Radiotherapy and Oncology xxx (2017) xxx–xxx

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Radiotherapy and Oncology

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Original article

Metastatic nasopharyngeal carcinoma: Patterns of care and survival for

patients receiving chemotherapy with and without local radiotherapy
Chad G. Rusthoven a,⇑, Ryan M. Lanning a, Bernard L. Jones a, Arya Amini a, Matthew Koshy b,c,
David J. Sher d, Daniel W. Bowles e,f, Jessica D. McDermott e,f, Antonio Jimeno e, Sana D. Karam a
a
University of Colorado School of Medicine, Department of Radiation Oncology; b University of Chicago School of Medicine, Department of Radiation and Cellular Oncology; c University
of Illinois at Chicago School of Medicine; d University of Texas Southwestern School of Medicine, Department of Radiation Oncology; e University of Colorado School of Medicine,
Department of Medicine, Division of Medical Oncology; and f Denver Veterans Affairs Medical Center, Eastern Colorado Health Care System, United States

a r t i c l e i n f o a b s t r a c t

Article history: Background and purpose: Radiotherapy (RT) to the primary nasopharyngeal tumor is frequently offered to
Received 2 February 2017 patients with metastatic nasopharyngeal carcinoma (mNPC). However, only limited data exist to support
Received in revised form 20 March 2017 RT in this setting. We used the National Cancer Database (NCDB) to evaluate outcomes for mNPC patients
Accepted 22 March 2017
receiving chemotherapy with and without local RT.
Available online xxxx
Methods: The NCDB was queried for patients with mNPC with synchronous metastatic disease at diagno-
sis who received chemotherapy. Overall survival (OS) was analyzed using the Kaplan–Meier method, Cox
Keywords:
proportional hazards models, and propensity score-matched analyses.
Nasopharynx
Radiation
Results: From 2004 to 2013, 718 cases were identified (39% chemotherapy-alone, 61% chemotherapy
Systemic therapy + RT). At a median follow-up of 4.4 years, RT was associated with improved survival on univariate anal-
Metastasis ysis (median OS 21.4 vs 15.5 months; 5-year OS 28% vs 10%; p < 0.001) and multivariate analyses (HR,
Oligometastatic 0.61; CI, 0.51–0.74; p < 0.001). Propensity score analysis with matched baseline characteristics demon-
strated a similar OS advantage with RT (HR, 0.68; CI, 0.55–0.84; p < 0.001). The benefits of RT remained
consistent in models controlling for single vs multi-organ metastases and anatomic sites of metastatic
involvement. RT dose was an independent prognostic factor as both a continuous and categorical vari-
able, with OS benefits observed among patients receiving 50 Gy. Long-term survival of >10 years was
only observed in the RT cohort.
Conclusions: This analysis supports strategies incorporating local RT with chemotherapy for mNPC.
Prospective trials evaluating RT integration for mNPC are warranted.
Ó 2017 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2017) xxx–xxx

Worldwide, approximately 86,000 cases of nasopharyngeal car-
cinoma (NPC) are diagnosed annually, with roughly 6–8% of
patients presenting with synchronous metastatic disease (mNPC)
[1,2]. Platinum-based chemotherapy represents the primary treat-
ment modality for mNPC [3–5]. Strategies incorporating radiation
therapy (RT) to the primary nasopharyngeal tumor and regional
lymph nodes are also included as options in the contemporary
National Comprehensive Cancer Network (NCCN) guidelines [5],
although only limited data exist to support RT in this setting.
Moreover, available series to support RT for mNPC come almost
exclusively from endemic populations in China and Southeast Asia,
where the incidence and biologic composition of NPC are distinct
from non-endemic western populations [3].
⇑ Corresponding author at. University of Colorado School of Medicine, Depart-
ment of Radiation Oncology, 1665 N. Aurora Court, Suite 1032, Mail Stop F706,
Aurora, CO 80045, United States
E-mail address: chad.rusthoven@ucdenver.edu (C.G. Rusthoven).
In this analysis, we used the NCDB to evaluate the patterns-of-
care and overall survival (OS) for mNPC patients receiving
chemotherapy with and without RT in the United States (US).
Methods
The NCDB is ahospital-based cancer registry sponsored by the
American College of Surgeons (ACoS) and American Cancer Society
(ACS) and includes approximately 70% of malignancies diagnosed
in the US [6]. Demographics, comorbidities, tumor characteristics,
and OS are recorded, as well as therapies including chemotherapy,
RT, and surgery. The ACoS and the Commission on Cancer are not
responsible for the analyses or conclusions drawn by investigators.
The following NCDB analysis was performed with approval from
our local institutional review board.
Eligibility criteria included patients 18 years old with newly-
diagnosed NPC with metastatic disease (M1) at diagnosis, all trea-
ted with chemotherapy, with known vital status at last follow up

http://dx.doi.org/10.1016/j.radonc.2017.03.019
0167-8140/Ó 2017 Elsevier B.V. All rights reserved.

