Induction Redux: Once More With Taxanes

For more than two decades, induction chemotherapy has been an attractive treatment strategy in patients with locoregionally advanced squamous cell head and neck cancer. In previously untreated patients, overall response rates of 70% to 90% and complete response rates of 30% to 50% have been reproducibly reported after combination chemotherapy with regimens such as fluorouracil plus cisplatin. These responses were gratifying to both patients and their physicians and promised the benefit of decreased morbidity and increased survival after definitive locoregional management. When phase III clinical trials of this approach were completed, however, the results proved disappointing. With rare exception, these studies were unable to demonstrate either a survival benefit or an improvement in locoregional control with induction chemotherapy before definitive management. Despite the impressive clinical responses seen with induction chemotherapy, interest in this treatment strategy subsequently waned. Concurrent chemotherapy and radiation therapy schedules have proven far more successful. Multiple studies of both single-agent chemotherapy and combination chemotherapy administered with concomitant definitive radiation have been conducted, and clear survival and locoregional control benefits have been demonstrated. Radiation with concurrent single-agent cisplatin has been established as a standard of care in the management of patients with unresectable head and neck cancers, patients with nasopharyngeal cancers, and postoperative patients with poor prognostic features and as a larynx preservation strategy. These conclusions have been confirmed and strengthened by the large Meta-Analysis of Chemotherapy on Head and Neck Cancer, which reported an 8% overall survival benefit (P .0001) from concurrent chemoradiotherapy regimens. However, this same meta-analysis was unable to demonstrate an overall survival advantage after neoadjuvant treatment, although when only those induction trials using a platinum and fluorouracil combination were examined, a marginally favorable benefit was noted (P .05). Despite this limited survival benefit from sequential treatment schedules, systemic chemotherapy has had an impact on the incidence of distant metastases. Both in the induction and adjuvant settings, the fluorouracil plus cisplatin combination has significantly decreased the likelihood of distant metastatic failure. That this did not result in improved overall survival likely reflects the limited importance of distant metastases in a disease usually marked by locoregional failure. As chemoradiotherapy schedules have become more intensive, this historical pattern of disease failure seems to have been altered. Recent single-institution phase II trials of aggressive chemoradiotherapeutic protocols, using multiagent chemotherapy and altered-fractionation radiation, have reported locoregional control rates in excess of 90% and the emergence of distant metastases as the most frequent cause of treatment failure. These data have rekindled interest in the potential use of induction chemotherapy in conjunction with definitive concurrent treatment in an effort to further improve survival by decreasing distant metastases. Along with this renewed interest in induction chemotherapy have been continued attempts to improve on the well-tested fluorouracil plus cisplatin combination. The taxanes have been identified as agents with considerable biologic activity in head and neck cancer, although for recurrent or metastatic head and neck cancer, the two-drug combination of paclitaxel and cisplatin has proven no more efficacious than conventional fluorouracil and cisplatin. More promising have been the phase II trials in previously untreated patients, which have explored threedrug combinations of cisplatin, fluorouracil, and a taxane. Response rates of 88% to 93%, with complete response rates as high as 59%, have been reported from these trials. Thus, the question of the most effective JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 34 DECEMBER 1 2005