Management of Stage 0 Cancer Carcinoma in situ (stage 0) is treated with local ablative or extricative measures such as cryosurgery, laser

ablation, and loop excision. Surgical removal is preferred to allow for further pathologic evaluation in order to rule out microinvasive disease. Hysterectomy should be reserved for patients with other gynecologic indications to justify the procedure. After local treatment, these patients require lifelong surveillance. Management of Stage IA1 Cancer The treatment of choice for stage IA1 disease is surgery. Total hysterectomy, radical hysterectomy, and conization are accepted procedures. Lymph node dissection is not required if the depth of invasion is less than 3 mm and no lymphovascular invasion is noted. Selected patients with stage IA1 disease but no lymphovascular space invasion who desire to maintain fertility may have a therapeutic conization with close follow-up, including cytology, colposcopy, and endocervical curettage. Patients with medical comorbidities who are not surgical candidates can be successfully treated with radiation. According to National Comprehensive Cancer Network guidelines, pelvic radiation therapy is currently a category 1 recommendation for women with stage IA disease and negative lymph nodes after surgery who have high-risk factors, including large primary tumor, deep stromal invasion and/or lymphovascular space invasion.Management of Stage IA2, IB, or IIA Cancer For patients with stage IB or IIA disease, treatment options are either combined external beam radiation with brachytherapy or radical hysterectomy with bilateral pelvic lymphadenectomy. Radical trachelectomy with pelvic lymph node dissection is appropriate for fertility preservation in women with stage IA2 disease, and those with stage IB1 disease whose lesions are 2 cm or smaller. Most retrospective studies have shown equivalent survival rates for both procedures, although such studies usually are flawed because of patient selection bias and other compounding factors. However, a recent study showed identical overall and disease-free survival rates Current surgical guidelines for stage IA2 to IIA cervical cancers now allow for minimally invasive techniques such as traditional laparoscopic and robotically assisted laparoscopic techniques in the surgical management of these tumors. Indeed, it has been shown that these less morbid procedures are equally as effective in gaining adequate surgical margins and lymph node dissection, while gaining the added advantage of less surgical recovery time Analysis of women who underwent radical hysterectomy with lymphadenectomy, from the Surveillance, Epidemiology, and End Results (SEER) database, revealed that patients with node-negative, early stage cervical cancer who underwent a more extensive lymphadenectomy had improved survival.

Compared with patients who had fewer than 10 nodes removed, patients with 21-30 nodes removed were 24% less likely to die, and those with greater than 30 nodes removed were 37% less likely to die from their tumors. Quality-of-life data, particularly in the psychosexual area, is relatively scant. Postoperative radiation to the pelvis decreases the risk of local recurrence in patients with high-risk factors (positive pelvic nodes, positive surgical margins, and residual parametrial disease).[26] A randomized trial showed that patients with parametrial involvement, positive pelvic nodes, or positive surgical margins benefit from a postoperative combination of cisplatin-containing chemotherapy and pelvic radiation.[27] Postoperative radiation is also recommended in patients who have at least 2 intermediate risk factors, to include tumor size greater than 2 cm, deep stromal invasion, or lymphovascular space invasion. For patients with IB2 or IIA and tumors larger than 4 cm, radiation and chemotherapy is selected in most cases. There are risks associated with combined-modality therapy, but many of these patients will meet either intermediate- or highrisk criteria after radical hysterectomy. Management of Stage IIB-IVA Cancer For locally advanced cervical carcinoma (stages IIB, III, and IVA), radiation therapy was the treatment of choice for many years. Radiation therapy begins with a course of external beam radiation to reduce tumor mass to enable subsequent intracavitary application. Brachytherapy is delivered using afterloading applicators that are placed in the uterine cavity and vagina. Additionally, the results from large, well-conducted, prospective randomized clinical trials have demonstrated a dramatic improvement in survival with the combined use of chemotherapy and radiation.[28, 29, 30] Consequently, the use of cisplatin-based chemotherapy in combination with radiation has become the standard of care for primary management of patients with locally advanced cervical cancer.[17] Management of Stage IVB and Recurrent Cancer Individualized therapy is used on a palliative basis. Radiation is used alone for control of bleeding and pain symptoms, while systemic chemotherapy is used for disseminated disease.[31] For recurrent disease, the choice of therapy is influenced by prior treatments. Treatment of pelvic recurrences after primary surgical management should include single-agent chemotherapy and radiation, while treatment for recurrences elsewhere should include combination chemotherapy. For central pelvic recurrence following radiation, modified radical hysterectomy (if recurrence < 2 cm) or pelvic exenteration should be undertaken. For recurrent disease after chemotherapy and radiation, a disease-free interval of more than 16 months is considered to