Please cite this article in press as: Rusthoven CG et al. Metastatic nasopharyngeal carcinoma: Patterns of care and survival for patients receiving
chemotherapy with and without local radiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.019
2 Chemotherapy and Radiation for Metastatic Nasopharyngeal Carcinoma
and known status for the use of radiotherapy and surgery (Supple-
mental Fig. 1). Patients dying within the first month from diagnosis
and those undergoing surgical resection or surgery-NOS were
excluded. Treatment coding in the NCDB is limited to the first
course of treatment, defined as all methods of therapy recorded
in the treatment plan and administered to the patient before dis-
ease progression or recurrence [7]. Available coding for local
nasopharyngeal RT includes external beam radiation to the head
and neck or sinuses. Because the NCDB records RT data for only
one anatomic site per patient, it is not possible to determine which
patients received both local RT and RT to distant metastatic sites.
Patients coded to receive RT to distant sites were analyzed in the
chemotherapy without local RT cohort. Data regarding specific
chemotherapy agents and cycle numbers are not available.
Tumor histology was categorized in a manner similar to prior
publications [8], including keratinizing squamous cell carcinoma
(ICD-O codes 8070/8071), non-keratinizing differentiated carci-
noma (codes 8072/8073), and non-keratinizing undifferentiated
carcinoma (codes 8020/8021/8082 and any non-keratinizing carci-
nomas assigned an undifferentiated grade). Data regarding histo-
logic and serum Epstein-Barr virus (EBV) testing are not
available. Available surrogates for EBV-associated disease included
non-keratinizing histology and a study-defined Chinese/Southeast
Asian category encompassing races from endemic populations
with near-uniform EBV-positive disease [3,9]. It was not possible
to further stratify Southern Chinese or other endemic groups such
as North Africans or Arctic natives.
The primary objective for analysis was the comparison of OS
outcomes for patients with mNPC treated with chemotherapy with
and without local RT. Survival was estimated using the Kaplan–
Meier method and compared using Cox proportional hazards mod-
els. Multivariate Cox models were adjusted for factors selected a
priori including RT, age, sex, year of diagnosis, treatment center,
insurance status, comorbidity scores, T-classification (T), N-
classification (N), tumor histology, and race. Separate multivariate
models including the above cofactors, with the exception of RT
administration, were used to analyze RT-specific factors including
RT dose, treatment technique (intensity-modulated radiotherapy
[IMRT] vs other), and the sequencing of chemotherapy and RT.
For analytic purposes, induction-chemotherapy and subsequent
RT was defined as chemotherapy initiation 21 days prior to RT
initiation. Concurrent-chemotherapy included initiation 20 days
prior to and  42 days (6 weeks) after RT initiation. Adjuvant-
chemotherapy included initiation 43 days after RT initiation.
Due to the coding of only one chemotherapy start date in the
NCDB, it is unknown what percentage of patients receiving
induction-chemotherapy continued to receive chemotherapy con-
currently with subsequent RT. Metastatic sites including lung,
liver, bone, and brain metastases were available among patients
diagnosed in the year 2010 or later; the impact of RT was assessed
in this subset controlling for metastatic spread (single vs multi-
organ and individual anatomic sites) in addition to the aforemen-
tioned multivariate factors. The proportional hazards assumption
was assessed for all covariates and returned no significant results
[10]. Median follow up was assessed using the reverse Kaplan–
Meier method [11]. Baseline characteristics were compared using
the v2 and Mann–Whitney U test for categorical and continuous
variables, respectively.
Propensity score-matched analyses were performed comparing
outcomes with chemotherapy vs chemotherapy plus local RT. One-
to-one matching without replacement was completed using the
nearest-neighbor match on the logit of the propensity score for
