Neoadjuvant Therapy - Head and neck cancer

Neoadjuvant (induction) therapy prior to surgery is sometimes referred to as sequential chemoradiotherapy when chemotherapy is followed by definitive radiotherapy. This latter approach specifically excludes or limits the extent of surgery, except in treatment failures, and is growing in importance as an "organ preservation" approach for locally advanced resectable disease. The neoadjuvant concept has been expanded to include novel studies of neoadjuvant chemotherapy followed by concomitant chemoradiotherapy.

The use of chemotherapy as induction treatment prior to local therapy for advanced HNSCC has been evaluated for about 20 years. The strong rationale for this approach comes from mathematical models of cell kinetics and acquired drug resistance and from preclinical in vivo data. The principal objectives of induction are as follows: to promote regression and thereby enhance subsequent locoregional therapy; to identify patients with responding lesions that might be controlled by more conservative local treatment (organ preservation) rather than by extensive surgical procedures; to use chemotherapy before tumor and normal vasculature is altered by surgery or radiation; to identify responding tumors that may benefit from adjuvant chemotherapy following surgery or radiotherapy; and to provide early treatment for micrometastatic disease.

Early nonrandomized neoadjuvant trials based their selections of agents on trials in recurrent disease. Single-agent early trials achieved response rates of 30% to 40%. Gradually, neoadjuvant studies expanded to include multiagent therapy including cisplatin plus infusional 5-FU, which produced response rates of 70% to 80% (CR rates of 30% to 40%) but no long-term benefit. More recently, attempts to develop more active therapy include the integration of taxanes and regional therapy.

Over 30 randomized multiagent trials of neoadjuvant therapy with or without adjuvant chemotherapy compared with local therapy control groups have been reported to date. Although none have shown that neoadjuvant therapy significantly improves survival, many of these trials had major design limitations. These limitations include suboptimal patient numbers, relatively inactive induction regimens (median complete response rate < 20%), variations in locoregional therapies (surgery alone, surgery and radiotherapy, radiotherapy alone), heterogeneous study populations with multiple primary sites, and resectable and unresectable cases (Table 90-27). None of the neoadjuvant regimens produced a CR rate of greater than 50%. Most of the randomized studies had such small study numbers (fewer than 75 patients per arm) that they could not detect significant survival differences below 25%.

Organ preservation is an important goal of primary chemotherapy. Those patients fortunate enough to survive their cancer often face a lifetime of significant morbidity because of cosmetic and functional debilities from surgical resection. Despite marked advances in reconstructive surgery and rehabilitation, patients who have undergone laryngectomy, glossectomy, or composite resection still have major debility. Unfortunately, the importance of organ and function preservation often is ignored. Many opt to receive the less effective therapy of radiation alone to avoid curative surgery. They risk shorter survival rather than face increased survival with severe surgical morbidity. An active area of HNSCC research involves chemoradiotherapy (sequential or concomitant) to facilitate organ-preserving approaches for advanced disease. This research is designed to preserve anatomic structures without compromising survival. In such studies, extensive surgery is reserved to salvage patients who fail to respond to initial therapy or whose disease recurs.