Adjuvant Capecitabine Following Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma

This multicenter, open-label randomized clinical trial conducted in China compares the efficacy and safety of adjuvant capecitabine with concurrent chemoradiotherapy vs concurrent chemoradiotherapy alone for treatment of patients with locoregionally advanced nasopharyngeal carcinoma.

N asopharyngeal carcinoma (NPC) is a unique head and neck cancer endemic in East and Southeast Asia, 1,2 where it is invariably associated with Epstein-Barr virus (EBV). [3][4][5][6] Most patients with NPC present with locoregionally advanced disease (LA-NPC), harboring a proclivity for metastatic recurrences to the bones, liver, and lungs. 7 Induction chemotherapy or adjuvant chemotherapy in addition to concurrent chemoradiotherapy (CCRT) is the recommended standard of care in high-risk LA-NPC, defined as T3-4N+ or N2-3 in previous randomized clinical trials. [8][9][10][11] The updated network meta-analysis of chemotherapy in NPC report 12 supports the efficacy of either systemic intensification strategy for superior survival in LA-NPC.
The role of adjuvant chemotherapy in LA-NPC, using regimens such as cisplatin with fluorouracil 9,13-16 or gemcitabine, 17 gemcitabine and paclitaxel, 18 and capecitabine at metronomic dosing 19 has been investigated. The use of adjuvant fluorouracil and gemcitabine in combination with cisplatin yielded no difference in failure-free survival (FFS) and overall survival (OS), due in part to its inferior tolerability compared with induction chemotherapy, with only 50% to 75% of patients able to receive the full treatment dose. 9,15-17 Chen et al 9 did not demonstrate a survival benefit using adjuvant fluorouracil with cisplatin after follow-up of approximately 5 years 16 despite enriching for a high-risk subset of patients with LA-NPC; of note, only 62.9% of participants tolerated 3 cycles of adjuvant fluorouracil with cisplatin. Although superiority of adjuvant fluorouracil with cisplatin was not demonstrated, it cannot be concluded based on that trial that CCRT alone was noninferior to CCRT and adjuvant fluorouracil with cisplatin.
Capecitabine has proven single-agent activity in recurrent metastatic NPC and is efficacious when combined with cisplatin for induction chemotherapy in patients with LA-NPC. [20][21][22][23][24][25] In addition, a recent randomized clinical trial of adjuvant capecitabine given at metronomic dosing for 1 year conferred FFS and OS benefits among patients with high-risk LA-NPC. 19 Here, we report the efficacy and safety results after a median follow-up of 58.0 months in a randomized clinical trial of adjuvant capecitabine given at the full dose for 6 months.

Study Design and Participants
The trial was designed by investigators from 4 institutions (Trial Protocol in Supplement 1), and patients were recruited from 3 centers in China (eTable 1 in Supplement 2). Eligibility criteria were (1) histologically confirmed, newly diagnosed, nonkeratinizing NPC; (2) age 18 to 70 years; (3) Karnofsky performance status of at least 80 points; (4) TNM stage III-IVb based on American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) 7th edition stage classification system 26 ; (5) no prior radiotherapy, chemotherapy, or surgery (except for diagnostic investigations) for the tumor; (6) adequate organ function; and (7) presence of 1 or more of the following unfavorable prognostic factors: T3-4N2 or T1-4N3 27 ; plasma EBV DNA titer higher than 20 000 copies/mL 28 ; primary gross tumor volume (GTV) greater than 30.0 cm 3,29 ; a maximum standard uptake value of primary GTV higher than 10.0 on fluorodeoxyglucose F 18 positron emission tomography/computed tomography ( 18 F-FDG PET/CT) 30 ; or multiple nodal metastases and at least 1 larger than 4.0 cm. 31 Exclusion criteria included (1) prior malignant tumors within 5 years of NPC diagnosis; (2) concurrent pregnancy; (3) concurrent immunotherapy or hormone therapy for other diseases; and (4) severe comorbidities. The protocol was reviewed and approved by the Ethics Committee of Sun Yat-sen University Cancer Center (SYSUCC) and by ethics committees and institutional review boards of the other participating hospitals on March 19, 2014. The study was registered on ClinicalTrials.gov May 7, 2014, 32 and was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The first patient was recruited on March 31, 2014, and the second patient was recruited on July 23, 2014. Trial accrual was completed on July 27, 2018. Data analyses were performed based on a data collection cutoff date of February 9, 2022. All patients provided written informed consent. No one received compensation or was offered any incentive for participating in this study. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

