G. Colucci

Phase III Randomized Trial of FOLFIRI Versus FOLFOX4 in the Treatment of Advanced Colorectal Cancer: A Multicenter Study of the Gruppo Oncologico Dell’Italia Meridionale

PURPOSE We performed this phase III study to compare the irinotecan, leucovorin (LV), and fluorouracil (FU) regimen (FOLFIRI) versus the oxaliplatin, LV, and FU regimen (FOLFOX4) in previously untreated patients with advanced colorectal cancer. PATIENTS AND METHODS A total of 360 chemotherapy-naive patients were randomly assigned to receive, every 2 weeks, either arm A (FOLFIRI: irinotecan 180 mg/m(2) on day 1 with LV 100 mg/m(2) administered as a 2-hour infusion before FU 400 mg/m(2) administered as an intravenous bolus injection, and FU 600 mg/m(2) as a 22-hour infusion immediately after FU bolus injection on days 1 and 2 [LV5FU2]) or arm B (FOLFOX4: oxaliplatin 85 mg/m(2) on day 1 with LV5FU2 regimen). RESULTS One hundred sixty-four and 172 patients were assessable in arm A and B, respectively. Overall response rates (ORR) were 31% in arm A (95% CI, 24.6% to 38.3%) and 34% in arm B (95% CI, 27.2% to 41.5%; P = .60). In both arms A and B, median time to progression (TTP; 7 v 7 months, respectively), duration of response (9 v 10 months, respectively), and overall survival (OS; 14 v 15 months, respectively) were similar, without any statistically significant difference. Toxicity was mild in both groups: alopecia and gastrointestinal disturbances were the most common toxicities in arm A; thrombocytopenia and neurosensorial were the most common toxicities in arm B. Grade 3 to 4 toxicities were uncommon in both arms, and no statistical significant difference was observed. CONCLUSION There is no difference in ORR, TTP, and OS for patients treated with the FOLFIRI or FOLFOX4 regimen. Both therapies seemed effective as first-line treatment in these patients. The difference between these two combination therapies is mainly in the toxicity profile.

Adjuvant colon cancer chemotherapy: where we are and where we'll go.

Many patients with early-stage colon cancer are cured with surgery alone, even if the standard of care remains an uniform approach to adjuvant chemotherapy based primarily on tumour stage. Consequently, it is important to individualize decision-making in this subset of patients with the aim to identify potential prognostic and predictive markers in colon cancer. While 5-fluorouracil, leucovorin, and oxaliplatin are widely known as gold treatment in the post-operative of stage III, well-validated molecular markers might help define which patients with stage II disease are likely to benefit from adjuvant therapy as well. Herein we review the use of adjuvant chemotherapy in colon cancer and analyzed the date on the clinical development of molecular markers to individualize another therapeutic approach in colon cancer.

5-Fluorouracil and folinic acid with or without CPT-11 in advanced colorectal cancer patients: A multicenter randomised phase II study of the Southern Italy Oncology Group

PURPOSE The combination regimen CPT-11 plus bolus and infusion 5-fluorouracil (5-FU) with high-dose leucovorin (hybrid regimen LV5FU2) has been tested for activity and toxicity against advanced colorectal carcinoma in a randomised, multicenter phase II trial. PATIENTS AND METHODS A total of 102 chemotherapy-naïve patients were randomised in a 1:2 fashion to receive: leucovorin 100 mg/m2 administered as a two-hour infusion before 5-FU 400 mg/m2 as an intravenous bolus, and FU 600 mg/m2 as a 22-hour infusion immediately after 5-FU bolus injection repeated on days 1 and 2 (LV5FU2 regimen, arm A, 34 patients) or CPT-11 at 180 mg/m2 (150 mg/m2 for patients of age > or = 70 and < 75 years) only on day 1 immediately before LV5FU2 therapy (LV5FU2 + CPT-11 regimen, arm B 68 patients). Both treatments were repeated every two weeks. The presence of a calibration arm assured consistency and more realistic evaluation of results achieved with the LV5FU2 + CTP-II regimen. RESULTS Thirty-three and sixty-four patients were evaluable in arm A and B, respectively. The overall response rate was 18% in arm A (95% CI: 7%-34%) and 40% in arm B (95% CI: 28%-52%). Median time to progression, median duration of response and survival were similar in both groups. Responders (CR + PR) survived statistically longer than non-responders only in arm B (20 vs. 10 months, P = 0.0016). All patients were evaluable for toxicity which was mild in both groups; gastrointestinal disturbances were the most common. There were no treatment-related deaths. Grade 3-4 toxicity was uncommon in both arms. CONCLUSIONS The addition of CPT-11 to the hybrid LV5FU2 regimen provided a significant overall response rate (40%) with relatively mild toxicity. The overall response rate was 18% in patients treated with LV5FU2 alone in the calibration arm. Thus, considering other encouraging data from the literature, the CPT-11 + FU-LV combination therapy can be regarded as a new, very effective treatment option for first-line treatment of advanced colorectal cancer patients.

