There are two basic intents to the addition of chemotherapy to the treatment regimen for head and neck cancer: (1) there is potentially a synergistic effect with radiotherapy by the chemotherapy altering the radiobiologic parameters a, b, and TD (the effective tumor-doubling time), and (2) the chemotherapy might be effective at eradicating micrometastases and thus reducing the incidence of distant metastases.

Early trials tested the sequential use of chemotherapy and radiotherapy. To date there has been no consistent overall improvement in locoregional control or survival, using sequential chemotherapy. However, there have been several large randomized studies that have shown a reduction in the incidence of distant metastases even though the basic intent of these studies was different. The Intergroup Study 0034 investigated the effect of adding sequential chemotherapy after surgery and prior to radiotherapy for patients with operable tumors.

The Head and Neck Contracts study compared three arms: one arm with “standard therapy” consisting of surgery and postoperative radiotherapy, one arm with induction chemotherapy prior to “standard therapy,” and one arm with induction chemotherapy followed by “standard therapy” followed by maintenance chemotherapy. A Southwest Oncology Group (SWOG) study investigated the use of induction chemotherapy prior to surgery, and the Veterans Administration (VA) laryngeal study investigated using the response to induction chemotherapy as a predictor of radioresponsiveness. The Pardua, Italy, study compared the effect of four cycles of neoadjuvant chemotherapy plus radiation to radiation alone for patients with inoperable tumors. The common finding in all these studies was a reduction in the overall incidence of distant metastases for the patients on the chemotherapy arm (in the case of the Head and Neck Contracts study it was only for the group on the maintenance chemotherapy arm).

A recent meta-analysis performed by the MACH-NC Collaborative Group showed no survival benefit to adjuvant or neoadjuvant chemotherapy in an analysis of 3,670 patients who had been entered onto 39 different trials. Hence, other than in an organ preservation approach as is often used for advanced laryngeal cancer, interest has shifted to the use of concomitant chemotherapy. In a separate meta-analysis involving 1,908 patients entered into 26 randomized trials, the MACH-NC Collaborative Group found an absolute survival benefit at 5 years of 8% with the use of concomitant chemotherapy (p < .0001). There have been two major randomized trials for nasopharyngeal tumors and laryngeal tumors that show a benefit to concomitant chemotherapy and radiotherapy. These studies are discussed in the site-specific sections of this section.

There is evidence that concomitant chemotherapy can improve results even if hyper- fractionated or accelerated radiotherapy regimens are used. Brizel and colleagues compared hyperfractionated radiotherapy with concomitant chemotherapy to hyperfractionated radiotherapy alone for patients with locally advanced tumors. The chemotherapy consisted of low-dose cisplatin and 5-FU, with two additional cycles of chemotherapy being given after completion of the radiotherapy. At 3 years, the locoregional control was 70% in the combined modality group compared to 34% in the radiation-alone group (p = .07) while the overall survivals were, respectively, 55% and 34% (p = .08). The rates of confluent mucositis were equivalent on the two arms, 77% versus 75%. A German study showed a mixed benefit to concomitant chemotherapy and radiotherapy versus radiotherapy alone for patients with locally advanced head and neck cancer when a concomitant-boost regimen was used. The chemotherapy consisted of carboplatinum and 5-FU, and there was second randomization testing the effects of giving granulocyte colony-stimulating factor (G-CSF) prophylactically. At 2 years there was a nonstatistically significant trend toward improved locoregional control and local control-specific survival for tumors of the oropharynx with the addition of chemotherapy but no suggestion of benefit for patients with tumors of the hypopharynx. The use of G-CSF appeared to adversely impact survival. Given the potential for increased toxicity, the use of concomitant chemotherapy and altered fractionated radio-therapy should be confined to the clinical trial setting.