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/m2 on day 1, cisplatin 75 mg/m2 on day 1, and fluorouracil 750 mg/m2 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.

Induction chemotherapy in the treatment of nasopharyngeal carcinoma: Clinical outcomes and patterns of care

“…These findings are also supported in induction studies DECIDE and PARADIGM for other head and neck sites where the induction arm had significantly more adverse events compared to the concurrent CRT alone arm. These studies also did not find an OS benefit with induction therapy 32, 33…”

Gemcitabine-Based Chemoradiation in the Treatment of Locally Advanced Head and Neck Cancer: Systematic Review of Literature and Meta-Analysis

“…The role of induction chemotherapy is still not fully elucidated. At this moment, there is no evidence that sequential administration of induction chemotherapy followed by CCRT is superior to CCRT alone, although some signals for a benefit in patients with oropharynx cancer and patients with bulky nodes are available [18][19][20].…”

Correlation of Ki-67 Proliferative Antigen Expression and Tumor Response to Induction Chemotherapy Containing Cell Cycle-Specific Agents in Head and Neck Squamous Cell Carcinoma

“…Prospective trials can reduce the impact or eliminate the limitations of this retrospective analysis. Although the clinical application of the hypothesis of our retrospective analysis may be critiqued due to the decline in interest in induction chemotherapy in HNSCC following two negative randomized induction chemotherapy trials [37,38], chemotherapy remains the backbone of treatment of incurable HNSCC and in this setting the potential of Ki-67 expression as a predictive marker of tumor response to chemotherapy should be assessed. Our analysis provides benchmark data to develop prospective trials to further assess this question.…”