Jean Pierre Lotz

CPT-11 (Irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer

CPT-11 (irinotecan) has shown activity in patients with advanced colorectal cancer resistant to leucovorin (LV) and 5-fluorouracil (5-FU). In this study, the simplified bimonthly LV-5-FU regimen was combined with CPT-11 (FOLFIRI) as third-line therapy for patients with advanced colorectal cancer. Continuous infusion of 5-FU was administered with disposable pumps as outpatient therapy. FOLFIRI consisted of CPT-11 180 mg/m2 as a 90-min infusion day 1; LV 400 mg/m2 as a 2-h infusion during CPT-11, immediately followed by 5-FU bolus 400 mg/m2 and 46-h continuous infusion of 2.4-3 g/m2 every 2 weeks. Among the 33 patients treated, 2 had partial responses for an overall response rate of 6%; 20 patients were stabilised (61%) and 11 had disease progression (33%). From the start of FOLFIRI, median progression-free survival was 18 weeks and median survival was 43 weeks. For the 242 cycles analysed, NCI-CTC toxicities grade 3-4 per patient were nausea 15%, diarrhoea 12% and neutropenia 15%. Overall, 10 patients (30%) experienced grade 3-4 toxicity. 7 patients (21%) had grade 2 alopecia. FOLFIRI generated activity and acceptable toxicity, in heavily pretreated patients, with limited diarrhoea, mostly asymptomatic neutropenia and manageable nausea and relatively uncommon alopecia. This regimen is suitable for studies in chemotherapy-naïve patients.

High-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX 7)

This phase II study examined a regimen (FOLFOX7) of leucovorin (LV), high-dose intensity oxaliplatin, and 5-fluorouracil (5-FU), as second-line therapy for metastatic colorectal cancer. 48 patients were enrolled - 36 refractory and 12 resistant to prior therapy with LV-5-FU. Oxaliplatin (130 mg/m2) was infused with LV (400 mg/m2) over 2 h on day 1, followed by bolus 400 mg/m2 and a 46-h infusion (2400 g/m2) of 5-FU, every 2 weeks. Patients who responded or were stable received eight cycles. Patients were evaluated every 2 months. 20 patients (42%) had partial responses (95% confidence interval (CI): 28-56%), 19 (40%) had stable disease and 9 (19%) progressed. Median progression-free survival (PFS) was 6 months and median survival 16.1 months. Toxic effects of National Cancer Institute-Common Toxicity Criteria (NCI-CTC) grade 3/4 were: peripheral neuropathy 15%, nausea 8%, diarrhoea 11%, neutropenia 9%, thrombocytopenia 11%. Overall, 38% of patients experienced grade 3/4 toxicities, and 64% received 90% or more of the scheduled oxaliplatin dose intensity during the first four cycles. FOLFOX7 was highly active, with good tolerability, in pretreated patients resistant to LV-5-FU [corrected].

Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer

BACKGROUND Studies of bimonthly 48-hour regimens of high-dose leucovorin (LV) (FOLinic acid), 5-fluorouracil (5-FU) by continuous infusion combined with OXaliplatin (FOLFOX) in pretreated patients with metastatic colorectal cancer suggest that oxaliplatin dose intensity is an important prognostic factor for response rate and progression-free survival (PFS). To help define the optimal dose schedule for oxaliplatin in pretreated metastatic colorectal cancer, we retrospectively analyzed data from three phase II studies using different FOLFOX regimens (FOLFOX2, 3 and 6). PATIENTS AND METHODS Data on 126/161 patients were analyzed. FOLFOX2 included oxaliplatin 100 mg/m2; FOLFOX3, 85 mg/m2; and FOLFOX6, 100 mg/m2 (added to a simplified LV-5-FU regimen), all as two-hour infusions. A total of 47 patients received low dose intensity oxaliplatin (LDI: < or = 85 mg/m2/2 weeks) and 79 patients high dose intensity oxaliplatin (HDI: > 85 mg/m2/2 weeks). RESULTS Objective responses occurred in 31 (39%) HDI patients and 9 (19%) LDI patients (P = 0.03). Median PFS was 28 weeks, with 52% of HDI patients progression free at 6 months, and 26 weeks with 36% of LDI patients progression free at six months (P = 0.02). Increased oxaliplatin dose intensity was not associated with increased neurotoxicity or other toxicities. FOLFOX are among the most effective regimens for treating LV-5-FU-resistant metastatic colorectal cancer. CONCLUSIONS This study shows that oxaliplatin dose intensification significantly improves response rate and PFS in pretreated metastatic disease without increasing severe toxicity.

