Adjuvant Capecitabine Following Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: A Randomized Clinical Trial

Abstract

Importance: Induction or adjuvant chemotherapy with concurrent chemoradiotherapy (CCRT) are first-line treatment options for treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Adjuvant platinum regimens are, however, poorly tolerated, highlighting the unmet need for an efficacious, tolerable adjuvant regimen.

Objective: To investigate the efficacy and safety of adjuvant capecitabine with CCRT for the treatment of patients with LA-NPC.

Design, setting, and participants: This open-label randomized clinical trial recruited patients from March 31, 2014, to July 27, 2018, at 3 institutions in China, with at least 3 years of follow-up. The data collection cutoff date was February 9, 2022. Eligibility included stage III-IVb nasopharyngeal carcinoma and at least 1 of the following: T3-4N2 or T1-4N3; plasma Epstein-Barr virus DNA titer higher than 20 000 copies/mL; primary gross tumor volume larger than 30.0 cm3; fluorodeoxyglucose F 18 positron emission tomography/computed tomography maximum standard uptake value of the primary gross tumor volume larger than 10.0; or multiple nodal metastases and any larger than 4.0 cm.

Interventions: Patients were randomly assigned 1:1 to receive either capecitabine (1000 mg/m2 twice daily for 14 days every 3 weeks for 8 cycles) or observation following CCRT (100 mg/m2 cisplatin every 3 weeks for 2 to 3 cycles, depending on duration of radiotherapy).

Main outcomes and measures: Failure-free survival in the intention-to-treat cohort was assessed using Kaplan-Meier survival curves compared with the log-rank test. Unstratified Cox proportional hazards regression models were used to estimate hazard ratios, with corresponding 95% CIs based on the Wald test.

Results: There were 180 patients enrolled (median [IQR] age, 47 [40-55] years; 143 [79.4%] men). Among 90 patients in the capecitabine group, 76 (84.4%) had at least 2 high-risk factors; among 90 patients in the control group, 80 (88.9%) had at least 2 high-risk factors. All patients completed CCRT, except 1 patient in the capecitabine group who received 1 cycle of cisplatin. Of the 90 patients in the capecitabine group, 85 (94.4%) received capecitabine, with 71 (78.9%) completing 8 cycles. With a median (IQR) follow-up of 58.0 (49.5-80.1) months, 18 events were recorded in the capecitabine group vs 31 events in the control group. Failure-free survival was improved with adjuvant capecitabine (3 years, 83.3% vs 72.2%; 5 years, 78.5% vs 65.9%; hazard ratio, 0.53 [95% CI, 0.30-0.94]; P = .03). The incidence of grade 3 treatment-related adverse events (TRAEs) was higher in the capecitabine group than in the control group (54 of 90 patients [60.0%] vs 46 of 90 patients [51.1%]). Treatment-related adverse events included xerostomia (17 [18.9%] vs 9 [10.0%] patients), mucositis (21 [23.3%] vs 15 [16.7%] patients), and anorexia (8 [8.9%] vs 4 [4.4%] patients). The incidence of grade 3 delayed treatment-related adverse events was comparable in both groups (9 of 83 [10.8%] vs 7 of 81 [8.6%] patients).

Conclusions and relevance: In this randomized clinical trial, adjuvant capecitabine at the full dose following CCRT was well tolerated and improved failure-free survival among patients with LA-NPC and high-risk factors. Further investigations assessing optimal dose and duration are warranted.

Trial registration: ClinicalTrials.gov Identifier: NCT02143388.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Chua reported receiving personal fees from Astellas, Janssen, Bayer, Pfizer, Merck Sharp & Dohme, Varian, IQVIA, Telix Pharmaceuticals; receiving personal fees and nonfinancial support from AstraZeneca, nonfinancial support from Decipher Biosciences and MedLever; being a consultant for immunoSCAPE; being a coinventor of and patent holder in Singapore for a high-sensitivity lateral flow immunoassay for detection of analyte in sample; and serving on the board of directors of Digital Life Line Pte Ltd, which owns the licensing agreement of the patent, all outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Trial Profile

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. aPatient purchased adjuvant capecitabine off protocol from another hospital.

Figure 2.. Survival Curves in the Intention-to-Treat Set

DMFS represents distant metastasis–free survival; FFS, failure-free survival; HR, hazard ratio; LRFS, locoregional relapse–free survival; and OS, overall survival.