck Cancer 1203

of Ad5CM p53 as a surgical adjuvant were observed.572 In phase II multicenter trials, tolerability was highly accepted with adverse events most related to pain, fever, or chills. Clinical improvement of qualityof-life systems has been documented as well as antitumor activity in recurrent/refractory squamous carcinoma head and neck patients.105 In addition, the phase I trial in squamous carcinoma of the head and neck also investigated Ad5CMV p53 as a surgical adjuvant with encouraging preliminary observations considering this approach.573 Phase III studies are now being initiated in multiple approaches including advance refractory head and neck cancer and surgical adjuvant approaches. Phase I and II trials of a selectively replicating adenovirus (ONYX-015) in single modality and in combination modality with chemotherapy with recurrent head and neck cancer have also been performed. The basis of these studies is that the ONYX-015 is an E1B gene-deleted adenovirus that replicates in and destroys cancer cells lacking p53 function and has been demonstrated to replicate in p53 mutant tumors in patients. Investigators have demonstrated in phase I and II studies that intratumoral injection was well tolerated and induced tumor regressions in approximately one-third of refractory head and neck cancer patients treated daily for 5 days.105 In another phase II trial, intratumoral ONYX-015 in combination with cisplatin and 5-fluorouracil has shown significant responses in over 60% of patients and is now being initiated in phase III randomized trials.574 Other exciting developments in head and neck cancer are likely to be initiated due to the lack of treatments available to patients with refractory of recurrent head and neck cancer and the ready ability to biopsy as well as access patients with recurrent local regional disease. In addition, studies that are targeting immune modulation approaches in head and neck cancer are also being initiated. Vaccine approaches with modulation of cytokine expression through a variety of mechanisms including gene therapy, dendritic cell stimulation, and activated T-cell infusions are all being considered as potential strategies for patients with head and neck cancer. Continued thoughtful approaches to the clinical dilemmas associated with head and neck cancer patients and realistic expectations of these investigation approaches are necessary for continued progress. PRIMARY CHEMOTHERAPY Although chemotherapy has not improved the short survival of patients with recurrent or metastatic HNSCC, promising results are beginning to emerge from the intense study of chemotherapy as an adjunct to standard primary treatment (surgery and/or radiotherapy) of advanced local disease. A patients prognosis and treatment depend on the primary tumor site and TNM stage. Primary chemotherapy is not called for in early-stage (T12N0M0) disease, usually cured through standard treatment. After cure, early-stage patients require chemoprevention, however, because of their high risk of second primary tumors.5 Chemotherapy can play a role in the primary treatment of more than 60% of all HNSCC patients or those who are diagnosed with advanced or extensive (T34N23M0) local/regional disease. This is so because advanced HNSCC is both a local/regional and a systemic phenomenon. Although optimal surgery or radiotherapy has improved local or regional control, it has not improved survival. Two years after standard treatment, clinical evaluations indicate that less than 40% of these patients will be disease-free: local invasion and regional lymph node metastases are diagnosed in 60% and distant metastases in 15 to 25%.575 The rate of distant metastases is actually far greater. Autopsy series show that occult distant metastases are present in up to 50% of HNSCC fatalities.241,576581 Severe morbidities after surgery, high mortality rates, and the poor outcome of chemotherapy for recurrent tumors led to clinical investigations of many therapeutic variations of primary chemotherapy. These approaches fall into three main categories: (a) neoadjuvant or induction chemotherapy (before standard surgery and/or radiotherapy), (b) maintenance, or true adjuvant, chemotherapy (following definitive standard primary therapy), and (c) concomitant or alternating chemotherapy (in combination with radiotherapy, usually in unresectable HNSCC). The principal goals of primary chemotherapy in

1204 SECTION 27 / Neoplasms of the Head and Neck

HNSCC are to enhance local/regional control (relapse prevention, organ preservation, and primary curative treatment), decrease distant metastases, and improve overall survival. Many reports have used the terminology of primary chemotherapy loosely. Some authors refer to adjuvant chemotherapy as any and all primary chemotherapy.186,257,433 They intend this phrase merely to distinguish it from the treatment of recurrent disease. However, we distinguish among neoadjuvant, adjuvant, and concomitant chemotherapy. We use the term adjuvant chemotherapy only to refer to prevention of relapse after standard therapy. Neoadjuvant chemotherapy refers specifically to tumor reduction prior to definitive therapy, and concomitant or alternating chemotherapy applies to chemotherapy given concomitantly with radiotherapy intended to achieve definitive control of local, regional, and micrometastatic disease. Although many phase II studies of chemotherapy in HNSCC have been conducted, the great heterogeneity of head and neck disease and patient populations mandates controlled trials to establish the role of chemotherapy. Innovative single-arm phase I and II trials are important, however, for testing promising new agents and combinations before phase III study. The following discussion focuses primarily on results from randomized phase III chemotherapy trials in primary HNSCC. The problem of small trial populations and heterogeneous tumors creates the need for multicenter cooperative studies in HNSCC. NEOADJUVANT THERAPY Neoadjuvant (induction) therapy prior to surgery is sometimes referred to as sequential chemoradiotherapy when chemotherapy is followed by definitive radiotherapy. This latter approach specifically excludes or limits the extent of surgery, except in treatment failures, and is growing in importance as an organ preservation approach for locally advanced resectable disease. The neoadjuvant concept has been expanded to include novel studies of neoadjuvant chemotherapy followed by concomitant chemoradiotherapy.582 The use of chemotherapy as induction treatment prior to local therapy for advanced HNSCC has been evaluated for over 15 years.433,455,456,583589 The strong rationale for this approach comes from mathematical models of cell kinetics and acquired drug resistance and from preclinical in vivo data.590 The principal objectives of induction are as follows: to promote regression and thereby enhance subsequent local/regional therapy, to identify patients with responding lesions that might be controlled by more conservative local treatment (organ preservation) rather than by extensive surgical procedures, to use chemotherapy before tumor and normal vasculature was altered by surgery or radiation, to identify responding tumors that may benefit from adjuvant chemotherapy following surgery or radiotherapy,438 and to provide early treatment for micrometastatic disease. Early nonrandomized neoadjuvant trials based their selections of agents on trials in recurrent disease. Single-agent early trials achieved response rates of 30 to 40%.456,465 Gradually, neoadjuvant studies expanded to include multi-agent therapy.456 The first major advance of chemotherapy in this area came in the late 1970s when Randolph and colleagues492 and Wittes et al.456 reported a 71% objective response rate (20% complete responses) in 21 HNSCC patients receiving cisplatin and continuous-infusion bleomycin. Single-arm studies that followed and confirmed Randolphs initial report achieved overall response rates in advanced untreated HNSCC ranging from 37 to 87%, including complete response rates of approximately 20%.505,585,586,592594 The addition of other drugs to cisplatin/bleomycin to create three- and four-drug regimens produced significant increases in toxicity without improving response or survival rates.455,465 The next advance occurred in the early 1980s when Wayne State investigators reported a neoadjuvant trial of cisplatin infusional 5-fluorouracil, which produced a response rate of 88% (complete, 54%). The unprecedented complete response rate of greater than 50% was perhaps the most important finding because of the significant impact complete responses have on survival. Wayne State data suggested that 5-fluorouracil was better given for 5 days than for 4 days and that three cycles were significantly more active than were two; their complete response rates doubled between the second and third cycles.502,595,596

