Introduction

Numerous clinical trials have demonstrated outcome improvements with the addition of chemotherapy to definitive radiation therapy (RT) for nasopharyngeal cancer (NPC) [1,2]. However, these have largely encompassed locally-advanced cases, while lower-stage disease has been underrepresented. To this extent, a phase III study of RT with or without chemotherapy for stage II (T1-2N1 or T2N0) NPC demonstrated a significant improvement in 5-year overall survival (OS) from 86% to 95% [3].

Despite the efficacy of chemoradiotherapy (CRT) for stage II disease, stage I (T1N0) patients have been excluded from nearly every phase III study of RT with or without chemotherapy. Stage I cases are commonly treated with RT alone [4]. However, there are currently very little available data regarding optimal management for stage I NPC, largely owing to the rarity of these cases. A study analyzing whether T1N0 cases benefit from additional chemotherapy has never been performed.

Although challenging to assess with single- or multi-institutional analyzes owing to the rarity of T1N0 NPC, along with the uncommon chemotherapy to RT, the National Cancer Data Base (NCDB) provides a unique resource with which to address these novel but clinically important issues. This study had multiple goals as the first investigation to evaluate the addition of chemotherapy to definitive RT for T1N0 NPC. We first sought to address practice patterns associated with delivery of chemotherapy. Next, we aimed to determine whether addition of chemotherapy influenced OS.

Material and methods

The NCDB is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society, which consists of de-identified information regarding tumor characteristics, patient demographics, and patient survival for approximately 70% of the US population [5–9]. All pertinent cases are reported regularly from CoC-accredited centers and compiled into a unified dataset, which is then validated. The NCDB contains information not included in the Surveillance, Epidemiology, and End Results database, including details regarding use of systemic therapy. The data used in the study were derived from a de-identified NCDB file. The American College of Surgeons and the CoC have not verified and are neither responsible for the analytic or statistical methodology employed nor the conclusions drawn from these data by the investigators. As all patient information in the NCDB database is de-identified, this study was exempt from institutional review board evaluation.

Inclusion criteria for this study were patients with newly-diagnosed and histologically-confirmed clinical T1N0 nasopharyngeal cancer treated with RT for curative intent. Patients receiving any form of pharyngectomy were excluded, as this is clearly a nonstandard treatment strategy. Other exclusion criteria were benign or sarcomatous histology, palliative care treatment, and unknown information on RT and/or chemotherapy. In accordance with the variables in NCDB files, information collected on each patient broadly included demographic, clinical and treatment data.

All statistical tests were performed with SAS software (Cary, NC); tests were two-sided, with a threshold of p < .05 for statistical significance. Chi-square tests were used to assess differences in patient, tumor and treatment characteristics between cases who received chemotherapy and those who did not. Univariable and multivariable logistic regression was used to determine which characteristics were associated with receipt of chemotherapy. All initially examined variables were considered for inclusion into models for stepwise selection. Cox proportional hazards modeling was utilized to evaluate associations between the receipt of chemotherapy and OS. The proportional hazards assumption in the Cox models were met. Survival analysis (performed using Kaplan–Meier methodology) evaluated OS, defined as the interval between the date of diagnosis and the date of death or last contact. Endpoints such as local control and cancer-specific survival are not recorded in the NCDB.

Results

A complete flow diagram of patient selection is provided in Figure 1. In total, 396 patients met study analysis criteria (2004–2013). Table 1 displays notable clinical characteristics of the analyzed patients as stratified for chemotherapy delivery. A total of 147 (37%) patients underwent CRT, whereas 249 (63%) received RT alone. After univariate analysis was performed to assess factors associated with chemotherapy receipt, multivariable analysis revealed that patients treated at academic/integrated facilities were less likely to receive chemotherapy (odds ratio (OR) 0.530, 95% confidence interval (CI) 0.330–0.849, p = .008). Additionally, there was a racial predilection, as non-black and non-white patients (consisting of a heterogeneous mixture of various Asian, Polynesian, and Native American races) were independently less likely to receive additional chemotherapy (OR 0.324, 95% CI 0.144–0.717, p = .006).

Patterns of care and outcomes with the addition of chemotherapy to radiation therapy for stage I nasopharyngeal cancer

All authors

Vivek Verma, Jeffrey M. Ryckman, Charles B. Simone II & Chi Lin

https://doi.org/10.1080/0284186X.2017.1351039

Published online:

19 July 2017

Figure 1. Patient selection diagram.