Randomization and Masking
Patients were randomly assigned to receive in a 1:1 ratio either capecitabine (capecitabine group) or observation (control group) following CCRT. Randomization was performed at the Clinical Trials Center of SYSUCC on the day of study recruitment prior to CCRT. A computer-generated sequence was used to obtain the randomization list without stratification. After obtaining informed consent, the investigators at each institution contacted the study coordinators at the Clinical Trials Center and received treatment assignment information. The statistician (Y.G.) and study coordinators were uninvolved in the treatment of patients and data monitoring.

Procedures
All patients underwent CCRT and received intravenous cisplatin at a dosage of 100 mg/m 2 every 3 weeks for 2 to 3 cycles depending on the duration of radiotherapy. Patients randomized to the capecitabine group then received 8 cycles of oral capecitabine at a dosage of 1000 mg/m 2 twice daily for 14 days ever y 21 days, 2 1 commenc ing 4 weeks after CCRT. Chemotherapy dose modifications were based on the nadir blood counts and acute toxic effects of the preceding cycle.
All patients received intensity-modulated radiotherapy (IMRT), based on the principles of ICRU (International Commission on Radiation Units and Measurements) reports 50 and 62. Details of the IMRT technique and delineation of target volumes, including primary GTV, GTV of all involved lymph nodes, high-and low-risk clinical target volumes, and the corresponding planning target volumes, were as previously described. 33 Prescribed doses were 68 to 72 Gy, 60 to 68 Gy, 60 to 64 Gy, and 54 to 58 Gy in 30 to 32 fractions to the primary planning target volume, lymph node planning target volume, highrisk planning target volume, and low-risk planning target volume, respectively. Plan review was performed centrally by study investigators (J.-G.L., J.Y., H.-Q.M., and C.Z.).
Patients underwent the following evaluations within 2 weeks before randomization: physical examination and nasopharyngoscopy, Karnofsky performance status evaluation, hematologic and biochemical analyses, EBV DNA titer, magnetic resonance imaging or CT of the head and neck, and 18 F-FDG PET/CT. If 18 F-FDG PET/CT was unavailable, CT of the chest and abdomen and skeletal scintigraphy were performed. Plasma EBV DNA assays were performed centrally at SYSUCC for standardization.
Trial participants were reviewed at the following intervals: weekly during IMRT, prior to each cycle of capecitabine, every 3 months for the first 3 years, and every 6 months thereafter. All end points were assessed and validated by the physician in charge. The surveillance protocol included hematologic and biochemical analyses, contrast-enhanced magnetic resonance imaging or CT of the head and neck region, and CT of the thorax and abdomen 3 and 6 months after CCRT and annually thereafter. A plasma EBV DNA assay was performed during the last week of CCRT, and nasopharyngoscopy was performed 1 month after CCRT to evaluate tumor response. When the presence of recurrence was indeterminate, 18 F-FDG PET/CT was performed. When feasible, fine-needle aspiration or biopsy was performed for patients with suspected recurrence. Salvage treatments for recurrent disease were at the discretion of the physician in charge.

Outcomes
The primary end point was FFS, defined as time from the date of randomization to a documented relapse or any death. Patients unavailable for follow-up or alive without disease relapse were censored at the date of last follow-up. Secondary end points included OS, defined as time from the date of randomization to any death, with patients unavailable for follow-up censored at the date of last follow-up; distant metastasis-free survival (DMFS), defined as time from date of randomization to documented distant metastasis or any death; and locoregional relapse-free survival (LRFS), defined as time from the date of randomization to documented locoregional relapse or any death. Patients with distant metastasis as a first event were censored for LRFS at the date of distant metastasis and vice versa; if distant metastasis and locoregional relapse occurred concurrently, patients were considered as having an event for both DMFS and LRFS. Patients unavailable for follow-up or alive without distant metastasis or locoregional relapse were censored at the date of last follow-up.
Treatment compliance and treatment-related adverse events (TRAEs) during and after treatment were also recorded. For the capecitabine group, TRAEs were assessed at baseline and prior to each chemotherapy cycle until capecitabine completion or at the time of treatment discontinuation. For the control group, TRAEs were assessed at baseline, prior to each concurrent cisplatin cycle and 3 and 6 months after CCRT. Grading of TRAEs was performed using the Common Toxicity Criteria for Adverse Events, version 4.0, and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Delayed TRAEs were assessed using the latter. 34