therapeutic approach (derived from age, sex, year, treatment cen-
ter, insurance status, comorbidity score, T, N, tumor histology,
and race). The caliper width was 0.05x the standard deviation of
Please cite this article in press as: Rusthoven CG et al. Metastatic nasopharyngeal carcinoma: Patterns of care and survival for patients receiving
chemotherapy with and without local radiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.019
the logit of the propensity score [12], which is estimated to elimi-
nate over 99% of the bias due to cofounding variables [13].
Sequential landmark analyses for patients surviving 1, 2, and
3 years and sensitivity analyses limited to patients starting RT
within 120, 90, 60, 30, and 10 day of chemotherapy initiation were
performed to account for potential selection biases favoring RT
delivery in patients with more favorable prognoses and potential
immortal-time biases among patients receiving delayed RT [14].
Subgroup analyses evaluating the impact of RT were performed
for covariates selected a priori including age, year, sex, treatment
center, comorbidities, T, N, histology, and race. A recursive-
partitioning analysis (RPA) was performed, using the methods
described by Ciampi [15], stratifying patients into prognostic tiers
with common clinical variables identified as significant on multi-
variate analysis. Survival outcomes with and without RT were
assessed within each prognostic tier.
Results
Our search criteria for patients with newly-diagnosed mNPC
treated with chemotherapy returned 718 cases from 2004–2013,
including 281 (39.1%) receiving chemotherapy alone and 437
(60.9%) receiving chemotherapy and local RT. Regional differences
in racial composition were observed, with Chinese and Southeast
Asian patients representing the majority of cases in the Pacific
region of the US and non–hispanic whites representing the major-
ity in all other regions (Map displayed in Supplemental Fig. 2).
Patient and treatment characteristics are displayed in Table 1.
RT use was associated with lower comorbidity scores, T4 disease,
and treatment at non-academic centers. The median and mode
RT doses were 66 Gy and 70 Gy, respectively (interquartile range
[IQR], 51.6–70 Gy).
The median follow up was 4.4 years. At last follow up, 74% (528)
of the analyzed patients were deceased. The median OS for the
entire cohort was 18.1 months. On univariate analysis, the addition
of RT to chemotherapy was associated with longer median OS com-
pared to chemotherapy alone (21.4 vs 15.5 months), as well as
improved 1-year (67% vs 58%), 3-year (37% vs 20%), 5-year (28%
vs 10%), and 8-year OS (18% vs 5%) (HR 0.63; CI 0.54–0.75;
p < 0.001) (Fig. 1A). Survival > 10 years was only observed in the
RT cohort (18% vs 0%).
On multivariate analysis, RT remained independently associ-
ated with improved OS (HR 0.61; CI 0.51–0.74; p < 0.001) (Table 2).
Additional prognostic factors for OS observed on multivariate anal-
ysis included younger age, treatment at an academic center, pri-
vate insurance, lower comorbidity scores, lower T-classification,
and non-keratinizing histology. A trend toward improved OS was
observed for Chinese/Southeast Asian patients compared to white
patients.
A propensity score analysis was performed matching 225
patients receiving chemotherapy alone with 225 patients receiving
chemotherapy and RT. Patient characteristics were well-balanced
across all covariates (Supplemental Table 1). This matched analysis
redemonstrated an association between RT and improved OS, with
comparable benefits to the overall analysis (median OS 22.7 vs
16.0 months; 5-year OS 27% vs 13%; HR 0.68; CI 0.55–0.84;
p < 0.001) (Fig. 1B).
On analyses of RT dose (Table 2), increasing dose was associated
with improved OS as a continuous variable (p < 0.001). When ana-
lyzed in dose groups of <30, 30–49.9, 50–69.9, and 70 Gy, the sur-
vival advantage of RT was observed with doses 50 Gy (Fig. 2). The
use of RT with both induction and concurrent chemotherapy
strategies was associated with improved OS over chemotherapy
alone (Table 2), with no significant differences between strategies.
 C.G. Rusthoven et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx 3