Display full size

Median follow-up was 54 months (range, 4–129 months). Kaplan–Meier estimates comparing OS in patients undergoing curative-intent RT with or without chemotherapy are illustrated in Figure 2. The 5-year OS in the respective groups were 75% and 77% (p = .428). In the overall cohort (N = 396), there were several predictors of OS on univariate analysis (Table 2). After multivariate adjustment for potential confounding factors (Table 2), increasing age (p = .016), Medicare (p < .001) or Medicaid/other governmental insurance (p < .001), and urban location (p = .013) predicted for poorer OS. Non-black and nonwhite (“other”) races (p = .046), and high-grade tumors (p = .010) were associated with improved OS. Notably, there was no independent impact of chemotherapy administration on OS (hazard ratio 1.195, 95% CI 0.755–1.893, p = .447).

Patterns of care and outcomes with the addition of chemotherapy to radiation therapy for stage I nasopharyngeal cancer

All authors

Vivek Verma, Jeffrey M. Ryckman, Charles B. Simone II & Chi Lin

https://doi.org/10.1080/0284186X.2017.1351039

Published online:

19 July 2017

Figure 2. Kaplan–Meier overall survival curves comparing those receiving radiotherapy alone (top curve) vs. chemoradiotherapy (bottom curve).

Display full size

Discussion

To our knowledge, this is the first report assessing practice patterns and outcomes of RT with or without chemotherapy for T1N0 NPC. Our study of a large national database of this rare condition most notably demonstrates practice patterns of the addition of chemotherapy to RT, and that the addition of chemotherapy to curative-intent RT does not influence OS.

Practice patterns in this study displayed racial and facility differences impacting receipt of chemotherapy. Non-black and non-white patients (the majority of which were of Asian descent) were less likely to receive chemotherapy; although this study is not able to be extrapolated to an endemic population such as in places of Asia, it is nevertheless noteworthy. Moreover, patients seen at academic/integrated facilities were less likely to receive chemotherapy, which indicates greater consistency with current national recommendations [4].

One of the few known retrospective studies evaluating CRT versus RT alone for stage I disease was performed by Cheng and colleagues [10]. In this study of 44 stage I–II patients, the 3-year locoregional control with CRT was 100%, versus 92% for RT alone (p = .10). However, the main limitation to that study was that nearly all stage I patients received RT alone, and thus the benefit to CRT remained so for stage II disease, corresponding to the randomized data discussed earlier [3]. To that extent, this study adds evidence to answer the question aimed by that investigation in a large volume of pure stage I patients.

This study implies that addition of chemotherapy does not influence OS, which carries caveats. In a cohort of patients without clear indications to administer chemotherapy, chemotherapy is most often given to an especially ‘high-risk’ subset that may warrant more aggressive therapy than RT alone [11,12]. Thus, the finding of equivalent OS could mean that the ‘high-risk’ population (that may do poorly anyway) ended up benefitting from chemotherapy to the point of equivalent OS. Hence, the main shortcoming of this study lies in its retrospective nature, which cannot compensate for selection biases as prospective data can. Altogether, when conservatively and judiciously taking all factors into account, this study does not imply causation and is not intended to suggest chemotherapy should be omitted in all T1N0 NPC cases. Rather, this hypothesis-generating study is intended to imply that there is likely not a role for chemotherapy administration in routine cases.

With regards to predictors of OS, the seemingly paradoxical finding of high-grade disease having a better prognosis can be explained by several high-grade NPC variants having improved prognosis, likely from increased radiosensitivity [13,14]. Moreover, grade as coded in the NCDB is not defined to be the same as WHO grade and/or Epstein–Barr virus association (the number of unknown values is also quite large for this parameter).

Although the NCDB provides a unique platform with which to study this important clinical question, this investigation is not without limitations. First, NCDB studies are inherently retrospective; they have potential for miscoding, and limited sample sizes of T1N0 cases (especially for those receiving nonstandard therapies). Second, NCDB studies do not keep track of precise reasons for the administration of chemotherapy, as discussed above (e.g., chemotherapy for tumor size/extension). Third, the NCDB does not allow for an assessment of subsequent lines of treatment (e.g., re-irradiation, further systemic and/or targeted therapy), which could influence overall survival. Additionally, the inherent limitation of ‘overall survival’ without other outcomes like local or locoregional control in a tumor with good prognosis is also acknowledged, and thus more conclusions may not be applicable with this national database. Furthermore, the NCDB also does not provide details such as performance status, Epstein–Barr virus status, radiotherapy field design/volumes/techniques, specific chemotherapy type, or qualitative extent of resection (e.g., based on post-treatment imaging).

Conclusions

Given the lack of T1N0 patients in randomized trials of RT versus CRT, this study evaluates patterns of care and outcomes of this clinical question. Racial and facility differences impacting receipt of chemotherapy were identified. This analysis did not identify an appreciable impact of chemotherapy on OS, and hence routinely adding chemotherapy to RT is not indicated.