Efficacy of FOLFIRI-3 (irinotecan D1,D3 combined with LV5-FU) or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR OPTIMOX1 study.

BACKGROUND: Second-line irinotecan-based chemotherapy is commonly used in metastatic colorectal cancers after first-line oxaliplatin-based chemotherapy. No standard schedule of irinotecan has been established in this situation. PATIENTS AND METHODS: Metastatic colorectal cancer patients included in the OPTIMOX1 phase III study received first-line oxaliplatin-based chemotherapy (FOLFOX). No second line was defined in the protocol, but data concerning second line were prospectively registered. Inclusion criterion was patients receiving an irinotecan-based second-line chemotherapy. Second-line progression-free survival (PFS) and tumor response were evaluated according to type of irinotecan-based regimen administered. RESULTS: A total of 342 patients received irinotecan-based chemotherapy as second-line chemotherapy: FOLFIRI-3 [n = 109, irinotecan 100 mg/m(2) days 1 and 3 combined with leucovorin (LV) 400 mg/m(2) day 1 and 46-h continuous 5-fluorouracil (5-FU) 2000 mg/m(2)], FOLFIRI-1 (n = 112, irinotecan 180 mg/m(2) day 1 combined with LV 400 mg/m(2) day 1, 5-FU bolus 400 mg/m(2) and 46-h continuous 5-FU 2400 mg/m(2)) and other various irinotecan-based regimens (n = 121). Median second-line PFS was 3.0 months (FOLFIRI-3: 3.7 months; FOLFIRI-1: 3.0 months; other regimens: 2.3 months). In multivariate analysis, FOLFIRI-3 regimen (relative risk 0.43, 95% confidence interval 0.28-0.68, P = 0.0003) and lactate deshydrogenase level at inclusion (P = 0.0006) in OPTIMOX1 were associated with a longer second-line PFS. CONCLUSION: In unselected patients pretreated with oxaliplatin, PFS in second line appeared to be improved by FOLFIRI-3 regimen.

A phase II study of FOLFIRI-3 (double infusion of irinotecan combined with LV5FU) after FOLFOX in advanced colorectal cancer patients.

In advanced colorectal cancer previously treated with oxaliplatin, efficacy of irinotecan-based chemotherapy is poor and the best regimen is not defined. We designed FOLFIRI-3 and conducted a phase II study to establish its efficacy and safety in advanced colorectal cancer patients previously treated with FOLFOX. FOLFIRI-3 consisted of irinotecan 100 mg m-2 as a 60-min infusion on day 1, running concurrently with leucovorin 200 mg m-2 as a 2-h infusion on day 1, followed by 46-h continuous infusion of 5-fluorouracil (5FU) 2000 mg m-2, and irinotecan 100 mg m-2 repeated on day 3, at the end of the 5FU infusion, every 2 weeks. Sixty-five patients entered the study. The intent-to-treat objective response rate was 23% (95% CI 13-33%). Disease was stable in 37% of patients, progressed in 26% and was not assessable in 14%. From the start of FOLFIRI-3, median progression-free survival was 4.7 months and median survival 10.5 months. Main toxicities (% of patients) were grade 3-4 diarrhoea 23% and grade 4 neutropenia 11%. FOLFIRI-3 is a promising regimen achieving high response rate and progression-free survival in patients previously treated with FOLFOX with a moderate toxicity.

Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study.

BACKGROUND: Since gemcitabine-oxaliplatin (GEMOX) has been used in pancreatic adenocarcinoma, we studied its activity and tolerability in advanced biliary tract adenocarcinoma (ABTA). PATIENTS AND METHODS: Consecutive adult patients with confirmed ABTA were recruited from four centers. Those in group A had performance status (PS) 0-2, bilirubin <2.5x normal and received GEMOX as first-line chemotherapy. Those in group B had PS >2 and/or bilirubin >2.5x normal and/or prior chemotherapy. All received gemcitabine 1000 mg/m2 as a 10 mg/m2/min infusion on day 1, followed by oxaliplatin 100 mg/m2 as a 2-h infusion on day 2, every 2 weeks. RESULTS: Tumor sites were gallbladder (19), extrahepatic bile ducts (5), ampulla of vater (3) and intrahepatic bile ducts (29). Results for group A (n = 3) were: objective response 36% [95% confidence interval (CI) 18.7% to 52.3%], stable disease 26%, progressive disease 39%, median progression-free survival (PFS) 5.7 months and overall survival (OS) 15.4 months. Results for group B (n = 23) were: objective response 22% (95% CI 6.5% to 37.4%), stable disease 30%, progressive disease 48%, PFS 3.9 months and OS 7.6 months. National Cancer Institute Common Toxicity Criteria grade 3-4 toxicities were neutropenia 14% of patients, thrombocytopenia 9%, nausea/vomiting 5% and peripheral neuropathy 7%. CONCLUSION: The GEMOX combination is active and well tolerated in ABTA.

