Predictive factors for 6 vs 12 cycles of Folfiri-Bevacizumab in metastatic colorectal cancer.

Early switching to de-intensified maintenance regimen is still a matter of debate in metastatic colorectal cancer (mCRC). The MARTHA trial, a S.I.C.O.G. phase III randomized trial, compared FOLOFIRI+bevacizumab (B) for 12 cycles (6 months) followed by B for up to 12 months (FOLFIRI +B*12 arm) vs FOLFIRI+B for 6 cycles (3 months) followed by capecitabine+B for 4 cycles followed by B for up to 12 months (FOLFIRI+B*6 arm). Chemotherapy-naïve mCRC patients were randomized, primary endpoint was progression free survival (PFS), with overall survival (OS) as a secondary endpoint. A novel analysis, the Death Pace Analysis (DPA), was performed to identify patients who benefited from a specific treatment. No PFS difference was seen in 198 enrolled patients (101 in FOLFIRI+B*12, 97 in FOLFIRI+B*6). A non-significant superior OS was observed for FOLFIRI+B*6 (HR 0.74, p 0.098). The DPA demonstrated that 14% of patients were identifiable as FOLFIRI+B*6-benefiting patients. According to a logistic regression analysis including 23 clinicopathological variables, baseline Hb was the only independent predictor of DPA-defined FOLFIRI+B*6-benefit status. Among patients with Hb ≤ 11.1 gr/dL a statistically significant prolonged OS was observed for FOLFIRI+B*6 over FOLFIRI+B*12 (median OS: 20.7 vs 12.6 months, respectively, HR 0.54, p 0.048). No survival difference was observed between arms in patients with Hb > 11.1. mCRC patients with low baseline Hb levels are better treated with FOLFIRI+B*6 first-line strategy. Possible biological explanations for this finding are being investigated.

First-line cisplatin with docetaxel or vinorelbine in patients with advanced non-small-cell lung cancer: a quality of life directed phase II randomized trial of Gruppo Oncologico Italia Meridionale.

BACKGROUND: Quality of life (QoL) has gained greater importance in the management of metastatic non-small-cell lung cancer due to the palliative nature of treatment. Docetaxel (DCT) and cisplatin (CDDP) doublet has been reported to be associated to a better QoL than the weekly vinorelbine (VNR) and CDDP regimen. Recently a newer more tolerated schedule of the VNR/CDDP regimen has been published and is widely employed in medical practice. The impact of these regimens on patients' QoL as well as symptoms control and type and grading chemo-related side-effects has been compared prospectically. METHODS: Patients received CDDP 75 mg/m(2) plus DCT 75 mg/m(2) on day 1 every weeks (arm A) or CDDP 80 mg/m(2) on day 1 plus VNR 30 mg/m(2) day 1 and 8 every 3 weeks (arm B). G-CSF and/or EPO were employed as needed. Health-related QoL was assessed at entry and after every cycle by the EORTC-QLQ-C30 and LC13 questionnaires, toxicity by the NCI-NCCN CTC vs 2, and intent-to-treat objective response by the Recist criteria. RESULTS: The QoL questionnaires were completed by 37 pts (88%) in the DCT/CDDP arm and 39 pts (87%) in the VNR/CDDP one. Baseline mean scores and rates at which pts failed to complete QoL assessment were similar in the two arms. Global health status of the EORTC QLQ-C30 scale and specific symptoms control (LC13 module) improved during treatment without any statistically significant difference between the two arms. Emotional functioning remained stable in both groups during treatment, whereas physical and role improved slightly. In the DCT/CDDP arm 14 pts (33%; 95%CL 24-40%) had PR, and 10 (24%) SD for a 57% TGCR. In the VNR/CDDP arm 12 pts (27%) achieved PR, 18 (41%) SD a 68% TGCR. Differences were not statistically significant. Median time-to-progression was 4.2 months in the DCT/CDDP arm and 4.5 months in the VNR/CDDP one, and median overall survival was 12.1 (range 1-26+ months) and 12.5 months (range 1-28+ months) for DCT/CDDP and VNR/CDDP arms, respectively. Febrile neutropenia rate was higher in the VNR/CDDP arm (p=0.02) as well as G3-4 anemia (p=0.005) and G-CSF/EPO use (p=0.019). CONCLUSIONS: Global and specific health-related QoL data similar in both treatment groups with no statistically significant difference. Efficacy measures, overall response rate, time-to-progression and overall survival were equivalent in both arms. However, severe anemia and febrile neutropenia are statistically more frequent in the VNR/CDDP arm than in the DCT/CDDP one. These data should be considered in treatment decision-making for pts with advanced non-small-cell lung cancer and for the design of future trials with chemotherapy plus biologics.

Gemcitabine combined with either pemetrexed or paclitaxel in the treatment of advanced non-small cell lung cancer: a randomized phase II SICOG trial.