Recent study suggests that complete response rates continue to increase from cycle 3 to 5. Subsequent studies used a variety of doses and schedules of cisplatin and 5-fluorouracil and confirmed the activity of this combination, although generally at lower objective (mean, 77%; range, 38 to 100%) and complete (mean, 34%; range, 13 to 54%) response rates.433,482,502 The RTOG used the Wayne State regimen and corroborated its activity by achieving a 38% complete response rate. More recently, many uncontrolled trials have attempted to further enhance the activity of cisplatin/5-fluorouracil. They have given highdose cisplatin with fixed-dose 5-fluorouracil; high-dose 5-fluorouracil with fixed-dose cisplatin; cisplatin intra-arterially rather than intravenously; other cytotoxic drugs, such as bleomycin, methotrexate, cyclophosphamide, mitoguazone, or Vinca alkaloids; and dose-intensive multi-course alternating regimens.482,502,597599 These trials have produced increased toxicity and no consistent improvements in response or survival. Phase II and III trials of carboplatin/5-fluorouracil yielded response rates of 70 to 80% (complete in 30 to 40%)results comparable to those of cisplatin/5-fluorouracil.475,512 Randomized trials of neoadjuvant therapy versus standard local therapy have been conducted with single- and multi-agent regimens. Eight of these trials using single-agent neoadjuvant treatment have been reported. All used methotrexate (standard or high dose with leucovorin). The only trial reporting significantly improved survival used methotrexate intra-arterially in SCC of the oral cavity, oropharynx, and maxillary antrum.600 Twenty-nine randomized multi-agent trials of neoadjuvant therapy without (21 trials) or with (8 trials) adjuvant chemotherapy compared with local therapy control groups have been reported to date. Although none has shown that neoadjuvant therapy significantly improves survival, many of these trials had major design limitations, including suboptimal patient numbers, relatively inactive induction regimens (median complete response rate under 20%), variations in local/regional therapies (surgery alone, surgery and radiotherapy, radiotherapy alone) and heterogeneous study populations with multiple primary sites, and resectable and unresectable cases. None of the neoadjuvant regimens produced a complete response rate of over 50%. Twenty-one of the 29 randomized studies had such small study numbers (fewer than 75 patients per arm) that they could not detect significant survival differences below 25%. Organ preservation is second to improving survival as a goal of primary chemotherapy. Those patients fortunate enough to survive their cancer often face a lifetime of significant morbidity because of cosmetic and functional debilities from surgical resection. Despite marked advances in reconstructive surgery and rehabilitation, patients who have undergone laryngectomy, glossectomy, or composite resection still have major debility. Unfortunately, the importance of organ and function preservation often is ignored. Many opt to receive the less effective therapy of radiation alone to avoid curative surgery.259 They risk shorter survival rather than face increased survival with severe surgical morbidity. An active area of HNSCC research involves chemoradiotherapy (sequential or concomitant) to facilitate organpreserving approaches for advanced disease. This research is designed to preserve anatomic structures without compromising survival. In such studies, extensive surgery is reserved to salvage patients who fail to respond to initial therapy or who recur. Laryngeal preservation is the most advanced application of organ preservation chemotherapy. In advanced laryngeal SCC (T3 or T4, and/or nodal metastasis), total laryngectomy improves survival at the price of impaired speech, and up-front irradiation preserves the voice at the price of a decreased chance of survival. Survival remains low with strategies to combine radiotherapy and surgery because of the high frequency of local/regional and distant recurrence. Loss of natural speech, of course, is the chief forfeit of surgery for laryngeal cancer. Laryngectomy also can result in the need of a neck stoma (for breathing), an inability to smell or sneeze, a diminished sense of taste, and problems with swallowing. Cosmetic and psychological consequences can be great. Although preservation of the voice long has been an important goal of the treatment of these patients, interest in the issue has heightened over recent years. A trend of decreasing use of radical surgery so as to