Table 1
Patient Characteristics.

Total Chemo + RT Chemo Alone p-value

All Patients 718 437 (61%) 281 (39%)
Age Median 55 55 56 0.635
Range 18–90 40–90 18–90
Interquartile Range 46–65 46–64 45–66
Sex Male 552 336 (61%) 216 (39%) 0.995
Female 166 101 (61%) 65 (39%)
Year 2004 49 35 (71%) 14 (29%) 0.300
2005 52 34 (65%) 18 (35%)
2006 47 26 (55%) 21 (45%)
2007 88 51 (58%) 37 (42%)
2008 68 43 (63%) 25 (37%)
2009 70 45 (64%) 25 (36%)
2010 89 55 (62%) 34 (38%)
2011 86 54 (63%) 32 (37%)
2012 78 50 (64%) 28 (36%)
2013 91 44 (48%) 47 (52%)
Treatment Center Academic 243 139 (57%) 104 (43%) 0.015
Non-Academic 373 245 (66%) 128 (34%)
Unspecified 102 53 (52%) 49 (48%)
Insurance Status Private 317 212 (67%) 105 (33%) 0.061
Medicare 171 95 (56%) 76 (44%)
Medicaid/Other Govt 134 76 (57%) 58 (43%)
Uninsured 78 45 (58%) 33 (42%)
Unspecified 18 9 (50%) 9 (50%)
Comorbidities 0 589 371 (63%) 218 (37%) 0.038
1 101 53 (52%) 48 (48%)
2 28 13 (46%) 15 (54%)
Race/Ethnicity* White, Non-Hispanic 373 229 (61%) 144 (39%) 0.759
White, Hispanic 49 33 (67%) 16 (33%)
Black 124 70 (56%) 54 (44%)
Chinese/Southeast Asian 110 65 (59%) 45 (41%)
Other Asian/Pacific Islander 39 26 (67%) 13 (33%)
Other/Unspecified 23 14 (61%) 9 (39%)
Histology Keratinizing SqCC 272 173 (64%) 99 (36%) 0.087
Non-Keratinizing, Differentiated 89 57 (64%) 32 (36%)
Non-Keratinizing, Undifferentiated 184 116 (63%) 68 (37%)
Other/Unspecified 173 91 (53%) 82 (47%)
T 1 120 58 (48%) 62 (52%) <0.001
2 112 74 (66%) 38 (34%)
3 127 75 (59%) 52 (41%)
4 251 183 (73%) 68 (27%)
Unk 108 47 (44%) 61 (56%)
N 0 68 44 (65%) 24 (35%) 0.353
1 157 90 (57%) 67 (43%)
2 254 163 (64%) 91 (36%)
3 129 71 (55%) 58 (45%)
Unk 110 69 (63%) 41 (37%)
RT Dose Continuous Median 66 Gy 66 Gy – –
Mode 70 Gy 70 Gy –
Interquartile Range 51.6–70 Gy 51.6–70 Gy –
Range 2–85 Gy 2–85 Gy –
RT Dose Groups (Gy)* <30 28 (4%) 28 (6%) – -
30–49.9 56 (8%) 56 (13%) –
50–69.9 137 (19%) 137 (31%) –
70 170 (24%) 170 (39%) –
Unspecified 46 (6%) 46 (11%)
RT Technique* IMRT 218 (30%) 218 (50%) –
3D CRT 9 (1%) 9 (2%) –
Unspecified 210 (29%) 210 (48%) –
Sequencing* Concurrent ChemoRT 229 (32%) 229 (52%) – -
Upfront Chemo->RT 175 (24%) 175 (40%) –
RT->Adjuvant Chemo 8 (1%) 8 (2%) –
Unspecified 25 (3%) 25 (6%) –

Legend. Chemotherapy (Chemo). Local radiation therapy (RT). Intensity-modulated radiation therapy (IMRT). 3D Conformal radiation therapy (3DCRT). Gray (Gy). Unknown
(unk). Other government insurance (Govt). *Percentages displayed for RT Dose Groups, RT Technique, and Sequencing are column-percentages; all other factors display row-
percentages.
*
Race/Ethnicity categories are defined further in the legend of Supplemental Fig. 2.

Data on the timing of chemotherapy and radiation are displayed
in Supplemental Fig. 3. Overall, the median time from diagnosis to
chemotherapy initiation was 33 days (IQR, 21–50). In the RT
cohort, the median time from chemotherapy initiation to RT
initiation was 4.5 days (IQR, 0–73). Sensitivity analyses were
performed analyzing the impact of RT limited to patients starting
RT within 120, 90, 60, 30, and 10 days of chemotherapy initiation,
respectively. RT was associated with consistent improvements in
OS within each timing subgroup, with multivariate HRs ranging
from 0.59 to 0.68 (all p < 0.001) (Supplemental Fig. 4).

Please cite this article in press as: Rusthoven CG et al. Metastatic nasopharyngeal carcinoma: Patterns of care and survival for patients receiving
chemotherapy with and without local radiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.019
4 Chemotherapy and Radiation for Metastatic Nasopharyngeal Carcinoma

Fig. 1. Overall survival for patients with mNPC treated with chemotherapy with and without local radiation therapy. Legend. (A) All patients. (B) Propensity score-matched
patients.

