Clinical prognostic factors for patients with recurrent head and neck cancer: implications for randomized trials.

The purpose of our study was to determine the clinical prognostic factors for the duration of the overall survival from recurrence (OSR) in patients with recurrent head and neck squamous-cell carcinoma. We performed a retrospective analysis on 496 patients treated between 1982 and 1993 at the Antoine Lacassagne Center. The significant favorable prognostic factors for the OSR were: initial T(1-2) (p = 0.008), no initial nodal involvement (p = 0.002), no initial chemotherapy exposure (p = 0.002), induction chemotherapy response (p = 0.001), duration of disease-free interval (DFI; p = 0.0001), performance status (PS) 0-1 (p = 0.004) and local-regional recurrence (p = 0.001). In the multivariate analysis, the apparent nonsignificance of all factors apart from the DFI suggested that relevant prognostic factors could be embedded in the DFI. Multivariate analysis was performed after excluding the DFI. The results indicated that local-regional recurrence, PS 0-1 and no initial chemotherapy exposure remained significant favorable prognostic factors for the OSR. The advantages of taking into account such prognostic factors are to eliminate the patient selection bias and to ensure a fairer comparative evaluation of new or already existing agents in recurrent head and neck cancer.

Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck.

This phase II study determined response rate of patients with locally advanced or metastatic head and neck cancer treated with pemetrexed disodium, a new multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. 35 patients with local or metastatic relapse of squamous cell carcinoma of the head and neck (31 male, 4 female; median age 53 years) were treated with pemetrexed 500 mg m(2)administered as a 10-minute infusion on day 1 of a 21-day cycle. Patients received 1 to 8 cycles of therapy. 9 patients (26.5%) had an objective response, with a median response duration of 5.6 months (range 2.9-20 months). 15 (44.1%) had stable disease, and 8 (23.5%) had progressive disease. 2 patients were not assessable for response. Median overall survival was 6.4 months (range 0.7-28.1 months; 95% CI: 3.9-7.7 months). 24 patients (68.6%) experienced grade 3/4 neutropenia, with febrile neutropenia in 4 (11.4%). Grade 3/4 anaemia and thrombocytopenia occurred in 11 (34.3%) and 6 (17.1%) patients, respectively. The most frequent non-haematological toxicity was grade 3/4 mucositis (17.1%; 6 patients). In conclusion, pemetrexed is active in squamous cell carcinoma of the head and neck. Although substantial haematological toxicities were experienced by patients, subsequent studies have shown that these toxicities can be proactively managed by folic acid and vitamin B(12)supplementation.

Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors.

Pemetrexed disodium (ALIMTA), "pemetrexed") is a novel, multi-targeted antifolate that has demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung, breast, mesothelioma, colorectal, pancreatic, gastric, bladder, cervix, and head and neck. Pemetrexed inhibits multiple folate-dependent enzymes involved in both purine and pyrimidine synthesis including thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide ribonucleotide formyltransferase. As a single agent, pemetrexed exhibits a moderate toxicity profile at a dose of 500 mg/m(2) by 10-minute infusion once every 21 days with myelosuppression being the dose-limiting toxicity. Folic acid added to the diet in preclinical studies reduced toxicities while maintaining antitumor activity. Based on this observation and clinical toxicities, folic acid and vitamin B(12) dietary supplementation has been recently introduced into all ongoing trials. Studies combining pemetrexed with other active chemotherapeutic agents demonstrate that these combination therapies may become important treatment regimens in a variety of cancer types. Currently, pemetrexed phase III trials are ongoing in mesothelioma and non-small cell lung cancer with future trials planned to explore this unique multitargeted antifolate.

Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer.

PURPOSE: The Hoosier Oncology Group has previously reported the results of its phase II trial of the combination of cisplatin plus gemcitabine. In that study of 27 assessable patients with advanced or metastatic non-small-cell lung cancer (NSCLC), the response rate was 33%, with a median survival of 8.4 months. Based on such favorable results, the Hoosier Oncology Group designed this randomized phase III study of gemcitabine plus cisplatin compared with cisplatin alone in chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS: Patients were randomized to receive either cisplatin (100 mg/m(2) intravenously on day 1 of a 28-day cycle) or the combination of cisplatin (100 mg/m(2) intravenously on day 1) plus gemcitabine (1,000 mg/m(2) administered intravenously on days 1, 8, and 15 of a 28-day cycle). RESULTS: From August 1995 to February 1997, 522 assessable chemotherapy-naive patients were randomized. Toxicity was predominantly hematologic and was more pronounced in the combination arm, with grade 4 neutropenia occurring in 35.3% of patients compared with 1.2% of patients on the cisplatin monotherapy arm. The incidence of neutropenic fevers was less than 5% in both arms. Grade 4 thrombocytopenia occurred in 25. 4% of patients on the combination arm compared with 0.8% of patients on the cisplatin monotherapy arm. No serious hemorrhagic events related to thrombocytopenia were reported for either arm. The combination of gemcitabine plus cisplatin demonstrated a significant improvement over single-agent cisplatin with regard to response rate (30.4% compared with 11.1%, respectively; P <.0001), median time to progressive disease (5.6 months compared with 3.7 months, respectively; P =.0013), and overall survival (9.1 months compared with 7.6 months, respectively; P =.004). CONCLUSIONS: For the first-line treatment of NSCLC, the regimen of gemcitabine plus cisplatin is superior to cisplatin alone in terms of response rate, time to disease progression, and overall survival.