Adding Induction Chemotherapy to Chemoradiotherapy Does Not Improve Survival in Patients With N2 or N3 Locally Advanced Head and Neck Cancer
In a phase III trial reported in the Journal of Clinical Oncology, Cohen et al found that induction chemotherapy before chemoradiotherapy did not improve overall survival vs chemoradiotherapy alone in patients with N2 or N3 locally advanced squamous cell carcinoma of the head and neck. The study was underpowered for statistical conclusions because target accrual was not met and overall survival was greater than predicted in both treatment groups.
Study Details
In the trial, 273 treatment-naive patients with nonmetastatic N2 or N3 squamous cell carcinoma of the head and neck were randomly assigned to receive chemoradiotherapy alone (n = 135; docetaxel, fluorouracil [5-FU], and hydroxyurea plus radiotherapy at 0.15 Gy twice per day every other week) or two 21-day cycles of induction chemotherapy (docetaxel at 75 mg/m2 on day 1, cisplatin at 75 mg/m2 on day 1, and 5-FU at 750 mg/m2 on days 1 to 5) followed by chemoradiotherapy (n = 138). The primary endpoint was overall survival.
Patients in the induction chemotherapy group and control group had a mean age of 57 years, 82% and 87% were male, 84% and 85% were white, and 15% and 14% were African American. The two groups were generally well balanced for smoking and alcohol history, Karnofsky performance status, primary tumor site, T stage, N stage, American Joint Committee on Cancer stage, and comorbidities.
The trial was initiated in December 2004 with a target population of 400 to provide 88% power to detect a hazard ratio (HR) of 0.625 for overall survival for the induction vs control group. Slow accrual resulted in amendment to a smaller sample size and prolonged follow-up. However, the lower-than-expected event rates in both groups resulted in only 56% power to detect the hazard ratio of 0.625.
No Survival Difference
After minimum follow-up of 30 months, there were no differences in the induction vs control groups for overall survival (unadjusted HR = 0.91, 95% confidence interval [CI] = 0.59–1.41, P = .68), distant failure-free survival (unadjusted HR = 0.83, 95% CI = 0.55–1.25, P = .37), or recurrence-free survival (unadjusted HR = 0.76, 95% CI = 0.51–1.12, P = .16). The overall response rate to induction chemotherapy was 64%, and response rates after chemoradiotherapy were 79% in the induction group and 74% in the chemoradiotherapy-alone group.
Toxicity
During induction chemotherapy, the most common adverse events of any grade were those due to myelosuppression. Grade 2 or higher mucositis occurred in approximately one-third of patients, and fatigue, alopecia, dehydration, and nausea occurred in approximately one-quarter.
The most common grade 3 or 4 adverse events during induction were febrile neutropenia (11%) and mucositis (9%). The most common grade 3 or 4 adverse events during chemoradiotherapy in both groups combined were mucositis (49%), dermatitis (21%), and leukopenia (18%). Serious adverse events were more common in the induction chemotherapy group (47% vs 28%, P = .002) but were of similar frequency during chemoradiotherapy (26% vs 28%).
The investigators concluded, “[Induction chemotherapy] did not translate into improved overall survival compared with chemoradiotherapy alone. However, the study was underpowered because it did not meet the planned accrual target, and overall survival was higher than predicted in both arms. [Induction chemotherapy] cannot be recommended routinely in patients with N2 or N3 locally advanced [squamous cell carcinoma of the head and neck].
Ezra E.W. Cohen, MD, of University of California, San Diego, Moores Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by sanofi-aventis and the Robert and Valda Svendsen Foundation. For full disclosures of the study authors, visit jco.ascopubs.org.
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