PURPOSE: To estimate the safety, activity, and impact on quality of life of a combination of gemcitabine and pemetrexed in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) in the context of a randomized two-stage phase II study. PATIENTS AND METHODS: Patients in stage IIIB or IV NSCLC were randomly allocated to receive either gemcitabine 1250 mg/m(2) on day 1, and pemetrexed (Alimta) 500 mg/m(2) followed by gemcitabine 1250 mg/m(2) on day 8 of a 3-weekly cycle (GA arm), or paclitaxel 120 mg/m(2) followed by gemcitabine 1000 mg/m(2), both given on days 1 and 8 of a 3-weekly cycle (PG arm). RESULTS: 105 (GA arm, 51; PG arm, 54) eligible patients (stage IV, 32 and 30, respectively) were enrolled into this study; thereafter, accrual was stopped due to first-stage analysis. The response rate was 20% (95% confidence interval [CI], 10-33%) in the GA arm, and 32% (95% CI, 20-46%) in the PG arm. Median progression-free survival was 5.1 (95% CI, 3.7-6.5) months in the GA arm, and 8.3 (95% CI, 5.9-10.7) months in the PG arm, while median overall survival was 10.5 (95% CI 7.1-13.9), and 13.3 (95% CI 11.7-14.9) months, respectively. Severe neutropenia (36% vs 22%), and febrile neutropenia (14% vs 7%) were more common with the GA regimen, while hair loss (52% vs 16%) and any grade peripheral neuropathy (31% vs 2%) occurred more frequently with PG regimen. Other severe side effects of GA regimen were diarrhoea (10%), liver enzyme derangement (10%), and fatigue (8%). CONCLUSION: The GA regimen was tolerated and moderately active in advanced or metastatic NSCLC. However, this combination did not yield any advantage in comparison with the PG regimen, and does not deserve further evaluation.

Oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer: a multicenter phase II trial of the Southern Italy Cooperative Oncology Group.

PURPOSE: This phase II trial assessed the tolerability and efficacy of a triplet of oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer. METHODS: Patients with unresectable or metastatic gastric cancer, unexposed to palliative chemotherapy, received oxaliplatin 85 mg/m(2) iv and irinotecan 150 mg/m(2) iv on day 1, 6S-folinic acid 250 mg/m(2) iv and fluorouracil 750 mg/m(2) iv on day 2, every 2 weeks. Response rate (RR) was assessed after a minimum of four cycles, and treatment continued up to 12 cycles. RESULTS: Sixty-three patients were treated, with a median of eight (range 1-12) cycles/patient. Two complete and 19 partial responses were registered (RR 33% [95% CI, 22-46%]). Median progression-free survival was 7.5 (95% CI, 5.6-9.4) months, and median overall survival was 12.1 (95% CI, 10.8-13.4) months. Most common grade > or =3 toxicities were neutropenia (59%), febrile neutropenia (7%), vomiting (20%), and diarrhoea (10%). All-grade neurotoxicity affected 33% of patients. CONCLUSIONS: Oxaliplatin, irinotecan, and fluorouracil/folinic acid administered every 2 weeks are safe and active in advanced gastric cancer.

Safety and efficacy of irinotecan plus high-dose leucovorin and intravenous bolus 5-fluorouracil for metastatic colorectal cancer: pooled analysis of two consecutive southern Italy cooperative oncology group trials.

BACKGROUND: A biweekly regimen of irinotecan 200 mg/m2 on day 1 and levo-leucovorin (LV) 250 mg/m2 plus 5-fluorouracil (5-FU) 850 mg/m2 via intravenous bolus on day 2 was assessed in 2 consecutive randomized trials in metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Individual data of 254 patients were merged, and baseline features potentially affecting overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and occurrence of severe toxicity were analyzed by univariate and multivariate analyses. RESULTS: In the pooled series, ORR was 33% (95% confidence interval [CI], 27%-39%). Liver-only disease (47% vs. 25%; P=0.0012) and absence of previous weight loss (38% vs. 20%; P=0.0189) were significantly associated with a higher ORR on the multivariate analysis. Absence of weight loss (hazard ratio, 1.40; 95% CI, 1.02-1.93; P=0.0377) was significantly associated with a longer PFS (7.5 months vs. 6 months). Median OS was 15.1 months (95% CI, 13.5-16.6 months). Primary surgery, good performance status (PS), only one metastatic site, and oxaliplatin-based second-line treatment independently predicted a longer OS. Grade 4 neutropenia was significantly associated with a PS>or=1, whereas risk of grade>or=3 diarrhea was directly related to age and previous weight loss. CONCLUSION: Patients with no weight loss and/or preserved PS and with a limited disease extent appeared to obtain the greatest benefit from our irinotecan/5-FU/LV regimen, with acceptable toxicity. Notably, the regimen was effective and well tolerated by elderly patients. This regimen may represent the rationale for assessing the addition of novel antiangiogenic drugs to the treatment of metastatic CRC.

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.

Combination regimen of epirubicin, vinorelbine and 5-fluorouracil continuous infusion as first-line chemotherapy in anthracycline-naive metastatic breast cancer patients.

We investigated the activity and toxicity of a combination of vinorelbine 25 mg/m2 on days 1 and 15; epirubicin 25 mg/m2 on days 1, 8, 15; and 5-fluorouracil continuous infusion at 200 mg/m2 every day, administered as first-line chemotherapy in anthracycline-naive metastatic breast cancer patients. Fifty-three patients entered the study. Cycles were repeated every 28 days. Objective response was 60% by World Health Organisation (WHO) criteria and 63% by Response Evaluation Criteria in Solid Tumours (RECIST). The median time to progression was 12.7 months (17.6 months in responders) and the median survival duration was 32.9 months. The dose-limiting toxicity was leucopenia (grade 3/4 in 36% of patients). Grade 3/4 non-haematological toxicities included mucositis in 11% of patients, skin and cardiac toxicity in 4% and 2%, respectively. The combination of vinorelbine, epirubicin and 5-fluorouracil continuous infusion was found to be an active and manageable first-line regimen for metastatic breast cancer patients.