A dose finding followed by a phase II study of oral UFT (uracil/tegafur) and lv (leucovorin) plus i.v. mitomycin (MMC) in patients (pts) with metastatic colorectal cancer (MCRC): Phase I results

3709 Background: UFT/LV is an orally available regimen with proven activity in MCRC pts. Two randomized phase III trials (J.Y. Douillard et al., JCO 2002; J. Carmichael et al, JCO 2002) showed equivalent survival and significant safety improvements of UFT/LV when compared to bolus IV 5FU/LV. MMC combined with IV 5FU produces a 33%-39% response rate in pts with MCRC. This multicenter study was performed to evaluate the safety and the activity of UFT/LV in combination with MMC in pts with MCRC. METHODS In the phase I part of the trial DLTs and MTD were identified in order to recommend a dose for the Phase II portion of the study. Cohorts of 3 to 6 pts were treated with MMC (10 mg/m2, IV d1) and LV (90 mg/d, po x 28 d) at fixed doses; the starting dose of UFT was 200 mg/m2/d. Doses of UFT were increased by 50 mg/m2 increments up to 300 mg/m2 x 28 d. Treatment was repeated every 5 weeks. RESULTS Twelve pts (9 female and 3 male) with pretreated MCRC and measurable disease were enrolled in the Phase I portion of the study. Ten (83%) patients received study treatment in the second line setting, while the two other patients as first and third line, respectively. Median age was 62 years (range 44 -76); PS 0/1/2 in 9/2/1 patients. No DLTs were observed in the first two UFT dose levels (200 and 250 mg/m2/d). Among the first 3 pts enrolled at level 3 (300 mg/m2/d), one pt developed G3 anemia and G2 thrombocytopenia that did not resolve within 14 days. Therefore, 3 additional pts were accrued at this level, with no DLTs being observed. The most common toxicities (NCI-CTC) reported during the first cycle in all 12 pts were as follows: G1 (pts): anemia 2, thrombocytopenia 5, neutropenia 1, vomiting 1, diarrhea 1, fatigue 1, alopecia 1; G2 (pts): thrombocytopenia 1, fever 2, vomiting 2, diarrhea 1; G3 (pts): anemia 1. Overall, the combination of UFT/LV and MMC was well tolerated with no grade 4 toxicity reported. Efficacy data from the phase I portion are pending. CONCLUSIONS The recommended dose for phase II is UFT 300 mg/m2/d x 28, LV 90 mg/d x 28 days and MMC 10 mg/m2 d 1 given every 5 weeks. The phase II portion of the study is currently ongoing. No significant financial relationships to disclose.

Is Tubulointerstitial Damage a Reliable Index for Predicting Renal Outcome in Primary Membranous Nephropathy

Interstitial changes are often observed in primary glomerular disease. However, the severity of these changes is not always mirrored by the glomerular involvement. Aim of this study is to evaluate if the presence of tubular, interstitial and vascular changes can predict the renal outcome of primary membranous glomerulonephritis (MGN).