preserve normal function and improve quality of life is developing in a variety of other solid tumor settings as well. Two examples are limb preservation in osteosarcoma and breast preservation in breast cancer. Based on promising pilot data587,597,601 in 1985, the Veterans Affairs Cooperative Studies Program (VACSP) initiated a multi-institutional randomized prospective trial that attempted laryngeal preservation in previously untreated patients with locally advanced resectable laryngeal cancer (Fig. 86.9).429 Patterns of treatment failure differed (Table 86.28). At a median follow-up of 8 years, an increased local/regional recurrence rate and a decreased distant metastasis rate were seen in the sequential chemoradiotherapy group in comparison with the surgery-radiotherapy group. The findings also indicated that delay of definitive local therapy in chemotherapy nonresponders was not detrimental. Chemotherapy responders and nonresponders in the experimental arm had about the same rate of survival. Eight-year rates were similar (approximately 30%) in the two study arms, and laryngeal preservation was achieved in over 60% of the chemotherapy recipients. Sequential chemoradiotherapy was least effective in advanced local (T4) and regional disease (N2, N3); over 50% of these patient subgroups required salvage laryngectomy.429 These long-term results from the large VACSP trial indicate that sequential induction chemotherapy and definitive radiotherapy can be an effective strategy for achieving laryngeal preservation in a high percentage of patients without compromising overall survival. The trials success argues strongly for adoption of this new treatment strategy in order to spare patients the functional, psychological, and cosmetic deformities resulting from total laryngectomy. Although the VACSP study shows that induction chemotherapy plus radiotherapy is as effective as the previous standard treatment of surgery and postoperative radiotherapy, the question of what role chemotherapy actually plays has been raised. Does it add efficacy or is it merely predictive? For certain laryngeal cancer subsets such as T3N0 glottic tumors, it appears that definitive radiotherapy alone with surgery held in reserve as a salvage gives essentially the same results as either arm of the VACSP study and is much more cost-effective.579 Considerations of cost are becoming important in an increasingly managed care environment. There is currently a Head and Neck Intergroup randomized trial for stage T23N03 tumors of the supraglottic and glottic larynx that compares radiotherapy alone versus concomitant radiotherapy and cisplatin versus the VACSP cisplatin/5-fluorouracil radiotherapy experimental arm that addresses this question. Two recent European phase III trials add further support to this organ preservation approach. A French trial had a design similar to the VA trial, except that it used carboplatin instead of cisplatin and included all head and neck cancer subsites. The local/regional therapy was surgery and/or radiotherapy, determined by the treating physician. Patients were assigned randomly to chemotherapy followed by standard local therapy (in 152 patients) or standard local therapy alone (154 patients). The neoadjuvant carboplatin plus 5-fluorouracil produced overall and complete response rates of 57% and 31%, respectively. The chemotherapy-radiotherapy arm produced an increased 4-year survival rate (49% vs. 38%, p = .053) and organ preservation rate (48% vs. 20%, p 5 .001), compared with the standard local therapy arm.430

CHAPTER 86 / Head and Neck Cancer 1205

Table 86.28. Veterans Affairs Cooperative Studies Program Trial in Laryngeal Cancer: Patterns of First Site Failure
Failure Site/ Type Surgery + Radiotherapy Chemotherapy + Radiotherapy

Local recurrence Regional recurrence Distant metastasis Second primary tumor Total

4 9 29 10 52 (31%)

20 14 18 3 55 (33%)

The EORTC reported the most recent phase III trial. This trial randomized 197 patients with locally advanced hypopharyngeal cancer: 100 patients were randomized to chemoradiotherapy with cisplatin/5fluorouracil and 97 to standard local therapy of total laryngectomy, partial pharyngectomy, and radical neck dissection and postoperative radiotherapy. In this study, patients in the neoadjuvant arm who achieved less than a complete response after two cycles of cisplatin/5fluorouracil underwent immediate surgical therapy as outlined in the standard arm. At a follow-up of 3 years, survival rates were similar in the two arms and 28% of patients in the neoadjuvant arm were alive, were disease-free, and had preserved their larynxes.294 Future trials aimed at laryngeal preservation will need to establish chemotherapy regimens that achieve higher complete response rates, investigate innovative fractionated-radiation schemes, and assess concomitant chemoradiation programs (approaches detailed elsewhere in this chapter). Promising new combinations are being tried to overcome the major disappointment of neoadjuvant chemotherapeutic approaches; that is, despite achieving high response rates of 70 to 90% (20 to 40% complete) in advanced untreated patients, neoadjuvant chemotherapy has not translated into improved survival.586,593,608,672 Data suggest that neoadjuvant regimens capable of significantly improving survival must be able to produce reproducible complete response rates of over 50%. So far, complete response rates in phase II trials have appeared to be inflated and always drop in phase III trials. Although developed most often in recurrent disease, promising new dose-intensive regimens are designed for later integration into primary chemotherapy. The following discussion includes trials of new combinations in both the recurrent-disease and neoadjuvant settings. Preclinical data suggested a promising new line of work to potentiate 5-fluorouracil cytotoxicity.569,604606 Laboratory studies indicate that 5-fluorouracil resistance can be overcome by adding reduced folates (e.g., leucovorin) before 5-fluorouracil exposure due to enhanced stability of the active ternary complex with thymidylate synthase. Although still in development, combined leucovorin with cisplatin and 5-fluorouracil (PFL regimen) has already produced the highest complete response rates reported in locally advanced HNSCC. Vokes and colleagues were among the first to test this concept clinically in HNSCC.605 Using a variation of the PFL regimen in untreated

Figure 86.9. Veterans Affairs Laryngeal Cancer Study Group trial schema: induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer (see text).

