Improved Outcome by Adding Concurrent Chemotherapy to Cetuximab and Radiotherapy for Locally Advanced Head and Neck Carcinomas: Results of the GORTEC 2007-01 Phase III Randomized Trial

Abstract

Purpose To investigate the effect of adding concurrent chemotherapy (CT) to cetuximab plus radiotherapy (RT; CT-cetux-RT) compared with cetuximab plus RT (cetux-RT) in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Patients and Methods In this phase III randomized trial, patients with N0-2b, nonoperated, stage III or IV (nonmetastatic) LA-SCCHN were enrolled. Patients received once-daily RT up to 70 Gy with weekly cetuximab or with weekly cetuximab and concurrent carboplatin and fluorouracil (three cycles). To detect a hazard ratio (HR) of 0.64 for progression-free survival (PFS) with 85% power at a two-sided significance level of P = .05, 203 patients needed to be included in each arm. Results Four hundred six patients were randomly assigned to either CT-cetux-RT or cetux-RT. Patient and tumor characteristics were well balanced between arms, including p16 status. With a median follow-up of 4.4 years, the HR for PFS favored the CT-cetux-RT arm (HR, 0.73; 95% CI, 0.57 to 0.94; P = .015), with 3-year PFS rates of 52.3% and 40.5% and median PFS times of 37.9 and 22.4 months in the CT-cetux-RT and cetux-RT arms, respectively. The HR for locoregional control was 0.54 (95% CI, 0.38 to 0.76; P < .001) in favor of CT-cetux-RT. These benefits were observed regardless of p16 status for oropharynx carcinomas. Overall survival (HR, 0.80; P = .11) and distant metastases rates (HR, 1.19; P = .50) were not significantly different between the two arms. The CT-cetux-RT arm, compared with cetux-RT, had a higher incidence of grade 3 or 4 mucositis (73% v 61%, respectively; P = .014) and of hospitalizations for toxicity (42% v 22%, respectively; P < .001). Conclusion The addition of concurrent carboplatin and fluorouracil to cetux-RT improved PFS and locoregional control, with a nonsignificant gain in survival. To our knowledge, this is the first evidence of a clinical benefit for treatment intensification using cetux-RT as a backbone in LA-SCCHN.

A randomized phase 3 trial comparing nimotuzumab plus cisplatin chemoradiotherapy versus cisplatin chemoradiotherapy alone in locally advanced head and neck cancer

“…The addition of nimotuzumab improved 2-year PFS and decreased the hazard of progression by 31%. Hence we believe that our results echo the findings of the RTOG 0522 subgroup analysis and the recently reported GORTEC (the French Head and Neck Radiation Oncology Group) study, 18 suggesting that younger patients and those with adverse prognostic features typically benefit from the nimotuzumab-weekly cisplatin concurrent combination (lighter CRT). The improvement in OS was not significant.…”

“…The use of nimotuzumab in this cohort of patients led to a decrease in the risk of progression by nearly 50%, which translated into a decrease in the risk of death by 37%. Hence we believe that our results echo the findings of the RTOG 0522 subgroup analysis and the recently reported GORTEC (the French Head and Neck Radiation Oncology Group) study, 18 suggesting that younger patients and those with adverse prognostic features typically benefit from the nimotuzumab-weekly cisplatin concurrent combination (lighter CRT). Second, in the RTOG 0522 study, concurrent cetuximab with cisplatin led to more adverse events, which, in turn, led to more toxicity-related radiation interruptions (26.9% vs 15.1%, respectively).…”

Treating Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck Unsuitable to Receive Cisplatin-Based Therapy

“…A recent study demonstrated that the addition of concurrent carboplatin and fluorouracil to cetuximab (three cycles) + radiotherapy resulted in improved PFS and locoregional control. However, the gain in OS was not significant (119).…”

“…There are no phase III data showing benefit of cetuximab in combination with radiotherapy in the non-platinum-eligible population. Notably, combinations of cetuximab with noncisplatin chemoradiotherapy agents, such as carboplatin plus paclitaxel or 5-FU, are currently being investigated and have thus far shown promising results (117)(118)(119). A recent study demonstrated that the addition of concurrent carboplatin and fluorouracil to cetuximab (three cycles) + radiotherapy resulted in improved PFS and locoregional control.…”

Nimotuzumab-cisplatin-radiation versus cisplatin-radiation in HPV negative oropharyngeal cancer

“…This population, even in RTOG 0522 showed a trend towards improvement with the addition of cetuximab [8]. Another phase 3 study, exploring the role of cetuximab along with carboplatin -5 FU with radiation, reported improvement in outcomes with the addition of cetuximab [9]. The probable reason for this was probably due to the predominant HPV negative disease.…”