designate the tumor as platinum sensitive and, therefore, more likely to respond to platinum-based chemotherapy.[37] Chemotherapy now consists of a platinum-based doublet, as a recent Gynecologic Oncology Group study compared the use of single-agent cisplatin versus the combination of cisplatin and paclitaxel for stage IVB cervical cancer in a randomized phase III study and found the combination to be superior to the single agent cisplatin.[38] Recent phase III trials have also shown that paclitaxel/cisplatin therapy is now considered the standard of care.[33, 34, 38, 39] The National Comprehensive Cancer Network (NCCN) also recommends bevacizumab, docetaxel, gemcitabine, ifosfamide, 5-fluorouracil, mitomycin, irinotecan, and topotecan as possible candidates for second-line therapy (category 2B recommendation), as well as pemetrexed and vinorelbine (category 3 recommendation). In addition, it should be noted that bevacizumab as single-agent therapy is also acceptable.[31] For recurrences in a previously irradiated field or for a disease-free interval of less than 16 months, a recurrence is less likely to respond to subsequent therapies, and these patients should be strongly encouraged to participate in clinical trials. Special efforts should be made to ensure comprehensive palliative care, including adequate pain control, for these patients. Complications of Radiation Therapy During the acute phase of pelvic radiation therapy, the surrounding normal tissues such as the intestines, the bladder, and the perineum skin often are affected. Acute adverse GI effects include diarrhea, abdominal cramping, rectal discomfort, or bleeding. Diarrhea usually is controlled by either loperamide (Imodium) or atropine sulfate (Lomotil). Small, steroidcontaining enemas are prescribed to alleviate symptoms from proctitis. Cystourethritis also can occur, which leads to dysuria, frequency, and nocturia. Antispasmodics often are helpful for symptom relief. Urine should be examined for possible infection. If urinary tract infection is diagnosed, therapy should be instituted without delay. Proper skin hygiene should be maintained for the perineum, and topical lotion should be used if erythema or desquamation occurs. Late sequelae of radiation usually appear 1-4 years after treatment. The major sequelae include rectal or vaginal stenosis, small bowel obstruction, malabsorption, and chronic cystitis. Complications From Surgery The most frequent complication of radical hysterectomy is urinary dysfunction as a result of partial denervation of the detrusor muscle. Other complications include foreshortened vagina, ureterovaginal fistula, hemorrhage, infection, bowel obstruction, stricture and fibrosis of the intestine or rectosigmoid colon, and bladder and rectovaginal fistulas. Other Procedures

Invasive procedures such as nephrostomy or diverting colostomy sometimes are performed in this group of patients to improve their quality of life. Total pelvic exenteration may be considered in patients with an isolated central pelvic recurrence. Nutrition Proper nutrition is important for patients with cervical cancer. Every attempt should be made to encourage and provide adequate oral food intake. Nutritional supplements such as Ensure or Boost are used when patients have had significant weight loss or cannot tolerate regular food due to nausea caused by radiation or chemotherapy. In patients with severe anorexia, appetite stimulants such as megestrol (Megace) can be prescribed. For patients who are unable to tolerate any oral intake, percutaneous endoscopic gastrostomy tubes are placed for nutritional supplementation. In patients with extensive bowel obstruction as a result of metastatic cancer, hyperalimentation sometimes is used. Prevention of Human Papillomavirus Infection Several measures are effective to prevent HPV infection and hence prevent cervical cancer. Sexual abstinence or barrier protection and/or spermicidal gels during sexual intercourse are protective. Evidence suggests that HPV vaccines prevent HPV infection. A vaccine for HPV, Gardasil, is approved by the FDA for girls and women 9 to 26 years of age for prevention of cervical cancer caused by HPV types 6, 11, 16, and 18.[40] The ACS recommends routine HPV vaccination for girls 1112 years old; catch up vaccination or completion of the vaccination series can be conducted up to age 18 years. The ACS found insufficient data to recommend for or against universal HPV vaccination in women 19-26 years of age, and the ACS recommends against vaccination after age 26 years. Screening for cervical cancer should continue in vaccinated women, following the same guidelines as in unvaccinated women. Medication Summary Chemotherapy should be administered in conjunction with radiation therapy to most patients with stage IB (high risk) to IVA. Cisplatin is the agent used most commonly, although 5fluorouracil also is used frequently. For patients with metastatic disease, cisplatin remains the most active agent. Topotecan, ifosfamide, and paclitaxel also have significant activity in this setting. The combination of topotecan and cisplatin improves overall survival. However, acute toxicities are also increased. Chemotherapy Agents These agents inhibit cell growth and proliferation. Cisplatin Intrastrand cross-linking of DNA and inhibition of DNA precursors are among the proposed mechanisms of action for cisplatin. This agent is used in combination with radiation therapy. Fluorouracil (Adrucil)

Fluorouracil is a pyrimidine antagonist. Several mechanisms of action have been proposed, including inhibition of thymidylate synthase and inhibition of RNA synthesis. This agent is also a potent radiosensitizer. Ifosfamide (Ifex) Ifosfamide forms DNA interstrand and intrastrand bonds that interfere with protein synthesis. Paclitaxel (Abraxane) The mechanisms of action of paclitaxel are tubulin polymerization and microtubule stabilization. Topotecan (Hycamtin) Topotecan inhibits topoisomerase I, inhibiting DNA replication. Patients who have received prior chemotherapy should be given a lower dose initially. Vaccines Two human papillomavirus (HPV) vaccines are now available for prevention of HPV-associated dysplasias and neoplasias, including cervical cancer, genital warts (condyloma acuminata), and precancerous genital lesions. The immunization series should be completed in girls and young women aged 9-26 years. Papillomavirus vaccine, quadrivalent (Gardasil) This quadrivalent HPV recombinant vaccine is the first vaccine indicated to prevent cervical cancer, genital warts (condyloma acuminata), and precancerous genital lesions (eg, cervical adenocarcinoma in situ; cervical intraepithelial neoplasia grades 1, 2, and 3; vulvar intraepithelial neoplasia grades 2 and 3; vaginal intraepithelial neoplasia grades 2 and 3) due to HPV types 6, 11, 16, and 18. Vaccine efficacy is mediated by humoral immune responses following the immunization series. Papillomavirus vaccine, bivalent (Cervarix) This recombinant HPV vaccine is prepared from the L1 protein of HPV types 16 and 18. It is indicated in girls and women (ages 10-25 y) for prevention of diseases caused by oncogenic HPV types 16 and 18 (ie, cervical cancer, cervical intraepithelial neoplasia grade 2 or higher, adenocarcinoma in situ, cervical intraepithelial grade 1).