1206 SECTION 27 / Neoplasms of the Head and Neck

advanced disease, investigators from the Dana-Farber Cancer Institute gave high-dose leucovorin (500 mg/m2/d for 6 days), cisplatin (25 mg/m2/d for 5 days), and 5-fluorouracil (800 mg/m2/d for 5 days), all by continuous infusion, starting the 5-fluorouracil 24 hours after the cisplatin and leucovorin.607 Preclinical data suggested that prior exposure to cisplatin and leucovorin enhanced the cytotoxicity of 5-fluorouracil. The striking finding in this phase II study was an apparent shift in the degree of response. The 80% objective response rate is in line with cisplatin/5-fluorouracil and other cisplatin-based regimens; however, the overall clinical complete response rate was 66%, the highest complete response rate reported to date with any chemotherapy regimen in advanced HNSCC. The clinical complete response rate at the primary site was 77%, and 74% of these patients had a pathologic complete response. The clinical complete response in the regional (neck) nodes was 67% (83% in N2 and 46% in N3 disease). Toxicities were notable, including moderate to severe mucositis in 94% of patients, nausea and vomiting in 37%, and diarrhea in 17%, necessitating dose reductions after the first cycle in 31% of patients. Rash developed in 26% but significant myelosuppression was uncommon (less than 10%). As with the cisplatin/5-fluorouracil regimen, three cycles were critical in PFL administration; the complete response rate jumped from 26% to 66% with the third cycle. PFL has now been studied extensively over the past 6 years with conflicting results. A recent phase II study from the Memorial SloanKettering Cancer Center and M.D. Anderson Cancer Center did not confirm the initial promising PFL results: compared with prior experience with cisplatin/5-fluorouracil, this study found no increase in complete or overall response rates but greatly increased the toxicity.608,609 More than 10 phase II studies of various PFL regimens have now been reported, producing an overall median complete response rate of approximately 40%, which appears to represent a modest improvement over the 30% complete response rate generally observed with other cisplatin-based regimens, including cisplatin/5-fluorouracil. To date, only one randomized trial involving PFL has been reported. This small study (55 patients) from Argentina compared cisplatin/5-fluorouracil with PFL and reported no difference in complete and overall response rates or survival.610 The overall (and complete) response rates for cisplatin/5-fluorouracil were 65% (15%) compared with respective figures for PFL of 68% (13%). Toxicity was substantially increased, however, in the PFL arm. The addition of IFN- to cisplatin/5-fluorouracil (PFI) in various doses and schedules of all three agents has been tested in five uncontrolled trials. Although not having major clinical activity in advanced disease by itself, IFN- has been shown in vitro to potentiate the activity of both fluorouracil and cisplatin in some systems. The phase II results in recurrent disease overall indicate response rates and survivals similar to those of cisplatin/5-fluorouracil.611 Vokes et al. have extended this approach to add IFN- to PFL.569 Although producing a high rate of severe toxicity, recent results in a series of 71 mostly stage IV patients are impressive, with an overall response rate of 100% and a complete response rate of 51%. CONCOMITANT CHEMORADIOTHERAPY Concomitant chemoradiotherapy is the most promising primary chemotherapy approach to prolonging the survival of patients with locally advanced resectable and unresectable disease. It is the only systemic approach consistently shown to improve local/regional control and survival in randomized trials. Schedules of concomitant chemoradiotherapy can be synchronous, with both modalities administered close together or alternating, with both administered in a nonoverlapping fashion. Both of these schedules offer distinct therapeutic advantages over regimens of strictly sequential treatment. Radiotherapy and chemotherapy given concomitantly is a doseintensive approach that exploits the independent complementary activity of radiotherapy locally and chemotherapy distantly (spacial cooperation) and the potentially enhanced local activity (within the radiotherapy field).605,612,613 Chemoradiotherapy approaches must attempt to incorporate full doses of both modalities. Suboptimal doses and/or schedules of either (e.g., low-dose cisplatin or split-course

radiotherapy) compromise dose intensity and, ultimately, survival. Dose intensities possible with concomitant chemoradiotherapy are higher in 2 to 3 months than those allowed by sequential chemoradiotherapy given over twice the time. Even if no direct drug radiation synergy occurs, concomitant therapy should produce additive effects and avoid critical delays of either therapy. Unfortunately, the concomitant approach incurs severe toxicity (primarily mucositis), which is difficult to balance effectively with desired activity.605,614617 Concomitant single-agent chemoradiotherapy has been under investigation in head and neck cancer for over three decades. Numerous phase II trials have reported encouraging but inconclusive results. All cytotoxic drugs with major activity in this disease have been studied.605,613 Frequently, these have been administered in low doses during full-course conventional radiotherapy. The phase III trials are listed in Table 86.29. Bleomycin, an active single agent and radiosensitizer, has been included in numerous single-arm trials. Nine randomized studies of this drug alone with concomitant radiotherapy have been published. Of the four trials with relatively large study cohorts (exceeding 100 patients), two reported significant long-term survival improvements in the concomitant arm.618,619 A key feature of one positive trial was the use of very low-dose bleomycin, suggesting that the subtherapeutic dose of bleomycin enhanced radiosensitivity of the tumor.618 5-Fluorouracil, a radioenhancer in vitro620 and active also in head and neck cancer, has been tested in four randomized trials. All four trials observed improvements in disease-free and overall survival, which were statistically significant in three and two trials, respectively. The most recent phase III trial was a Canadian NCI-sponsored trial of 5fluorouracil in 175 patients.621 Patients with stage III disease were randomly assigned to radiotherapy either with 5-fluorouracil (1.2 g/m2/d) or saline (placebo) as a 72-hour infusion given in weeks 1 and 3 of radiotherapy. The complete response rate was higher in the 5-fluorouracil than in the placebo group (68% vs. 56%, p = .04). With minimum and median study follow-up times of 2 and 3.5 years, the median overall (p = .08) and progression-free (p = .06) survival rates favored the 5-fluorouracil group. Toxicity was also significantly greater in the 5-fluorouracil arm but did not interfere with radiation delivery. Methotrexate, a drug that produces severe mucositis at full doses (especially when combined with radiotherapy),506 was evaluated in two randomized trials. The largest concomitant trial622 gave only two doses (100 mg/m2 on days 0 and 14 with leucovorin rescue in selected patients with elevated methotrexate serum levels) along with nonstandard radiotherapy (40 to 55 Gy radiotherapy in 15 to 16 fractions over 3 weeks). At a median follow-up of 32 months, relapse-free (p, .016) and overall survivals (p = .075) were better in the methotrexate arm. The improvements in local control (p = .002) and survival (p = .009) were most striking in the oropharyngeal subset. The need for salvage surgery also was reduced in the methotrexate arm. Furthermore, toxicity was equivalent in the two treatment arms. Hydroxyurea is a ribonucleotide reductase inhibitor with S-phasespecific cytotoxicity440,605 and single-agent activity in HNSCC (see Table 86.24). Stefani and colleagues conducted the largest randomized, placebo-controlled trial of concomitant hydroxyurea and radiotherapy and found no increase in response or survival with this combination. Toxicity and distant metastases were increased in the concomitant arm. Mitomycin C, a bioreductive alkylating agent, is differentially metabolized, is selectively toxic to hypoxic (radiotherapy-resistant) cells, and produces little mucositis, which provides a favorable toxicity profile for chemoradiotherapy studies. Weissberg and colleagues reported a randomized comparison in HNSCC of radiotherapy alone versus radiotherapy plus mitomycin.623 Mitomycin was given at a dose of 15 mg/m2 on the fifth day of radiotherapy and in some cases on a second occasion 6 weeks later. Despite limited single-agent activity in HNSCC, at a median follow-up exceeding 5 years, the actuarial disease-free (p = .07) and local/regional disease-free (87 vs. 66%, p = .02) survivals were higher in patients treated with mitomycin. Cisplatin is ideal for concomitant chemoradiotherapy in HNSCC. It has established single-agent activity and synergistic interaction in vitro and nonoverlapping toxicities (no mucositis) in vivo with radiotherapy.624,625 Cisplatin recently received extensive clinical evaluation

