Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer

Abstract

Purpose: Induction chemotherapy (IC) before radiotherapy lowers distant failure (DF) rates in locally advanced squamous cell carcinoma of the head and neck (SCCHN). The goal of this phase III trial was to determine whether IC before chemoradiotherapy (CRT) further improves survival compared with CRT alone in patients with N2 or N3 disease.

Patients and methods: Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were randomly assigned to CRT alone (CRT arm; docetaxel, fluorouracil, and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week) versus two 21-day cycles of IC (docetaxel 75 mg/m(2) on day 1, cisplatin 75 mg/m(2) on day 1, and fluorouracil 750 mg/m(2) on days 1 to 5) followed by the same CRT regimen (IC + CRT arm). The primary end point was overall survival (OS). Secondary end points included DF-free survival, failure pattern, and recurrence-free survival (RFS).

Results: A total of 285 patients were randomly assigned. The most common grade 3 to 4 toxicities during IC were febrile neutropenia (11%) and mucositis (9%); during CRT (both arms combined), they were mucositis (49%), dermatitis (21%), and leukopenia (18%). Serious adverse events were more common in the IC arm (47% v 28%; P = .002). With a minimum follow-up of 30 months, there were no statistically significant differences in OS (hazard ratio, 0.91; 95% CI, 0.59 to 1.41), RFS, or DF-free survival.

Conclusion: IC did not translate into improved OS compared with CRT alone. However, the study was underpowered because it did not meet the planned accrual target, and OS was higher than predicted in both arms. IC cannot be recommended routinely in patients with N2 or N3 locally advanced SCCHN.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

© 2014 by American Society of Clinical Oncology.

Figures

Fig 1.

CONSORT diagram. Five patients' treatment deviated substantially from protocol at a single center, and all patients enrolled at that center were excluded from analysis. Six patients withdrew consent before receiving treatment, and one patient was determined to have been ineligible because of lung metastasis. CRT, chemoradiotherapy; IC, induction chemotherapy.

Fig 2.

Treatment delivery. (A) Induction chemotherapy delivery; percentage of patients receiving target dose and 110% of target dose, and

Fig 3.

Survival by treatment arm and corresponding P values. (A) Overall, (B) distant failure–free, and (C) recurrence-free survival. Blue lines indicate induction followed by concurrent chemoradiotherapy arm; gold lines indicate concurrent chemoradiotherapy arm.

Fig 4.

Competing risk analysis. Cumulative incidence of (A) death resulting from squamous cell carcinoma of head and neck (SCCHN), (B) death resulting from causes other than SCCHN, (C) locoregional recurrence without prior distant recurrence, (D) distant recurrence without prior locoregional recurrence, and (E) death without prior locoregional or distant recurrence. CRT, chemoradiotherapy; IC, induction chemotherapy.

Fig 5.

Subset analysis of overall survival for patients with (A) human papillomavirus, (B) oropharyngeal disease, (C) nonoropharyngeal disease, (D) N2a or N2b disease, and (E) N2c or N3 disease. CRT, chemoradiotherapy; IC, induction chemotherapy.

Fig 6.

Landmark analysis of survival based on response; overall survival by response to induction chemotherapy. P value is for comparison of responders versus nonresponders.

Fig A1.

Study schema. Patients randomly assigned to induction chemotherapy received docetaxel 75 mg/m2 (D), cisplatin 75 mg/m2 (P), and fluorouracil 750 mg/m2 (F). Chemoradiotherapy in all patients consisted of D, F, hydroxyurea, and radiation (DFHX).

Fig A2.

Overall survival analysis by T stage. Patients with (A) TX/0/1/2 tumors and (B) T3/4 tumors. CRT, chemoradiotherapy; IC, induction chemotherapy.