Oxaliplatin reintroduction in patients previously treated with leucovorin, fluorouracil and oxaliplatin for metastatic colorectal cancer.

BACKGROUND: FOLFOX, a bimonthly combination of leucovorin, 5-fluorouracil and oxaliplatin, is active in metastatic colorectal cancer, but sometimes causes cumulative sensory neurotoxicity. This retrospective study investigated FOLFOX reintroduction after a break in treatment or following disease progression on another regimen. PATIENTS AND METHODS: FOLFOX was reintroduced in 29 patients. During their previous FOLFOX therapy, 24 had achieved a response, four were stable and one had progression. Median progression-free survival (PFS) was 33 weeks. Grade 3 neuropathy developed in nine and grade 2 neuropathy in eight patients. RESULTS: Following FOLFOX reintroduction, six patients (21%) showed a response, 15 (52%) were stable and eight (28%) had progression. Median PFS was 18 weeks. Grade 3 neuropathy developed in four patients and grade 2 neuropathy in 11. Two patients with previous grade 3 neuropathy had no recurrence of neuropathy after eight and 18 cycles, respectively. Among 13 patients who received no treatment between periods of FOLFOX therapy, four (31%) had a response and eight (62%) had stable disease. CONCLUSION: Reintroduction of oxaliplatin was feasible and achieved a response or stabilization in 73% of patients. These results support the concept of intensified, repeated short courses of FOLFOX, a strategy currently being evaluated prospectively in the OPTIMOX study.

[Oxaliplatin in combination with 5-fluoro-uracil and folinic acid as treatment of metastatic colorectal cancer]. / In process citation.

Unusual aspect of the development of oxaliplatin was that substantial evidence of its activity was gathered when used in combination with protracted infusion of 5FU combined with leucovorin, preceeding the formal demonstration of its single activity in this disease. Phase II trials in previously treated patients by 5FU, have shown response rate of 10% with oxaliplatin in monotherapy and 18,4 to 58% with chronomodulated or bimonthly regimen combining oxaliplatin, 5FU and leucovorin. These trials have confirmed additive or synergistic antitumoral effects of this combination. Dose intensity of oxaliplatin may be important in determining the efficacy of the triple agent regimen. For previously untreated patients, Folfox4 (LV5FU2 + 85 mg/m2 of oxaliplatin) and chronomodulated regimen have obtained objective response rate ranged from 51 to 66%, with progression-free survival between 8.2 and 11 months and overall survival from 16 to 19 months. A better use of oxaliplatin in combination with 5FU and leucovorin may decrease the dose-limiting toxicity, i.e. the usually transient sensory neurotoxicity. Patients with initially unresectable metastases treated with this three-drug combination could sometimes underwent complete metastases surgery. Several studies are currently in progress either to confirm the high activity of the LV5FU-oxaliplatin combination or to define a strategy based on the best sequence or the best combinations with the other available drugs, irinotecan and raltitrexed.

Correlation between progression free survival and response rate in patients with metastatic colorectal carcinoma.

