Multiagent Trials - Head and neck cancer

Nearly all possible combinations and combination doses/schedules of methotrexate, cisplatin, bleomycin, and 5-FU and other agents listed in Table 90-26 have been tried in numerous single-arm studies of recurrent HNSCC. Results have covered a wide range of response rates, including generally low complete response rates, in heterogeneous subsets of patients.

There is a high level of enthusiasm currently for integrating the newer agents into combination chemotherapy for recurrent disease. Results of such approaches have been encouraging. A recent phase II trial of paclitaxel (175 mg/m² in a 3-hour infusion on day 1), ifosfamide (1,000 mg/m² in a 2-hour infusion on days 1 through 3) and cisplatin (60 mg/m² on day 1, repeated every 3 to 4 weeks) achieved positive results in recurrent HNSCC. This trial achieved an overall response rate of 58% (30 of 52), a complete response rate of 47% (9 of 52), and a median survival of 8.8 months. The relatively well-tolerated toxicity included transient grades 3 to 4 neutropenia in 90% of patients (the most frequent moderate to severe toxicity), neutropenic fever in 27%, grade 3 peripheral neuropathy in three patients (none had grade 4), and grade 3 mucositis in only one patient (none had grade 4). There were no deaths due to toxicity.

More recently, the above regimen was modified by the substitution of carboplatin for cisplatin. This regimen produced less neuropathy, gastrointestinal toxicity, and fatigue, and similar overall and complete responserates and survival rates in recurrent disease in comparison with the paclitaxel plus ifosfamide plus cisplatin (TIP) regimen.

A major current direction for new drug development is targeted therapy. This includes epidermal growth factor receptor (EGFR) inhibitors, p53-targeting agents, and farnesyltransferase inhibitors (FTIs), among other agents.

Concomitant Chemoradiotherapy for Recurrent Disease
A very novel approach in the recurrent-disease setting is represented by a phase I study of concomitant chemoradiotherapy with paclitaxel, 5-FU, and hydroxyurea with G-CSF support. This regimen was administered to 55 patients who had failed to respond to prior radiotherapy (n = 25) or surgery, had a coexistent or prior second malignancy, or had unresectable or metastatic disease and less than a 10% probability of a 2-year survival (Brockstein JCO 1998). Twenty such patients were treated at the recommended phase II dose level of hydroxyurea (500 mg orally twice daily for 11 doses), 5-FU (600 mg/m²/d by continuous infusion for 5 days), and paclitaxel (20 mg/m²/d by continuous infusion for 5 days), with twice-daily radiotherapy. Dose-limiting toxicities consisted of myelosuppression, mucositis, dermatitis, and diarrhea. Paclitaxel concentrations of >10 nmol/L were achieved in the plasma of 65% of patients. Complete responses were achieved in 70% of assessable patients. This study showed (1) the feasibility of adding infusional paclitaxel and hyperfractionated radiotherapy to 5-FU, hydroxyurea, and concomitant radiotherapy and (2) the achievement of radiosensitizing levels of paclitaxel in most patients. Based on the regimen's high locoregional control rate, further investigation in previously untreated patients is justified.