in concomitance with radiotherapy. Despite high complete local control rates from phase II trials, study follow-ups are short and the impact on disease-free and overall survival is unclear. The optimal dose, schedule, and sequence of cisplatin with radiotherapy have undergone extensive evaluation.521,624,626,627 Preclinical (in vitro and in vivo) and clinical chemoradiotherapy data suggest that cisplatin used predominantly as a cytotoxic agent (large and infrequent doses) is more active than cisplatin used predominantly as a radiosensitizer (small and frequent weekly or daily doses). The clinical data are more difficult to sort out, inasmuch as they are based on comparisons of dose and schedule from many uncontrolled single-institution trials of heterogeneous and small patient groups and multiple variables (different doses, schedules, and routes of cisplatin administration; differing schedules, fractionation programs, and total doses of radiotherapy). The many dose-schedule clinical trials of cisplatin with irradiation suggest that cisplatin at 100 mg/m2 on days 1, 22, and 43 of radiation treatment is most promising, mostly based on a large cooperative group phase II trial with long-term follow-up.628 Fifty-eight percent of the patients received adequate radiotherapy (more than 64.5 Gy) and the full three cycles of cisplatin. The complete response rate was 71% and the 3-year absolute survival was 43%results superior to those in historic controls (radiotherapy only). Acute and chronic toxicities were acceptable. The activity of intermittent standard- or high-dose cisplatin regimens is further supported by evidence that it can salvage patients who fail to respond to induction therapy with cisplatin and infusion 5-fluorouracil.629 Some recent single-arm work suggests that local control rates may be further improved with regional or higher dose cisplatin and hyperfractionated or accelerated radiotherapy schedules. Carboplatin has not yet received adequate clinical evaluation in concomitance with radiotherapy.624 Preliminary data limited to five phase I/II trials with differing doses and schedules of carboplatin and of radiotherapy in unresectable disease have produced complete responses in the range of 50 to 70%. These carboplatin trials included patients with more advanced primary and nodal stage disease than many concomitant cisplatin trials.628 Further study to establish optimal doses and schedules is needed. The same RTOG concomitant cisplatin radiotherapy regimen628 has been tested in 27 locally advanced NPC patients (26 stage IV). The complete response rate was 89%; disease-free and overall survival rates were higher and distant metastasis rates lower than those of historic controls (radiotherapy alone) from the RTOG database.630 An intergroup study by Al-Sarraf and colleagues showed that radiotherapy with concomitant chemotherapy was markedly superior to radiotherapy alone in nasopharyngeal cancer patients.631 In a randomized phase III trial, investigators from the SWOG, the RTOG, and the ECOG treated 194 patients with radiotherapy or radiotherapy with concomitant cisTable 86.29.

CHAPTER 86 / Head and Neck Cancer 1207

platin/fluorouracil chemotherapy. In the patients receiving radiotherapy alone, 24% maintained progression-free survival after 3 years, compared to 69% of the chemoradiotherapy group (p = .001). Further, the 3-year survival rate was 47 versus 78, respectively (p = 0.05).403 Pure radiosensitizer trials (i.e., drugs without independent activity in HNSCC) have been generally negative.166,631 Misonidazole, the best studied agent in this class, has achieved no improvement in survival in several randomized trials in a total of over 1,000 HNSCC patients.166 A recent double-blind, randomized Italian study of lonidamine with or without hyperfractionated radiotherapy reported improvements in complete response, response duration, and local control.632 The estimated 2-year disease-free survival was 51% in the lonidamine arm versus 25% without the drug. Concomitant multi-agent chemoradiotherapy began as a result of positive studies with concomitant single-agent chemotherapy and radiotherapy. The primary goal of these combined-agent trials was to reduce distant failures, which seem to be resistant to single-agent chemoradiotherapy; the secondary goal is to further enhance already excellent local control rates with concomitant approaches. Due to acute toxicity (mucositis), many trials used split-course radiotherapy, in which a period (or cycle) of concurrent chemoradiotherapy is followed by a planned interruption in all therapy to allow time for normal-tissue recovery. Much of this work has been done in phase I/II feasibility trials designed to sort out issues of maximized dose intensity and minimized normal tissue toxicity. A popular variant of, or hybrid between, synchronous and sequential combined-agent chemoradiotherapy is the alternating approach.617,633 Its rationale is based in part on preclinical in vivo work (murine model), indicating that the approach reduces normal-tissue toxicity and, therefore, represents a compromise between synchronous and sequential chemoradiotherapy. A distinct advantage of single-agent over combined-agent concomitant trials is the simplicity of study design and more effective (continuous, uninterrupted) conventional or hyperfractionated radiotherapy. The split-course radiotherapy necessary with combined agents is inferior to uninterrupted radiotherapy. The rationale for pursuing combined-agent trials is based on the assumption that combined agents are better than single agentsan assumption that has not been proved in HNSCC. Survival rates with single-agent cisplatin are equivalent to those of any combination chemotherapy. Combinedmodality approaches requiring reduced dose intensities of cisplatin may produce results inferior to cisplatin alone at high doses. Cisplatin-based concomitant multi-agent regimens have been studied in several recent phase II trials. An increasing trend toward employing combinations of cisplatin and 5-fluorouracil with conventional or hyperfractionated split-course radiotherapy has been

Phase III Studies of Concomitant Single-Agent Chemotherapy (CT) and Radiotherapy (RT) in Head and Neck Cancer
% Complete response rate % Disease-free survival (yr) RT RT + CT RT % Survival (yr) RT + CT

Drug/Author

RT

RT + CT

Bleomycin Shanta620 Vermund669 Fu619 5-Fluorouracil Methotrexate Gupta623 Hydroxyurea Stefani668 Mitomycin C Weissberg324

157(oc) 222 104

19 58 45

79* 63 67

17(5) 58(5) 26(5)

72* 53 64*

24(5) 42(5) 14(5)

66* 38 28

313 126 117

47

42

48(5) 31(2) 49(5)

60* 22 75

27(5) 51(2) 40(5)

42 29 48

*p < .05. Published or estimated from data/survival curves. Overall survival (p = .075); oropharyngeal (p < .002). p < .07. RT = radiotherapy; CT = chemotherapy; = not available; oc = oral cavity.