Fig. 2. Overall survival with radiation therapy stratified by dose (<30, 30–49, 50–69, and 70 Gy).

On subgroup analyses (Fig. 3), no significant interactions were
observed between the effect of RT and age, sex, year, treatment
center, comorbidities, T, N, tumor histology, or race. Notably, RT
was associated with improved OS for both non-keratinizing (HR
0.68; p = 0.016) and keratinizing tumor histologies (HR 0.68;
p = 0.019), as well as the Chinese/Southeast Asian group (HR
0.40; p = 0.004) and all other racial groups combined (HR 0.66;
p < 0.001).
Landmark analyses evaluating the impact of RT for long-term
survivors are displayed in Fig. 4. Overall, RT was associated with
improved OS at each landmark, with multivariate HRs for 1, 2,
and 3 year survivors of 0.52, 0.34, and 0.25, respectively (all
p < 0.001).
Sites of metastatic involvement specific to lung, liver, bone, and
brain metastases were available for 273 patients (38% of the total
cohort). On analyses limited to this subset, RT remained associated
with improved OS when controlling for single vs multi-system
organ involvement (HR 0.58, p = 0.002) and in a model controlling
for individual metastatic sites (HR 0.56, p = 0.001) (Supplemental
Table 2). No significant interactions were observed between RT
and these metastatic variables.
An RPA was performed stratifying all patients in this dataset
into 3 prognostic tiers (Supplemental Fig. 5), which included group
1 (non-keratinizing/other histology and < 50 years of age; median
OS 25.3 months), group 2 (non-keratinizing/other histology
and  50 years of age OR keratinizing squamous histology and
T1/2; median OS 18.6 months), and group 3 (keratinizing squa-
mous histology and T3/4/unknown; median OS 12.3 months). On
multivariate analysis, RT was associated with improved OS in each
group (all p < 0.05) with no significant interactions between RT and
the RPA prognostic tiers.
Discussion
Platinum-based chemotherapy represents the foundation of
treatment for mNPC, whereas the optimal integration of local RT
has remained largely undefined [3]. The NCCN guidelines include
strategies incorporating RT with chemotherapy as options for
mNPC [5] due to factors including suboptimal complete response
rates with chemotherapy alone (reported range 0–20%) [16,17],
the morbidity and mortality associated with local disease

Please cite this article in press as: Rusthoven CG et al. Metastatic nasopharyngeal carcinoma: Patterns of care and survival for patients receiving
chemotherapy with and without local radiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.019
 C.G. Rusthoven et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx 5

Table 2
Overall Survival Analyses.

