Single agents have only modest activity as treatment for metastatic pancreatic cancer with response rates of less than 10% and median survival rates of less than six months. Evaluations of single-agent gemcitabine and rubitecan as second-line treatment for relapsed pancreatic cancer have reported good patient tolerability and median survivals of 3.85 months and 4.7 months, respectively. Regimens incorporating two drugs have demonstrated encouraging activity and clinical impact compared with single-agent therapy. G-FLIP (gemcitabine, 5-fluo-rouracil, leucovorin, and cisplatin) is a regimen designed to incorporate four active single agents into a tolerable and active combination. A retrospective analysis evaluated the efficacy and safety of the G-FLIP regimen as second-line chemotherapy in a series of consecutively treated patients with metastatic pancreatic cancer.

G-FLIP was administered over 48 hours and repeated every two weeks. Day-one treatment consisted of sequentially administered gemcitabine 500 mg/m2, irinotecan 80 mg/m2, leuco-vorin 300 mg, and a 5-fluorouracil (5-FU) 400 mg/m2 bolus, followed by an infusion of 5-FU 600 mg/m2 over eight hours. Day-two treatment consisted of leucovorin 300 mg and a 5-FU 400 mg/m2 bolus, followed by cisplatin 50 to 75 mg/m2, and then an infusion of 5-FU 600 mg/m2 over eight hours.
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Thirty-four patients with histologically confirmed metastatic pancreatic cancer were consecutively treated. The median patient age was 64.5 years (range= 41-82 years) and all patients had objective disease progression on prior therapy; 32 patients had disease progression with gemcitabine, and 31 had disease progression with a gemcitabine/5-fluorouracil/cisplatin combination. Grade 3 to 4 hematological toxicities included anemia (23%), thrombocytopenia (53%), and neutropenia (38%). There were no grade 3 to 4 neutropenic fevers, treatment-related mortalities, or withdrawals. Nonhematological grade 3 to 4 toxicities were rare: nausea/vomiting (3%), neurotoxicity (3%), nephrotox-icity (6%), and diarrhea (3%). A partial response (PR) was attained in eight patients (24%) and seven patients had stable disease (SD). Seven and six patients who attained a PR or SD, respectively, had disease progression with prior gemcitabine-based therapy. The median time to disease progression for all 34 patients was 3.9 months, and 5.9 months for the eight patients who attained a PR. Median overall survival for all 34 patients was 10.3 months.

It was concluded that adding a single new drug such as irinotecan to the same first-line chemotherapy combination upon disease progression might be an important alternative to switching to different drug classes for treatment of relapsed/ resistant cancer. The promising clinical outcomes and moderate toxicity associated with G-FLIP in this heavily pretreated group warrant development of this novel regimen, including tests as first-line therapy in patients with diseases likely to be responsive to the drugs contained in this combination.

ADVANCED COLORECTAL CANCER

Raltitrexed, a specific thymidilate synthase inhibitor, was evaluated in patients with advanced (ACC) in relapse (> eight weeks) after a prior response or disease stabilization to first-line chemotherapy combination with irinotecan plus 5-FU plus leucovorin (LV). Twenty-five patients with metastatic ACC entered the pilot trial: 17 males and eight females. The median age was 61 (range= 47-70), median Karnovsky PS: 80 (70-90), and a life expectancy of at least three months. The sites of metas-tases were liver, 12; lung, 4; lymph nodes, 7; and peritoneal, 5. All patients had progressed after prior chemotherapy with irinotecan plus 5-FU plus leucovorin (LV). Raltitrexed was administered intravenously (IV) at a dose of 3 mg/m2 every 21 days.

Three patients (12%) achieved a partial response (PR), eight (32%) had stable disease (SD), and the remaining 14 (56%) developed progressive disease (PD). Median time-to-progression (TTP) was 5.5 months (range= 2-8.5), and median overall survival (OS) was eight months (range= 4-12.5). Toxicity was generally mild and consisted mainly of myelosuppression; neu-tropenia grade 1 to 2: 52%; grade 3: 28%; and anemia grade 1 to 2: 36%. Mild mucositis, grade 1 to 2, occurred in 13.5% of patients and was the principal non-hematologic toxicity. Response to treatment with raltitrexed is limited in patients with ACC failing after an initial response or non-progression to the weekly irinote-can plus 5-FU plus LV combination. It appears that a limited number of patients with PR/SD might derive clinical benefit, but final proof would require a large, randomized study.