1208 SECTION 27 / Neoplasms of the Head and Neck

reported.337,617,634638 Preclinical studies have demonstrated synergistic interactions between any two of these three treatments. Doses and schedules of cisplatin, 5-fluorouracil, and radiotherapy have varied considerably. The modulation of 5-fluorouracil by leucovorin and hydroxyurea as part of concomitant chemoradiotherapy regimens is under study.604,639641 Taylor and colleagues administered a regimen of concomitant cisplatin (60 mg/m2) and 5-fluorouracil (800 mg/m2 for 5 days) with conventionally fractionated (total 70 Gy) radiation given every other week for seven cycles.615,638 Results from 53 unresectable patients indicate a high rate of clinical complete (55%) and partial (43%) responses and a median failure-free survival of 51 months (range, 12 to 83). The overall median survival was 37 months. Further, survival of patients with a partial response to therapy was remarkably high and not significantly different from that of patients achieving a complete response. However promising they may be, studies of concomitant cisplatin, 5-fluorouracil (with or without modulators of 5-fluorouracil), and radiotherapy must be interpreted with caution in light of their radical designs and markedly increased normal-tissue toxicity. One study of alternating cisplatin/5-fluorouracil and hyperfractionated radiotherapy was terminated early because of excessive toxicity.634 Moreover, potential therapeutic gains with the concomitant regimen may be compromised by a significant decrease in the dose intensity of radiotherapy. Despite these potential drawbacks, the preliminary experience with concomitant cisplatin, 5-fluorouracil, and radiotherapy is promising and deserves future comparisons with conventional and hyperfractionated radiotherapy. These innovative concomitant approaches await confirmation of their efficacy in randomized trials. To date, there have been 15 phase III trials that have compared concomitant combination chemoradiotherapy with radiotherapy alone (in nine trials)403,637,642647 versus sequential chemoradiotherapy (in six trials).402,616,636,648650 Of the nine trials with radiotherapy-alone control arms, the majority reported improvement in survival using concomitant chemoradiotherapy. Of the six randomized trials comparing concomitant with sequential chemoradiotherapy, four reported significant improvements in diseasefree or progression-free survival and two reported significant improvements in overall survival. The most recently published trial compared sequential and concomitant cisplatin/5-fluorouracil in 214 patients.616 This trials major finding was a significant improvement in progressionfree survival (p = .03) in the concomitant arm due mostly to a reduction in the local/regional failure rate (55% vs. 39%). There were no significant differences in distant failure rates (only 7% and 10% in the concomitant and sequential arms, respectively) or in overall survival. Recently, several groups developed more intensive combination chemoradiotherapy approaches.651,652 Early results from these nonrandomized studies indicate that the severe toxicity may be balanced by improved survival results. Vokes et al.653 and Kies et al.654 have studied the administration of 5-fluorouracil plus hydroxyurea given synchronously with radiotherapy (FHX). FHX produced 23 complete responses in 24 stages II and III patients and a 2-year survival rate of 87%. Vokes has also applied this approach to stage IV disease. In a recent study, 71 patients were treated with FHX after PFLI (cisplatin, fluorouracil, leucovorin, interferon) induction. With a median followup time of 37 months, the 3-year disease-free and overall survival rates of 69% and 60% are far superior to historic figures for stage IV patients. However, toxicity was substantial: severe life-threatening mucositis and myelosuppression developed in 54% and 60%, respectively, and there were five treatment-related deaths. Adjuvant Chemotherapy. Adjuvant (maintenance) chemotherapy to eradicate micrometastases following local therapy (adjuvant therapy in the strict sense) has not been studied extensively in HNSCC.654 The principal objectives of adjuvant trials have been to control subclinical persistent disease after surgery or radiotherapy and to decrease the rates of local/regional and distant relapse. The ideal study design would include enrolment of (high-risk) patients with resectable advanced disease, early administration after local therapy to avoid drug resistance,

