Head and neck cancer Adjuvant Chemotherapy

Adjuvant chemotherapy to eradicate micrometastases following local therapy has not been studied extensively in HNSCC. The principal objectives of adjuvant trials have been to control subclinical persistent disease after surgery or radiotherapy and to decrease the rates of locoregional and distant relapse. The ideal study design would include enrollment of (high-risk) patients with resectable advanced disease, early administration after local therapy to avoid drug resistance, and an effective regimen. Although no study has met all of these criteria, promising leads for future studies have emerged.

A number of randomized studies have evaluated the impact of adjuvant multiagent chemotherapy with no clear survival impact. The most definitive data of adjuvant therapy were recently reported. The preliminary analysis of a phase III prospective adjuvant chemotherapy trial conducted by the RTOG in a "high-risk group" of patients with HNSCC was reported recently by Cooper and colleagues. Patients were randomized to receive radiotherapy alone (60 to 66 Gy) (231 patients) versus radiotherapy plus cis-diamminedichloroplatinum (CDDP) (100 mg/m² on days 1, 22, and 43) (228 patients), and the primary endpoint was locoregional control. In the postoperative adjuvant setting, there was no significant improvement in locoregional control or overall survival in the concurrent CDDP/radiotherapy arm.

Disease-free survival was significantly improved but at the cost of significant acute and total toxicity. The preliminary primary finding was surprising since the same concurrent regimen has been shown to increase overall and disease-free survival (when compared with radiotherapy alone) in advanced NPC and unresectable HNSCC.

Neoadjuvant (or Concomitant) plus Adjuvant Chemotherapy
This is an important primary therapy study design. The largest of these is an National Cancer Institute (NCI)-sponsored multi-institutional trial, begun in 1978, called the Head and Neck Contracts Program. Over 400 patients with resectable stage III or IV disease were randomized to (1) induction chemotherapy (one cycle of cisplatin and bleomycin) followed by standard therapy (surgery and radiotherapy in all study arms); (2) induction chemotherapy followed by standard therapy followed by six cycles of adjuvant monthly cisplatin (80 mg/m²) by 24-h continuous infusion; or (3) standard local therapy only. At a median follow-up of more than 5 years, the disease-free and overall survivals were not significantly different among the three arms. This study has been criticized because of its one cycle of induction chemotherapy, considered suboptimal (3% complete response, 34% objective response), and a striking noncompliance rate in the adjuvant-therapy arm (47% never received any maintenance therapy). Subset analyses of this study suggested improved disease-free and/or overall survival in three subgroups: lesions of the oral cavity, T1-2 primary lesions, and N1-2 regional disease. This approach is under active study with newer induction and concomittant regimens.