COMBINED RADIOTHERAPY AND CHEMOTHERAPY (CISPLATIN AND 5-FLUOROURACIL) AS PALLIATIVE TREATMENT FOR LOCALIZED UNRESECTABLE OR ADJUVANT TREATMENT FOR RESECTED PANCREATIC ADENOCARCINOMA: RESULTS OF A FEASIBILITY STUDY

PURPOSE To evaluate a cisplatin-containing chemoradiotherapy (CRT) regimen followed by chemotherapy for unresectable (locally advanced group, n = 32) and resected (adjuvant group, n = 10) pancreatic adenocarcinoma. The quality of palliation and percentage of secondary resections were also studied for unresectable disease. METHODS AND MATERIALS The protocol comprised CRT (45 Gy over 5 weeks), combined with 5-fluorouracil and cisplatin during the first and fifth weeks, followed, 3 weeks later, by 4 cycles of the same chemotherapy plus leucovorin. RESULTS All patients completed CRT but only 50% of each group finished the entire protocol. Gastrointestinal toxicity and weight loss were the major side effects during CRT. Enhanced hematological toxicity limited the post-CRT chemotherapy. For the locally advanced group, median survival was 9 months; 1- and 2-year survival rates were 31 and 12. 5%, respectively. The overall response rate was 16% and 50% had stable disease. A lasting palliative effect defined as improved performance status and decreased analgesic consumption, was recorded for 43% of the patients. Only three secondary resections have been performed. For the adjuvant group, median survival was 17 months. CONCLUSIONS Although toxic in advanced disease, this regimen significantly lowered pain and analgesic consumption, but had poor impact on secondary resectability. In an adjuvant setting, although equally toxic, this series was too small to allow conclusions to be drawn.

Effect of Low Molecular Weight Heparins and Fondaparinux Upon Thrombin Generation Triggered by Human Pancreatic Cancer Cells BXPC3

Low molecular weight heparins (LMWHs) and fondaparinux are widely used for prophylaxis and treatment of venous thromboembolic disease in cancer patients. However, the optimization of the antithrombotic treatment especially in patients with adenocarcinoma of the pancreas is a challenging issue. The understanding of the mechanism of action of the LMWHs and fondaparinux in cancer-induced hypercoagulability might help to optimize antithrombotic treatment. To this aim, we investigated the influence of BXPC3 pancreas adenocarcinoma cells on the antithrombotic activity of LMWHs and fondaparinux. Thrombin generation (TG) in normal platelet poor (PPP) and platelet rich plasma (PRP) spiked with clinically relevant concentrations of dalteparin, enoxaparin, nadroparin tinzaparin and fondaparinux was assessed with the Calibrated Automated Thrombogram assay. BXPC3 (5 cells/μl) were added to plasma. The mean rate index (MRI) of the propagation phase of TG and the endogenous thrombin potential (ETP) were analyzed. The IC50 of the studied compounds were determined and compared on the basis of anti-Xa and anti-IIa equivalent units. We demonstrate that the specific antithrombin (AT)-dependent anti-Xa activity of LMWHs and fondaparinux almost selectively inhibits the propagation phase of TG. The synergy between the anti-Xa and anti-IIa activities of LMWHs rather than the selective inhibition of FXa warrants abrogation of TG. The mean molecular weight and anti-Xa/anti-IIa ratio of the AT-dependent agents cannot predict the alteration of their capacity to inhibit TG. Tinzaparin was the most potent inhibitor of TG than the other LMWHs. Enoxaparin was more potent than nadroparin and dalteparin.