and an effective regimen. Although no study has met all of these criteria, promising leads for future studies have emerged. Seven randomized studies have evaluated the impact of adjuvant multi-agent chemotherapy with no clear survival impact: significant differences occurred in two trials (Table 86.30), one small positive trial,655 and one large negative trial of delayed adjuvant therapy.656 The most recent phase III trial was a Japanese multicenter study of uracil plus tegafur for 1 year in 398 patients with resectable advanced head and neck cancer.657 The minimum study follow-up was 36 months at the time of the report. Although no significant differences in overall or disease-free survival occurred, this study did report a significant systemic effect of adjuvant therapy (compared with the control group) as indicated by a reduction in the rate of distant metastases (7.9% vs. 14.6%, p = .03). Neoadjuvant (or Concomitant) Plus Adjuvant Chemotherapy. This is perhaps the most important primary therapy study design (Table 86.31). The largest of these is an NCI-sponsored multi-institution trial, begun in 1978, called the Head and Neck Contracts Program (HMP).659,660 Over 400 patients with resectable stage III or IV disease were randomized to (a) induction chemotherapy (one cycle of cisplatin and bleomycin) followed by standard therapy (surgery and radiotherapy in all study arms); (b) induction chemotherapy followed by standard therapy followed by six cycles of adjuvant monthly cisplatin (80 mg/m2) by 24-hour continuous infusion; or (c) standard local therapy only. At a median follow-up of more than 5 years, the disease-free and overall survivals were not significantly different among the three arms. This study has been criticized because of its one cycle of induction chemotherapy, considered suboptimal (3% complete response, 34% objective response), and a striking noncompliance rate in the adjuvanttherapy arm (47% never received any maintenance therapy). Subset analyses of this study suggested improved disease-free and/or overall survival in three subgroups: oral cavity, T12 primary lesions, and N12 regional disease.659 An important aspect of the planned design of one study, the administration of adjuvant therapy only to those who responded to the chemotherapy, reported a definite disease-free survival improvement in the adjuvant arm.438 These promising results are not definitive in light of the extremely small sample size, but they do justify future large-scale study of this strategy. SUMMARY AND FUTURE DIRECTIONS Advanced local disease is the focus of primary chemotherapy investigation in HNSCC. Advanced local HNSCC is not controlled adequately by standard surgery and/or radiotherapy alone: 2-year disease-free survival after standard therapy is less than 40%. Preclinical work strongly supports the early integration of chemotherapy into the primary management of advanced HNSCC.440,590 Primary chemotherapy in HNSCC falls into three main treatment categories: (a) neoadjuvant chemotherapy, designed to reduce tumor burden prior to definitive local control; (b) concomitant chemoradiotherapy, designed to be a third definitive treatment (in addition to surgery and radiotherapy) for controlling advanced local HNSCC; and (c) adjuvant chemotherapy, designed to maintain or prevent recurrence in patients after definitive local control.
Table 86.30. Randomized Trials of Adjuvant Chemotherapy for Head and Neck Cancer
% Disease-free survival (yr)* Author N Adjuvant chemotherapy % Survival (yr)*

Control Chemo. Control Chemo.

Szpirglas552 Bitter656 Domenge657 Intergroup405

95(at fom) 33(oc) 287(ecs) 448

MIB (3-arm) MBO PBM PF

47 (2) 24 (3) (3)

52 68

58 (4) 29 (3) (3)

58 65

*Published values or estimated from published data/survival curves. Statistically significant. Statistically significant favoring control. at = anterior tongue; fom = floor of mouth; oc = oral cavity; ecs = extracapsular spread; M = methotrexate; B = bleomycin; P = cisplatin; I = leucovorin; = not available.

Major goals of the first treatment category, neoadjuvant chemotherapy, are to prolong disease-free and overall survivals and to improve the quality of life for surviving patients by providing effective organ preservation approaches for the control of advanced HNSCC. Data from the numerous phase I and II neoadjuvant studies reveal many positive features of this approach: multi-agent response rates of 70 to 90% (complete in 20 to 50%), with 30 to 70% of clinically complete responders having complete pathologic tumor regression in biopsies or surgical specimens. Initial tumor stage or extentwhether defined by overall stage, T stage, N stage, or resectabilityis predictive of response to chemotherapy and survival. Response to chemotherapy is predictive of response to radiotherapy. Further, chemotherapy responders have a better prognosis than do nonresponders,349,593 but whether this is a benefit of chemotherapy or a result of unknown factors in the responding subset of patients is not clear. Local/regional control is adequate with surgery or radiotherapy alone in selected patients who respond completely to induction. Induction chemotherapy does not significantly increase the toxicity of subsequent radiotherapy, surgery, or chemotherapy.660 Major concerns about the neoadjuvant approach are the possibilities of delaying and compromising definitive local therapy and the risk that responding patients may refuse definitive local therapy. Furthermore, neoadjuvant chemotherapy definitely prolongs the treatment course, is expensive, and compromises later palliative chemotherapy in recurring patients. Of the over 40 phase III trials incorporating neoadjuvant chemotherapy, only one (using single-agent regional chemotherapy) reported significantly improved survival over that of patients receiving standard local therapy.600 These trials were flawed in many aspects, including study size, heterogeneous patient populations/disease sites/local therapies, and ineffective chemotherapy (median complete response rate of 10% in trials). Two randomized neoadjuvant trials, the VACSP and a more recent trial by LeFebvre et al.,431 both of which had large sample sizes and relatively homogeneous patient populations (advanced operable laryngeal cancer patients) and a relatively effective regimen of chemotherapy (cisplatin and infusion 5-fluorouracil at full doses), have confirmed the efficacy of this approach for laryngeal preservation. Although the VACSP trial produced a respectable complete response rate, it did not increase survival. Still, neoadjuvant chemotherapy could not be evaluated as an independent variable because the local/regional treatments in the two study arms were not identical. Even so, this study achieved the positive results of laryngeal preservation in 60% of patients and a significant decrease in distant relapse rate in the neoadjuvant arm. Phase I and II trials must continue to translate the preclinical study data into trials of new, more active regimens. Regimens deserving further study include the taxane/cisplatin-based induction regimen, combined cisplatin/5-fluorouracil/leucovorin, and other combinations with such agents as IFN- and hydroxyurea that enhance 5-fluorouracil cytotoxicity. Neoadjuvant trials also should investigate the issue of optimal numbers of chemotherapy cycles on response (clinical/histologic) and on survival. Future work should study the integration of biologic response modifiers, EGF blockade, differentiation agents, other cytotoxic drugs (e.g., taxanes, ifosfamide), and irradiation into primary therapy.494,661,662 The second major category of primary chemotherapy is that of regimens designed to achieve definitive local and distant control. So far, concomitant chemoradiotherapy is the only approach in this category that has shown potential by increasing survival in randomized
Table 86.31.

