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.

A distinct advantage of single-agent over combined-agent concomitant trials is the simplicity of study design and more effective (continuous, uninterrupted) conventional or hyperfractionated radiotherapy. The split-course radiotherapy necessary with combined agents is inferior to uninterrupted radiotherapy. The rationale for pursuing combined-agent trials is based on the assumption that combined agents are better than single agents, an assumption that has not been proved in HNSCC. Survival rates with single-agent cisplatin are equivalent to those of any combination chemotherapy. Combined-modality approaches requiring reduced dose intensities of cisplatin may produce results inferior to to those of cisplatin alone at high doses.

Cisplatin-based concomitant multiagent regimens have been studied in several recent phase II trials. An increasing trend toward employing combinations of cisplatin and 5-fluorouracil with conventional or hyperfractionated split-course radiotherapy has been reported. Preclinical studies have demonstrated synergistic interactions between any two of these three treatments. Doses and schedules of cisplatin, 5-fluorouracil, and radiotherapy have varied considerably. The modulation of 5-fluorouracil by leucovorin and hydroxyurea as part of concomitant chemoradiotherapy regimens is under study.

A number of phase III trials have compared concomitant combination chemoradiotherapy with radiotherapy alone or with sequential chemoradiotherapy. A majority of the trials with control arms of radiotherapy alone showed that concomitant chemoradiotherapy produces an improvement in survival. A phase III multiagent concurrent chemotherapy/radiothrerapy trial reported by Calais and colleagues (one of the two most recent such trials) tested radiotherapy alone (70 Gy, standard fractionation) versus the same radiotherapy with concurrent carboplatin plus 5-FU in 226 patients with satage III or IV cancer of the oropharynx. This study demonstrated improvements in locoregional control (66% vs 42%, p = .03) and survival (51 vs 31, p = .02) with concurrent chemotherapy/radiotherapy. Adelstein and colleagues conducted a randomized study of three treatment arms - standard radiotherapy (70 Gy); radiotherapy plus concurrent cisplatin (identical radiotherapy with concurrent cis-diamminedichloroplatinum II [DDP] at 100 mg/m² IV on days 1, 22, and 43); or three cycles of concurrent DDP (75 mg/m² on day 1) plus 5-FU (1,000 mg/m²/d on days 1 to 4) with split-course radiotherapy (30 Gy first cycle, and 30 to 40 Gy third cycle) - in 295 stage III or IV patients with unresectable disease. Preliminary results showed that the concurrent high-dose DDP/chemoradiotherapy arm produced the best median survival of 12.6 months and projected 3-year survival rates of 37% versus 20% (p = .016), respectively, compared with the radiotherapy-alone arm. Survival rates were similar in the two concomitant-chemotherapy groups, which had more pronounced severe toxicity than had the radiotherapyalone group. Therefore, in unresectable HNSSC, improved patient survival can be achieved with concurrent radiotherapy (single-agent DDP), compared with radiotherapy alone. Several groups developed more-intensive combination chemoradiotherapy approaches. Early results from these nonrandomized studies indicate that the severe toxicity may be balanced by improved survival results.