Clinical testing of new cytotoxic agents traditionally has been conducted first in patients with recurrent disease, followed by testing in combined modality treatments in patients with potentially curable disease. The majority of patients included in the following discussion has recurrent disease and constitute the principal study group; a minority have metastatic or advanced unresectable disease. We refer to this patient group generically as “recurrent,” although many studies discussed under this rubric include the minority cases also.

Chemotherapy has had no impact on overall survival in recurrent HNSCC. The purely clinical noninvestigational goal of chemotherapy in recurrent disease has been to achieve palliation, unlike the goal of primary chemotherapy trials, which is to cure locally advanced untreated cancer. The overall prognosis in recurrent HNSCC is dismal (median survival of 4 to 6 months).

Lumped diagnostically under HNSCC is a diverse group of cancers with markedly variable natural histories (fully discussed in the “Biology” section above) and, therefore, markedly variable responses to chemotherapy. Important diversities also occur in HNSCC relapse patterns, that is, at the primary site, in regional nodes, and at distant sites after definitive local therapy. These and many other diversities make it extremely difficult to interpret results of chemotherapy trials in cancers of this region.

Many chemotherapy studies encompass all guises of recurrent HNSCC. They run the gamut from minimal, resectable disease seen locally after radiation therapy to bulky regional and distant disease occurring after surgery, radiotherapy, and even primary and/or salvage chemotherapy. Often these last salvage patients are excluded from further chemotherapy trials because of their extremely poor prognosis. Other poor-risk patients, such as those with unresectable disease resistant to neoadjuvant chemotherapy or with short disease-free intervals or persistent disease after primary therapy, are included in many trials. Although patients with advanced resectable disease should be included in trials of primary therapy, the varying definition of resectable among different head and neck surgeons can place these patients in “recurrent” trials.

Single-Agent Trials
Response rates of different trials with the same agent have varied markedly due to HNSCC’s great heterogeneity and because of differences in trial designs. Pooled results indicate that eight drugs show single-agent response rates of 15% or higher and remission durations of 3 to 5 months (

Table 90-26). The five longest-studied of these agents are methotrexate, cisplatin, bleomycin, 5-FU, and carboplatin. The three newer agents in this group are paclitaxel, docetaxel, and ifosfamide.

Methotrexate, according to many oncologists, is the standard palliative therapy for recurrent or metastatic HNSCC. The standard dose and schedule for palliation are 40 mg/m²/wk intravenously or intramuscularly, with dose escalations to 60 mg/m₂/wk until mild toxicity or any tumor response is achieved. This methotrexate dose and schedule are relatively nontoxic, inexpensive, and convenient, features that are critical to palliative therapy.

Cisplatin is an important component of combinations of chemotherapeutic drugs for HNSCC. Most studies have given cisplatin in an intermittent standard-dose bolus schedule (80 to 120 mg/m₂ every 3 to 4 weeks).

The dose-response relationship between cisplatin and HNSCC has been studied by several groups but remains unproven. Driven by the major activity and legendary toxicities of cisplatin, analogue development has moved faster with this drug than with other drugs. Carboplatin is a second-generation platinum complex with activity equivalent to and toxicity less than those of cisplatin. Bolus carboplatin has pharmacokinetic and toxicity profiles similar to those of continuous-infusion cisplatin and has significantly less renal, otologic, neurologic, and gastrointestinal (nausea/vomiting) toxicity than bolus cisplatin. Reversible myelosuppression (primarily thrombocytopenia) is the dose-limiting toxicity for carboplatin.

Single-agent studies of carboplatin given monthly in bolus (400 mg/m²) or fractionated (80 mg/m²/d for 5 days) schedules produced objective response rates of 20% to 30% in recurrent and metastatic HNSCC. Combined carboplatin and cisplatin have not shown increased activity over the respective single agents.

Bleomycin has been studied extensively as a single agent and in combinations in HNSCC. Its spectrum of toxicity is distinctive. Dose intensity is directly associated with mucositis, and total cumulative dosage is directly associated with skin toxicity and with the most feared side effect, pulmonary fibrosis. Bleomycin’s lack of myelosuppression, even with prolonged continuous infusion, promotes its use in combinations. Continuous-infusion regimens produce less pulmonary toxicity but are not clearly more active clinically than intermittent-bolus schedules in HNSCC.

5-Fluorouracil has limited single-agent activity in HNSCC (

see Table 90-26). It has been given in varying doses as an intravenous bolus daily (for 5 days), weekly or every 3 or 4 weeks. The dose-limiting toxicity of bolus administration is myelosuppression; prolonged administration is limited by mucositis, diarrhea, and cutaneous erythema. Schedule dependency of 5-FU treatment has received little study in HNSCC, although long-term continuous low-dose infusion (eg, 6 weeks) is effective palliation for recurrent disease. Continuous-infusion regimens were designed initially to reduce myelosuppression and seem to have enhanced activity. Despite 5-FU’s modest single-agent activity in HNSCC, preclinical studies indicating its synergistic interaction with radiation and its enhanced cytotoxicity with chemical modulators (eg, leucovorin) have led to study of this agent in HNSCC.

Randomized trials have compared different single agents in recurrent HNSCC. Two phase III studies have directly compared cisplatin and methotrexate (randomized, two-arm design). In the first of these studies, Hong and colleagues gave cisplatin at 50 mg/m² on days 1 and 8 every month versus methotrexate at 40 to 60 mg/m²/wk. Both arms produced similar response rates, 28.6% and 23.5%, respectively. Similar findings were observed in subsequent study.

Three agents that more recently have shown activity in recurrent head and neck cancer are ifosfamide, paclitaxel, and docetaxel. Ifosfamide has been tested in a wide range of doses (from 5 to 17 g/m²/cycle) and fractionation schedules, producing an overall major response rate of 32% in a total of over 200 patients reported from several series.

The taxanes are the newest class of established active agents in head and neck. The best study is a recently completed ECOG phase II trial of paclitaxel (Taxol) at a dose of 250 mg/m² over 24 hours with G-CSF in 30 patients. This study reported an impressive 40% major response rate, a 9.2-month median survival, and a 33% 1-year survival rate, which are even more noteworthy coming from a multicenter cooperative group study. The major toxicity was neutropenia that lasted a mean duration of approximately 2 days. Docetaxel has produced response rates ranging from 21% to 42% in phase II studies in patients who have not previously received palliative chemotherapy. It is not clear whether paclitaxel and docetaxel are cross-resistant in head and neck cancer.

Topotecan, gemcitabine, vinorelbine, and irinotecan are newer agents undergoing study in the head and neck.

General classes of drugs with limited single-agent activity include the anthracyclines, Vinca alkaloids, mitomycin (and analogs), and nitrosoureas . The major role for anthracyclines in head and neck cancer appears to be in the therapy of nonsquamous cancers (salivary gland cancer, nasopharyngeal carcinoma, small cell carcinoma, sarcoma, and esthesioneuroblastoma). Following is a partial list of drugs that are inactive in recurrent HNSCC or do not appear to have advantages over parent compounds in single-agent trials: PCNU, bisantrene, hexamethylmelamine, mitoguazone, m-AMSA, aclacinomycin, doxorubicin, epirubicin, mitoxantrone, tallysomycin S10b, vindesine, dibromodulcitol, triazinate, gallium nitrate, 6-thioguanine, triazofurin, homoharringtonine, porfiromycin, mitozolomide, and lomustine.