Statistical Analysis
The sample size for this study was calculated using the PS: Power and Sample Size Calculation, version 3.1.2, software. A 2-sided log-rank test with 54 events in both groups provided at least 80.0% power to detect a hazard ratio (HR) of 0.46 when the 3-year FFS rate in the control group was 70.0% (estimated based on historical data 35-37 ) at a significance level of 5.0%. This HR would correspond to a 15.0% improvement in 3-year FFS with the addition of adjuvant capecitabine to CCRT. 38 Considering a 4-year recruitment period and 3 years of follow-up, 164 patients (82 per group) were needed, assuming the distribution of survival times for both groups would follow an exponential distribution. This yielded a total cohort size of 180 patients (90 per group), accounting for a dropout rate of 10.0%.
Primary efficacy analysis was performed based on the intention-to-treat (ITT) principle. Safety data were summarized for all patients who started the assigned treatment. Survival curves were derived using the Kaplan-Meier method and compared using the log-rank test. Unstratified Cox proportional hazards regression models were used to estimate HR. Corresponding 95% CIs were based on the Wald test. The proportional hazards assumption was tested by including timedependent covariates in the Cox models within the PROC PHREG module (test for interaction), and by assessing whether the Schoenfeld residuals were independent of time using simple linear regression and a trend test. Graphical methods were used to check the proportional hazards assumption using smoothed plots of scaled Schoenfeld residuals against time. Linear and log time scales were used for the assessment of proportional hazards. 39,40 Survival rates at 3 and 5 years were reported with corresponding 95% CIs calculated using log transformation of survival probabilities. Median follow-up time was estimated using the reverse Kaplan-Meier method.
At the data collection cutoff date of February 9, 2022, the prespecified number of events (54 events) for the primary end point was not reached. The trial steering committee opted to report the results on the following grounds: there was (1) a lower than expected number of events despite enriching for a high-risk study population, (2) there was a substantial decrease in events beyond the third year of follow-up (9 vs 40 events in the first 3 years), and (3) the study period had reached 8 years with a median follow-up of nearly 5 years and a minimum follow-up of 42.5 months for the last patient enrolled. A 2-sided P < .05 was considered statistically significant. Statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc); STATA, version 16 (StataCorp LLC); and R, ver-  All patients completed the prescribed course of IMRT, with comparable dosimetric outcomes (eTable 3 in Supplement 2). In the capecitabine group, 89 of 90 patients (98.9%) completed at least 2 cycles of concurrent cisplatin (1 patient received only 1 cycle due to grade 2 hepatotoxicity). All patients in the control group completed 2 cycles of concurrent cisplatin ( Figure 1 Table 1).

Outcomes
At 1 month after CCRT, endoscopic examination indicated that for 90 patients in the capecitabine group, 78 (86.7%) showed complete response and 12 (13.3%) showed partial response; and for 90 patients in the control group, 79 (87.8%) showed complete response and 10 (11.1%) showed partial response ( Table 1). The median (IQR) follow-up duration was 58.0 (49.5-80.1) months. The last patient enrolled in the trial was followed up for 42.5 months. We recorded 49 disease relapse or death events: 18 in the capecitabine group and 31 in the control group. Details regarding the patterns of relapse and salvage therapies are shown in eTables 5 and 6 in Supplement 2. Of note, 7 patients in the capecitabine group and 5 patients in the control group received anti-programmed cell death 1 antibodies.