Variable Multivariate Survival Analysis Univariate Survival Analysis

HR Low High p-value HR Low High p-value
Radiation Chemotherapy Alone Reference Reference
Chemotherapy and Radiation 0.614 0.511 0.737 <0.001 0.634 0.533 0.754 <0.001
Age Per year increase 1.015 1.004 1.026 0.010 1.014 1.008 1.021 <0.001
Year Per year increase 0.979 0.947 1.013 0.225 0.983 0.952 1.015 0.299
Sex Male Reference Reference
Female 0.891 0.717 1.107 0.297 0.877 0.712 1.079 0.214
Treatment Center Academic Reference Reference
Non Academic 1.283 1.050 1.568 0.015 1.268 1.047 1.536 0.015
Unspecified 1.630 1.109 2.397 0.013 1.094 0.834 1.436 0.515
Insurance Status Private Reference Reference
Medicare 1.447 1.107 1.891 0.007 1.905 1.543 2.353 <0.001
Medicaid/Other Govt 1.495 1.158 1.930 0.002 1.433 1.130 1.817 0.003
Uninsured 1.329 0.977 1.807 0.070 1.377 1.023 1.854 0.035
Unreported 0.706 0.377 1.325 0.279 0.718 0.392 1.317 0.285
Comorbidities 0 Reference Reference
1 1.453 1.137 1.857 0.003 1.585 1.251 2.008 <0.001
2 1.703 1.099 2.638 0.017 1.810 1.188 2.757 0.006
T 1 Reference Reference
2 1.224 0.893 1.678 0.210 1.074 0.790 1.461 0.648
3 1.479 1.092 2.003 0.012 1.255 0.936 1.684 0.129
4 1.527 1.163 2.004 0.002 1.208 0.934 1.563 0.151
Unk 1.676 1.213 2.316 0.002 1.422 1.049 1.928 0.024
N 0 Reference Reference
1 0.815 0.575 1.154 0.249 0.750 0.535 1.050 0.094
2 1.046 0.753 1.452 0.790 0.889 0.649 1.218 0.466
3 1.046 0.728 1.503 0.808 0.896 0.634 1.264 0.531
Unk 0.920 0.632 1.340 0.665 0.877 0.617 1.245 0.462
Race/Ethnicity White, Non-Hispanic Reference Reference
White, Hispanic 0.877 0.606 1.271 0.488 0.862 0.601 1.236 0.419
Black 0.937 0.725 1.210 0.617 0.975 0.771 1.234 0.836
Chinese/Southeast Asian 0.779 0.597 1.016 0.065 0.691 0.535 0.892 0.005
Other Asian/Pac Islander 0.826 0.541 1.263 0.378 0.836 0.555 1.260 0.393
Other/Unspecified 0.673 0.401 1.129 0.134 0.706 0.426 1.168 0.175
Histology Keratinizing SqCC Reference Reference
Non-Keratinizing, Diff 0.720 0.537 0.964 0.027 0.680 0.512 0.904 0.008
Non-Keratinizing, Undiff 0.769 0.608 0.973 0.029 0.664 0.531 0.829 <0.001
Other/Unspecified 0.877 0.697 1.104 0.264 0.843 0.678 1.049 0.125
Multivariate Survival Analysis Univariate Survival Analysis
Treatment-Specific Factors* HR Low High p-value HR Low High p-value
Sequencing Chemotherapy Alone Reference Reference
Concurrent ChemoRT 0.629 0.504 0.785 <0.001 0.695 0.567 0.851 <0.001
Induction Chemo->RT 0.573 0.455 0.722 <0.001 0.552 0.440 0.692 <0.001
RT->Adjuvant Chemo 1.089 0.503 2.359 0.828 0.967 0.456 2.052 0.931
Unspecified 0.707 0.428 1.167 0.175 0.649 0.401 1.050 0.078
RT Technique Chemotherapy Alone Reference Reference
IMRT 0.562 0.450 0.704 <0.001 0.559 0.453 0.691 <0.001
3D-CRT or Unspecified 0.648 0.521 0.806 <0.001 0.718 0.586 0.881 0.001
RT Dose (Continuous) Per Gy increase 0.990 0.987 0.993 <0.001 0.990 0.988 0.993 <0.001
RT Dose Groups (Gy) Chemotherapy Alone Reference Reference
<30 1.068 0.688 1.660 0.768 1.234 0.811 1.880 0.326
30–49.9 1.015 0.733 1.405 0.928 1.098 0.804 1.498 0.557
50–69.9 0.570 0.443 0.735 <0.001 0.604 0.474 0.770 <0.001
70 0.466 0.363 0.599 <0.001 0.480 0.379 0.608 <0.001
Unspecified 0.718 0.483 1.066 0.101 0.701 0.484 1.017 0.061

LEGEND: Govt = other government insurance. Comorbidity scores correspond to the Charlson-Deyo comorbidity score. Hazard Ratio (HR). Lower limit of the 95% confidence
interval (Low). Upper limit of the 95% confidence interval (High). RT = radiation therapy. IMRT = intensity-modulated radiation therapy. 3D-CRT = 3D conformal radiation
therapy. SqCC = squamous cell carcinoma. Diff = differentiated histology. Undiff = undifferentiated histology. Unk = unknown. *Separate multivariate models were required
for analysis of each treatment-specific factor because sequencing, technique, and dose groups include chemotherapy alone as the reference variable level. Induction
chemotherapy defined as chemotherapy initiation 21 days prior to radiation initiation. Concurrent chemoRT defined as chemotherapy initiation <21 days before and <6
weeks after RT initiation. Adjuvant chemotherapy defined as 6 weeks post RT initiation.

progression in mNPC [18–20], and the observation of long-term
survival in a subset of patients [21,22]. No randomized data are
currently available to clarify the role of RT and, given the lower
incidence in western populations [1], randomized trials specific
to mNPC may be prohibitively difficult to perform outside of
endemic regions. In China, one phase 3 trial is ongoing randomiz-
ing mNPC patients to chemotherapy with and without RT
(NCT02111460). A separate Chinese phase 3 trial is evaluating
chemoradiation for all patients with a randomization to different
systemic therapy regimens (NCT02633176). This analysis
represents, to our knowledge, the largest cohort of mNPC treated
with chemotherapy with and without RT.
In this analysis, we report the outcomes for over 700 patients in
the US with newly-diagnosed mNPC from 2004 to 2013, all treated
with chemotherapy, and managed either with or without RT. Local
RT was associated with 5.9-month improvement in median OS and
an 18% absolute improvement in 5-year OS (28% vs 10%). The
correlation between RT and improved OS remained consistent on