BACKGROUND: All endpoint measures currently used to evaluate chemotherapeutic treatment benefit in clinical trials of patients with metastatic colorectal carcinoma (MCRC) have disadvantages. Overall survival (OS) is the most objective parameter but is flawed as an efficacy criterion, partly because potentially active second-line treatments are not controlled in many Phase III studies, and measured OS may be influenced (positively or negatively) to an unknown degree by second-line therapy. Measuring progression free survival (PFS) may be a means of isolating the real impact of first-line regimens. METHODS: To test this hypothesis, the authors analyzed pooled data from all Phase III studies on first-line treatment in patients with MCRC reported from 1990 through 2000 for correlations between PFS, response rate (RR), and OS in MCRC patients that may suggest PFS as an improved indicator of the efficacy of first-line treatment. Spearman rho correlation coefficients (r) and regression equations were used. RESULTS: The authors analyzed data from 29 studies involving nearly 13,500 patients. Significant correlations were found between PFS and RR (r = 0.655; P < 0.0001; a 10% RR increment corresponded to a 1-month increase in PFS), between RR and OS (r = 0.408; P = 0.0009; an 11.4% RR increment corresponded to a 1-month increase in OS), and between PFS and OS (r = 0.481; P < 0.0001; a 1-month increase in PFS corresponded to a 0.68-month increase in OS). CONCLUSIONS: PFS is the most appropriate primary endpoint for MCRC studies, because it can express the antitumor activity of a first-line chemotherapy regimen regardless of measures used after disease progression. PFS deserves further evaluation as an endpoint measure.

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. Oncology Multidisciplinary Research Group (GERCOR).

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.

[Bimonthly 5-fluorouracil in elderly patients with metastatic colorectal cancer. Study of 50 patients]. / 5-fluorouracile bimensuel en traitement du cancer colorectal métastasé chez le sujet âgé. Etude de 50 patients.

PURPOSE: Recent advances in the management of colorectal cancer have improved the quality of life and the survival of patients treated with chemotherapy. In order to define the contribution of chemotherapy in elderly patients, we studied the tolerance and the efficacy of first-line chemotherapy in patients with metastatic colorectal cancer. METHODS: Patients aged over 75 years received, as outpatient therapy, a bimonthly 48 h leucovorin and fluorouracil regimen. Evaluation was assessed every six cycles (i.e., three months). RESULTS: Fifty patients were studied: 28 males and 22 females, aged between 75 to 87 years, 37 with colon cancer and 13 with rectal cancer. Among 45 patients capable of being evaluated, the response rate was 44%, with six complete responses (13%) and 14 partial responses (31%). Eighteen patients had stable disease (40%) and seven patients progressive disease (16%). Median progression-free survival was 8.8 months and median survival 16.4 months. Grade 3 to 4 toxicity occurred in 20% of the patients. Performance status improved in 56% of the patients. CONCLUSION: The bimonthly regimen is well tolerated in elderly patients and appears to prolong survival as well in younger patients.

Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR.

For patients resistant to leucovorin (LV) and 5-fluorouracil (5-FU), the addition of oxaliplatin (85 or 100 mg/m2) to bimonthly LV-5-FU has given a response rate of 20-46%. The highest response rate has been observed with oxaliplatin 100 mg/m2 (FOLFOX2). The present phase II study (FOLFOX6) infused oxaliplatin (100 mg/m2) with LV (400 mg/m2) as a 2-h infusion on day 1, followed by bolus 400 mg/m2 and a 46-h infusion (2.4-3 g/m2) of 5-FU, every 2 weeks. Among the 60 patients treated, 16 (27%) had partial responses (95% confidence interval: 15-38), 27 (45%) had stable disease, 15 (25%) experienced disease progression and 2 (3%) had non-measurable disease. From the start of FOLFOX6, median progression-free survival was 5.3 months and median survival 10.8 months. From the 448 cycles analysed, NCI-CTC grade 3-4 toxicities per patient were: peripheral neuropathy 16%, nausea 7%, diarrhoea 7%, mucositis 5%, neutropenia 24%, thrombocytopenia 2%. Overall 26 (46%) patients experienced grade 3-4 toxicities. Because of toxicity, only 36% of the patients received > or = 90% of the scheduled oxaliplatin dose intensity. FOLFOX6 was active in pretreated patients resistant to LV-5-FU and is being investigated as first-line therapy. We are now investigating FOLFOX7, a regimen with a higher oxaliplatin dose intensity and a lower 5-FU dose.

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

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.