CHAPTER 86 / Head and Neck Cancer 1209

testing. This survival benefit has appeared in trials in both resectable and unresectable HNSCC. Although early trials have used suboptimal intensities, concomitant chemoradiotherapy is designed ultimately to maximize dose intensities of both treatment modalities. All of the positive single-agent concomitant trials used suboptimal doses of active drugs (e.g., bleomycin and methotrexate) and full doses of relatively inactive drugs (e.g., mitomycin C). This indicates that chemotherapy enhances radiotherapy. Recent data from numerous phase II trials now support the promise of concomitant cisplatin/radiotherapy. The lack of overlapping toxicities allows the optimal administration of both modalities. Randomized trials are required, however. Concomitant multi-agent chemoradiotherapy (which includes synchronous therapy with split-course radiotherapy and alternating chemoradiotherapy) greatly increases acute toxicity and so requires creative study designs to make this approach feasible.663 The major problem with multi-agent regimens is the need to lower radiotherapys dose intensity, which compromises local control rates. Paradoxically, aggressive multi-agent chemoradiotherapy programs ultimately may be of decreased rather than increased dose intensity. Nevertheless, early results from many randomized trials are encouraging, with survival favoring the experimental (concomitant) arm in most of these studies. Six trials had no standard local-therapy-only arms. These studies have been criticized for comparing only two experimental arms. Although faulty, this study design has a silver lining: it has provided the best support for concomitant chemoradiotherapy.635,636,642,650 Before accepting concomitant chemoradiotherapy as standard, the results of these and other planned randomized trials (especially those with standard-therapy control arms) will need to mature with more patients, longer follow-ups, and more careful assessments of toxicity and quality of life. Concomitant therapy does appear to increase surgical complications, and clearly it has altered the natural history of locally advanced unresectable HNSCC. It has produced lower local/regional failure rates, which suggests that a direct chemotherapy-radiotherapy interaction occurs at primary sites. The lack of impact on distant relapse rates, however, suggests that concomitant chemoradiotherapy should be followed by adjuvant therapy, and support for this approach comes from randomized trials. A recent meta-analysis revealed that concomitant chemotherapy and radiotherapy significantly increases the morbidity of treatment but enhances tumor response and local control.343 No survival benefit is evident in trials of adjuvant chemotherapy, the third major treatment category. The adjuvant approach in HNSCC has not been adequately tested, however. Regimens, cycle number, and timing may not have been optimal; study size and stratification (e.g., by site and stage) have not been adequate to allow for this diseases heterogeneity; postoperative delays in initiating adjuvant therapy have compromised results; and toxicity and noncompliance rates have been uniformly high. In the HNCP study, nearly 50% of the patients randomized to adjuvant therapy did not receive any chemotherapy after surgery, and only 8% of all of the patients in the adjuvant arm completed the full six cycles.658 Still, this series produced a significant reduction in distant relapse rate, notwithstanding the inclusion of all of the many untreated patients in the analysis of this effect. This result underscores the potential value of adjuvant chemotherapy. The collective data suggest that adjuvant chemotherapy may be useful in the management of selected head and neck cancer patients:

Randomized Trials of Induction Plus Adjuvant Chemotherapy for Head and Neck Cancer
% Disease-free survival (yr)* % Survival (yr)* Control Chemotherapy Induction (schedule) % Response (complete) Local therapy Adjuvant (cycles)

Author

Control

Chemotherapy

Ervin439 HNCP659

114 462

PBML (2 cycles) PB (1 cycle)

78 (26) 37 (3)

S+R; R S+R

PBM (3 cycles) P (6 cycles)

61 (2) 55 (5)

84* 49-I64-Ad

35 (5)

37-I45-Ad

*Published values or estimated from published data/survival curves. M = methotrexate; P = cisplatin; L = leucovorin; S = surgery; R = radiotherapy; Ad = adjuvant; p = primary site.

1210 SECTION 27 / Neoplasms of the Head and Neck

8. 9.

those with disease in specific primary sites (e.g., the oral cavity), those with small-volume disease, and those with response who retain a high risk of relapse (see Tables 86.30, 86.31). The data indicate further that trials should incorporate active regimens of chemotherapy in the immediate postoperative period, either before or concomitant with radiotherapy. It also seems evident that large-scale studies designed to detect modest but clinically important survival differences will be required to test the role of adjuvant chemotherapy in HNSCC. The timing of therapy may be crucial. A novel strategy to circumvent the toxicity of adjuvant chemotherapy given after radiotherapy is adjuvant chemotherapy sandwiched between standard local therapies. This interposition of chemotherapy between surgery and radiotherapy is a carefully conceived strategy.664,665 Initiating chemotherapy after surgery means that tumor margins are not obscured by prior chemotherapy responses (nor in this protocol are they obscured by responses to prior radiotherapy). 12It eliminates the problem of patients who refuse surgery because they have responded to chemotherapy, and it allows chemotherapy to attempt its effect in an already debulked tumor. Drug delivery before radiotherapy is through an intact vascular supply. Furthermore, this approach avoids the expected toxicity of postirradiation chemotherapy. Ultimately, the optimum control of advanced HNSCC certainly may require primary chemotherapy in all three of its strategic roles (i.e., as neoadjuvant, concomitant, and adjuvant therapy). Meta-analysis, or analysis of pooled data from all randomized trials, reveals that concomitant chemotherapy has produced a significant reduction in local/regional failure.186 Unfortunately, the greatest hope for primary chemotherapythat it would eradicate systemic diseasehas not been fulfilled. This is so even though elegant mathematical and preclinical models support the early use of chemotherapy to eradicate micrometastases and, thus, to prevent distant relapse. Heterogeneous cancer cell populations and relatively low growth fractions may be the major hurdles to developing effective chemotherapy for this disease. Significant decreases429,658,664,666 and increases186,547,667,668 in distant relapse rates have been reported from the more than 50 phase III trials incorporating primary chemotherapy (see Tables 86.29, 86.30, 86.31). All types of analyses, including meta-analysis of the more than 50 trials, indicate that neither single- nor multi-agent regimens have consistently diminished distant relapse rates. Although overall results show no improvement, well-designed, large-scale, cooperative group trials achieved significantly reduced distant relapse rates.429,658,664,666,669 Through their large patient bases, these trials were able to show statistically significant, small improvements and, therefore, to suggest that currently available platinumbased chemotherapy may have clinically important, albeit modest, activity in micrometastatic disease. Future work should build on these findings and must continue to investigate further promising avenues, such as the use of bioadjuvant therapy using high-dose retinoid, IFN, and vitamin E to impact not only recurrence but also the development of second primary tumors in the systemic control of advanced HNSCC. REFERENCES
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80.

81. 82. 83.

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98. 99.

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