Please cite this article in press as: Rusthoven CG et al. Metastatic nasopharyngeal carcinoma: Patterns of care and survival for patients receiving
chemotherapy with and without local radiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.019
6 Chemotherapy and Radiation for Metastatic Nasopharyngeal Carcinoma

Fig. 3. Forest plot of the association between radiation therapy and overall survival by subgroup. Legend: Multivariate hazard ratios (HR) displayed are adjusted for the
factors described in the methods section. Lower limit of the 95% confidence interval (Low). Upper limit of the 95% confidence interval (High).

Fig. 4. Landmark analyses of overall survival for long-term survivors of 1, 2, and 3 years.

multivariate and propensity-score matched analyses controlling
for factors including age, comorbidities, treatment center, insur-
ance status, race, T, N, and histology. Comparable advantages with
RT were observed when controlling for single vs multi-organ
involvement and individual metastatic sites among patients with
available metastatic data. Additionally, survival of >10 years was
only observed in the RT cohort, supporting prior observations that
local control may be important to long-term survival in mNPC [18].
Published series including local RT for mNPC with synchronous
metastatic disease at diagnosis are summarized in Supplemental
Table 3. Similar to our analysis, the existing literature has charac-
terized a consistent association between RT and long-term survival
for mNPC [23–25]. In a Chinese cohort, Chen et al. reported
improved OS with chemotherapy plus RT over chemotherapy alone
(multivariate HR 0.4; p < 0.001). Similarly, Lin et al. observed med-
ian survival times of 36 vs 16 months for chemotherapy plus RT vs
chemotherapy alone, respectively (multivariate HR 0.34, p < 0.001).
With the exception of a small case series [26] and SEER analysis
reported in abstract form [27], the literature of local RT for mNPC
is limited to studies from endemic populations in China and South-
east Asia with uniformly non-keratinizing tumor histology. The
present study is, therefore, unique in its analysis of a non-
endemic western population including 76% white, black, and his-
panic patients, the inclusion of 38% of patients with keratinizing
squamous histology, and analyses of ethnic Chinese and Southeast
Asian patients living in the US.
Although data regarding histologic and serum EBV testing were
not available, surrogates for EBV-associated disease were present
in the form of tumor histology and race. In series of non-endemic
western populations, EBV-positive disease rates range from
approximately 50–60% overall, including roughly 60–90% of non-
keratinizing and 0–40% of keratinizing tumors, with HPV, tobacco,
and alcohol exposure being implicated as alternate potential dri-
vers for EBV-negative tumors [9,28–33]. The OS advantage of RT
within both the Chinese/Southeast Asian and non-keratinizing his-
tology subgroups parallels the benefits reported in series from

