NPC-0501 trial on the value of changing chemoradiotherapy sequence, replacing 5-fluorouracil with capecitabine, and altering fractionation for patients with advanced nasopharyngeal carcinoma.

BACKGROUND: A current recommendation for the treatment of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy (RT) with concurrent cisplatin followed by adjuvant cisplatin and 5-fluorouracil (PF). This randomized NPC-0501 trial evaluated the therapeutic effect of changing to an induction-concurrent sequence or accelerated-fractionation sequence, and/or replacing 5-fluorouracil with capecitabine (X). METHODS: Patients with American Joint Committee on Cancer/International Union Against Cancer stage III to stage IVB NPC initially were randomly allocated to 1 of 6 treatment arms (6-arm full-randomization cohort). The protocol was amended in 2009 to permit centers to opt out of randomization regarding fractionation (3-arm chemotherapy cohort). RESULTS: A total of 803 patients were accrued (1 of whom was nonevaluable) from 2006 to 2012. Based on the overall comparisons, neither changing the chemotherapy sequence nor accelerated fractionation improved treatment outcome. However, secondary analyses demonstrated that when adjusted for RT parameters and other significant factors, the induction-concurrent sequence, especially the induction-PX regimen, achieved significant improvements in progression-free survival (PFS) and overall survival. Efficacy varied among different RT groups: although no impact was observed in the accelerated-fractionation group and the 3-arm chemotherapy cohort, a comparison of the induction-concurrent versus concurrent-adjuvant sequence in the conventional-fractionation group demonstrated a significant benefit in PFS (78% vs 62% at 5 years; P = .015) and a marginal benefit in overall survival (84% vs 72%; P = .042) after adjusting for multiple comparisons. Comparison of the induction-PX versus the adjuvant-PF regimen demonstrated better PFS (78% vs 62%; P = .027) without an increase in overall late toxicity. CONCLUSIONS: For patients irradiated using conventional fractionation, changing the chemotherapy sequence from a concurrent-adjuvant to an induction-concurrent sequence, particularly using induction cisplatin and capecitabine, potentially could improve efficacy without an adverse impact on late toxicity. However, further validation is needed for confirmation of these findings.

Concurrent-Adjuvant Chemoradiation Therapy for Stage III-IVB Nasopharyngeal Carcinoma-Exploration for Achieving Optimal 10-Year Therapeutic Ratio.

PURPOSE: This is an updated combined analysis of 2 randomized studies (NPC-9901 and NPC-9902 trials) to evaluate the 10-year outcome attributed to the addition of concurrent-adjuvant chemotherapy for advanced locoregional nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Eligible patients with stage III-IVB nonkeratinizing NPC were randomly assigned to radiation therapy alone (RT: 218 patients) or chemoradiation therapy (CRT: 223 patients) using 3 cycles of cisplatin (100 mg/m2) concurrent with RT, followed by 3 cycles of cisplatin (80 mg/m2) and fluorouracil (1000 mg/m2/day for 4 days). All of the patients were irradiated with conventional fractionation to ≥66 Gy. The median follow-up was 13.9 years. RESULTS: Intention-to-treat analysis confirmed that the CRT group achieved significant improvement in 10-year failure-free rate (FFR: 62% vs 52%, P = .016), progression-free survival rate (PFS: 56% vs 44%, P = .008), and overall survival rate (OS: 60% vs 50%, P = .044). There was no significant increase in overall late toxicity rate (51% vs 48%, P = .34) or noncancer deaths (19% vs 16%, P = .52). Exploratory studies showed no difference in disease control between 2 or 3 cycles of concurrent cisplatin; however, patients given 3 concurrent cycles had a significant increase in hearing impairment (40% vs 24%, P = .017). Only those who continued to receive 2 or more cycles of adjuvant cisplatin-fluorouracil achieved significant improvement in distant control (73% vs 65%, P = .037) and maximal survival gain. CONCLUSION: The addition of concurrent cisplatin plus adjuvant cisplatin-fluorouracil could significantly improve overall survival and disease control without incurring a significant increase in late toxicity or noncancer deaths. Exploratory analyses suggested that both the concurrent and the adjuvant phases contributed to tumor control. Furthermore, the number of concurrent cycles could be reduced from 3 to 2 cycles in order to achieve a similar survival benefit without incurring an excessive increase in hearing impairment. This is a useful hypothesis that warrants further validation.

A multicenter, phase 3, randomized trial of concurrent chemoradiotherapy plus adjuvant chemotherapy versus radiotherapy alone in patients with regionally advanced nasopharyngeal carcinoma: 10-year outcomes for efficacy and toxicity.

BACKGROUND: Concurrent-adjuvant chemoradiotherapy (CRT) became a recommended treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) with the first report of a significant survival benefit from the Intergroup 0099 study. However, data on late toxicities are lacking. Previous reports from the current NPC-9901 trial have raised concerns about a failure to improve overall survival (OS) because of an inadequate impact on distant control and increases in toxicities/noncancer deaths. Validation of the long-term therapeutic ratio is needed. METHODS: In this phase 3, randomized trial, patients with nonkeratinizing NPC (stage T1-4/N2-3/M0) were randomly assigned to radiotherapy alone (176 patients) or to CRT (172 patients) with concurrent cisplatin followed by adjuvant cisplatin plus fluorouracil. RESULTS: The early findings of significant improvements in tumor control were maintained: the CRT group achieved significantly higher 10-year overall failure-free (62% vs 50%; P = .01) and progression-free survival rates (56% vs 42%; P = .006) because of superior locoregional control (87% vs 74%; P = .003), whereas the impact on distant control remained insignificant (68% vs 65%; P = .24). The initial differences in toxicities diminished with longer follow-up: 52% versus 47% at 10 years for late toxicities (P = .20), 4.1% versus 2.8% for deaths due to treatment toxicity, and 15.1% versus 13.1% for deaths due to incidental/unknown causes. The OS rate for the CRT group reached statistical superiority at 10 years (62% vs 49%; P = .047). CONCLUSIONS: Long-term results have confirmed that CRT can significantly improve OS without excessive late toxicities for patients with regionally advanced NPC. However, more potent therapy is needed for improving distant control, especially for patients with stage IVA/B disease. Cancer 2017;123:4147-4157. © 2017 American Cancer Society.