ITT set Safety analysis set
All patients randomly assigned to either adjuvant capecitabine (capecitabine group) or observation (control group) following concurrent chemoradiotherapy were included in the intention-to-treat (ITT) analysis according to their allocated treatments. All patients who received at least 1 dose of chemotherapy were included in the safety analysis. AEs represent adverse events; IMRT, intensity-modulated radiotherapy; PD, progressive disease. a Patient purchased adjuvant capecitabine off protocol from another hospital.
Treatment effects by high-risk factors for FFS in the ITT set are shown in eFigure 3 in Supplement 2. No interaction be-  . Among 85 patients, there were 65 occurrences of grade 1 or 2 hand-foot syndrome (76.5%) associated with capecitabine and 3 occurrences of grade 3 (3.5%). The incidence of grade 3 or 4 delayed TRAEs was 9 of 83 (10.8%) in the capecitabine group and 7 of 81 (8.6%) in the control group (eTable 7 in Supplement 2). The incidences of delayed TRAEs for any grade were comparable between the groups, apart from a higher incidence in the capecitabine group    Thus, our goal was to find a well-tolerated and effective regimen to add to a CCRT treatment backbone. Chen et al 19 found that metronomic capecitabine at a dose of 650 mg/m 2 twice daily for 1 year conferred a 9.6% FFS benefit despite 316 of 406 patients (77.8%) having received induction chemotherapy. That trial, but not ours, showed improved OS, although the cumulative dose intensities of capecitabine in both trials were comparable. The discordance in results thus suggests a need to further investigate the optimal duration and dosing of adjuvant capecitabine in LA-NPC because there could be antiangiogenic and immune modulation properties with metronomic dosing. 42,43 Patients' preferences and likelihood of compliance for a 6-month vs a 1-year course of treatment also need to be considered.
Although OS was not significantly different in the ITT population, the 3-year OS difference was 5.5% in favor of adjuvant capecitabine. The lack of statistical significance for OS is a consequence of the low number of death events even though we had enriched for high-risk factors in our study population (156 of 180 patients [86.7%] had ≥2 risk factors). The low number of deaths in our study could be due to the efficacious salvage therapies used at the time of recurrence, which included antiprogrammed cell death 1 antibody treatment and local metas-tasis-directed therapies (eTable 6 in Supplement 2). A metaanalysis of 19 trials investigating the role of CCRT in LA-NPC suggested that progression-free survival may be a justifiable surrogate for OS in this patient population. 42 This suggestion is further supported by recent trials for patients with NPC that reported FFS and corresponding OS benefits after 3 to 4 years of follow-up. 44-47 An updated meta-analysis will provide insights regarding whether progression-free survival remains a valid surrogate for OS among patients with LA-NPC given the emergence of effective salvage therapies.

Limitations
This study has several limitations. First, this trial did not meet the expected number of FFS events. The trial steering committee opted to report the study results at this juncture because longer follow-up may not have yielded the required number of events given the acute decrease in event rates beyond the third year of follow-up. Second, the high risk factors included in the eligibility criteria were chosen based on retrospective series. [27][28][29]31 In addition, EBV DNA assay and 18 F-FDG PET/CT are not widely available in the community, which may limit the applicability of our results. Third, a placebo control and masking of the physicians and patients to the treatments were not used in our trial. Fourth, most trial participants in both groups received only 2 cycles of 100 mg/m 2 of cisplatin with IMRT. Thus, there is a question of whether adjuvant capecitabine may only be beneficial for patients with high-risk LA-NPC (by the study criteria) who received this deintensified treatment. 48,49 To clarify, the predominant use of 2 cycles of cisplatin was due to the IMRT fractionation schema, as treatment was completed within 6 to 6.5 weeks. Several studies have reported that cumulative dosing of 160 to 200 mg/m 2 of cisplatin with radiotherapy is adequate to yield a survival advantage over radiotherapy alone among patients with LA-NPC. 50-52

Conclusions
The results of this randomized clinical trial indicated that treatment with adjuvant capecitabine following CCRT was well tolerated and had a high compliance rate. Long-term follow-up of nearly 5 years confirmed an FFS benefit with this treatment regimen. These results suggest that single-agent capecitabine may be considered an adjuvant regimen when treating patients with high-risk LA-NPC.