Please cite this article in press as: Rusthoven CG et al. Metastatic nasopharyngeal carcinoma: Patterns of care and survival for patients receiving
chemotherapy with and without local radiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.019
 C.G. Rusthoven et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx
endemic populations with uniformly non-keratinizing tumors [23–
25]. Subgroup analyses also demonstrated improved OS with RT for
patients with keratinizing squamous histology and those of non-
endemic races, suggesting comparable benefits from RT in subsets
enriched for EBV-negative disease. Beyond race and histology,
additional subgroup analyses (Fig. 3) demonstrated generally con-
sistent survival advantages with RT across stratifications by age,
sex, year, comorbidities, treatment center, T, N, and study-
defined RPA prognostic groups.
In contrast to our western cohort with synchronous M1 disease,
existing analyses of prognostic factors for mNPC have come pri-
marily from endemic populations with metachronous metastases
[18,34,35]. Younger age was associated with improved OS in our
analyses, similar to prior series of mNPC [18,34,35]. On multivari-
ate analysis, favorable outcomes were independently associated
with non-keratinizing histology along with a trend favoring Chi-
nese/Southeast Asian race, which have each been reported in
non-metastatic NPC [36]. Interestingly, advanced T-classification,
rather than N-classification, was prognostic for inferior OS,
implicating local disease status as an important driver of mortality
in this cohort, similar to other series of metastatic and recurrent
NPC [18–20]. The RPA analysis suggests that advanced T-
classification may be particularly relevant for patients with kera-
tinizing squamous tumors (Supplemental Fig. 5), which are known
to be less sensitive to chemotherapy and RT [3].
Data from this analysis also provide insights into the patterns-
of-care for mNPC in the US during a contemporary 10-year inter-
val. Overall, 61% of patients with mNPC treated with chemotherapy
also received local RT. Of those, 52% received concurrent
chemotherapy plus RT and 40% received induction chemotherapy
and subsequent RT. Unlike the series by Chen et al. supporting
induction chemotherapy and subsequent RT [23], no differences
were observed between upfront chemotherapy and subsequent
RT vs upfront concurrent chemoradiation strategies in this
analysis.
RT dose was prognostic as both a continuous and categorical
variable, with OS advantages observed with doses  50 Gy (deliv-
ered in 70% of patients receiving RT). Similar correlations between
higher doses of RT and survival have been consistently reported in
series from endemic populations [23,24,37,38], which might fur-
ther suggest the importance of durable local control in efforts to
alter the natural history of mNPC. Retrospective dose analyses
should, however, be interpreted cautiously in light of the potential
for unmeasured biases favoring high-dose RT in patients with bet-
ter prognoses (eg, oligometastatic, favorable performance status,
etc). Although 70 Gy delivered over 6–7 weeks may be appropriate
for some patients [26], abbreviated palliative regimens included in
the national guidelines [5] (e.g. 50 Gy/20 Fx) may be preferable for
others. Overall, when considering data from this analysis in the
context of decisions to offer RT and what RT regimens to use, the
OS advantages with RT and increasing hazard reductions associ-
ated with RT dose must be weighed carefully against the limita-
tions inherent to retrospective data as well as individualized
clinical and quality-of-life factors.
A range of time intervals were observed between chemotherapy
and RT initiation in this analysis (median 4.5 days; IQR, 0–73 days).
An initial peak of RT initiation was observed within 10 days of
chemotherapy followed by a steady wave of RT starts from 10–
120 days post-chemotherapy (Supplemental Fig. 3B). Overall, 53%
and 90% of patients initiated RT within 10 and 120 days after
chemotherapy initiation, respectively. Given this observed range,
landmark analyses limited to long-term survivors and sensitivity
analyses limited to patients starting RT within 120, 90, 60, 30,
and 10 days of chemotherapy were important measures to account
for the potential of immortal-time bias, where OS might artificially
favor the RT cohort because patients must live long enough to
Please cite this article in press as: Rusthoven CG et al. Metastatic nasopharyngeal carcinoma: Patterns of care and survival for patients receiving
chemotherapy with and without local radiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.019
7
initiate it [14]. The observation of consistent benefits with RT on
sequential landmark and sensitivity analyses suggest that
differences in survival were unlikely to be driven by this form of
bias.
This analysis has several important limitations. Given the retro-
spective design, all analyses are subject to the critical influences of
selection bias and potential imbalances in unquantified variables.
Performance status and overall metastatic burden could not be
controlled for beyond patient and disease status surrogates. Meta-
static sites limited to lung, liver, bone, and brain metastases were
available for only a subset (38%) of the overall cohort. No data were
available regarding treatment of metastatic sites in addition to
local RT, specific chemotherapy therapy agents, duration of sys-
temic therapy, salvage therapies, progression-free survival,
quality-of-life, or cause of death. We used several analytic tech-
niques including multivariate-adjustment, propensity matching,
recursive-partitioning, subgroup, landmark, and sensitivity analy-
ses evaluating the timing of RT in an effort to control for potential
confounding in a setting where prospective trial data do not exist.
The recursive-partitioning, landmark, and subgroup analyses of
patients with known metastatic sites specifically addressed poten-
tial imbalances in baseline prognoses and metastatic disease. The
fact that all analyses rendered generally consistent results
strengthens our observation of an association between RT and sur-
vival in this registry dataset.
Conclusion
In the largest reported analysis of chemotherapy with and with-
out local RT for mNPC, the addition of RT was associated with
improved OS. This analysis supports strategies incorporating RT
with chemotherapy in this setting. Prospective trials evaluating
RT integration for mNPC are warranted.
Funding
No specific funding.
Conflict of interest statement
The authors report no conflicts of interest regarding the manu-
script ‘‘Metastatic Nasopharyngeal Carcinoma: Patterns of Care and
Survival for Patients Receiving Chemotherapy with and without
Local Radiotherapy”.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.radonc.2017.03.
019.
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