Head and neck cancer Concomitant Chemoradiotherapy

Concomitant chemoradiotherapy is the most promising primary chemotherapy approach to prolonging the survival of patients with locally advanced resectable and unresectable disease. It is the only systemic approach consistently shown to improve locoregional control and survival in randomized trials. Schedules of concomitant chemoradiotherapy can be synchronous, with both modalities administered close together, or alternating, with both administered in a nonoverlapping fashion. Both of these schedules offer distinct therapeutic advantages over regimens of strictly sequential treatment.

Radiotherapy and chemotherapy given concomitantly is a dose-intensive approach that exploits the independent complementary activity of radiotherapy locally and chemotherapy distantly (spatial cooperation) and the potentially enhanced local activity (within the radiotherapy field). Chemoradiotherapy approaches must attempt to incorporate full doses of both modalities. Suboptimal doses and/or schedules of either (eg, low-dose cisplatin or split-course radiotherapy) compromise dose intensity and, ultimately, survival. Dose intensities possible with concomitant chemoradiotherapy are higher in 2 to 3 months than those allowed by sequential chemoradiotherapy given over twice the time. Even if no direct drug-radiation synergy occurs, concomitant therapy should produce additive effects and avoid critical delays of either therapy. Unfortunately, the concomitant approach incurs severe toxicity (primarily mucositis), which is difficult to balance effectively with desired activity.

Concomitant single-agent chemoradiotherapy has been under investigation in head and neck cancer for over three decades. Numerous phase II trials have reported encouraging but inconclusive results. All cytotoxic drugs with major activity in this disease have been studied. Frequently, these have been administered in low doses during full-course conventional radiotherapy.

Pure radiosensitizer trials (ie, trials of drugs without independent activity in HNSCC) have been generally negative. Concomitant multiagent chemoradiotherapy began as a result of positive studies with concomitant single-agent chemotherapy and radiotherapy. The primary goal of these combined-agent trials was to reduce distant failures, which seem to be resistant to single-agent chemoradiotherapy; the secondary goal is to further enhance already excellent local control rates with concomitant approaches. Due to acute toxicity (mucositis), many trials used split-course radiotherapy, in which a period (or cycle) of concurrent chemoradiotherapy is followed by a planned interruption in all therapy to allow time for normal tissue recovery. Much of this work has been done in phase I/II feasibility trials designed to sort out issues of maximized dose intensity and minimized normal tissue toxicity. A popular variant of, or hybrid between, synchronous and sequential combined-agent chemoradiotherapy is the alternating approach. Its rationale is based in part on preclinical in vivo work (murine model) indicating that the approach reduces normal-tissue toxicity and therefore represents a compromise between synchronous and sequential chemoradiotherapy.