Pascal Artru

Impact of Chemoradiotherapy After Disease Control With Chemotherapy in Locally Advanced Pancreatic Adenocarcinoma in GERCOR Phase II and III Studies

PURPOSE The management of locally advanced (LA) pancreatic cancer patients remains controversial. To select patients who could benefit from chemoradiotherapy (CRT), the therapeutic strategy used by the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) consisted of initial chemotherapy (CT) for at least 3 months. The decision to administer CRT or continue CT in nonprogressive patients was the investigators choice. PATIENTS AND METHODS Retrospective analysis of outcome in 181 patients with LA pancreatic cancer (76 women and 105 men; mean age, 61 years; range, 37 to 85 years) enrolled onto prospective phase II and III GERCOR studies was performed to compare the survival of patients who received CRT with that of patients who continued CT alone. RESULTS Median progression-free survival (PFS) and overall survival (OS) times for the 181 patients were 6.3 and 11.4 months, respectively. Fifty-three patients (29.3%) had metastatic disease after 3 months of CT and were not eligible for CRT. Among the 128 remaining patients (70.3%) who had no disease progression and who were, therefore, eligible for CRT, 72 (56%) received CRT (group A), whereas 56 (44%) continued with CT (group B). The two groups were balanced for initial characteristics (performance status, sex, age, and type of CT), as well as for induction CT results. In groups A and B, the median PFS times were 10.8 and 7.4 months, respectively (P = .005), and the median OS times were 15.0 and 11.7 months, respectively (P = .0009). CONCLUSION These results suggest that, after control of disease by initial CT, CRT could significantly improve survival in patients with LA pancreatic cancer compared with CT alone. A prospective phase III study is ongoing to evaluate this strategy.

Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study.

PURPOSE This study compared chemotherapy discontinuation with maintenance therapy with leucovorin and fluorouracil after six cycles of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy in the first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS Two hundred two patients with untreated metastatic colorectal cancer were randomly assigned to receive six cycles of modified FOLFOX7 (mFOLFOX7) followed by simplified leucovorin plus bolus and infusional fluorouracil until progression (arm 1 or maintenance arm, n = 98) or six cycles of mFOLFOX7 before a complete stop of chemotherapy (arm 2 or chemotherapy-free interval [CFI] arm, n = 104). Reintroduction of mFOLFOX7 was scheduled after tumor progression in both arms. The primary study end point was duration of disease control (DDC). RESULTS Median DDC was 13.1 months in patients assigned to the maintenance arm and 9.2 months in patients assigned to the CFI arm (P = .046). Median progression-free survival (PFS) and overall survival were 8.6 and 23.8 months, respectively, in the maintenance arm and 6.6 and 19.5 months, respectively, in the CFI arm. Median duration of maintenance therapy (arm 1) and CFIs (arm 2) were 4.8 months and 3.9 months, respectively. Overall response rates were 59.2% and 59.6% for the initial FOLFOX chemotherapy and 20.4% and 30.3% for FOLFOX reintroduction in arms 1 and 2, respectively. CONCLUSION The planned complete discontinuation of chemotherapy had a negative impact on DDC and PFS compared with the maintenance therapy strategy. These results suggest that chemotherapy discontinuation cannot be decided before therapy is initiated in patients with advanced colorectal cancer.

Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib the LAP07 randomized clinical trial

IMPORTANCE In locally advanced pancreatic cancer, the role of chemoradiotherapy is controversial and the efficacy of erlotinib is unknown. OBJECTIVES To assess whether chemoradiotherapy improves overall survival of patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine-based induction chemotherapy and to assess the effect of erlotinib on survival. DESIGN, SETTING, AND PARTICIPANTS In LAP07, an international, open-label, phase 3 randomized trial, 449 patients were enrolled between 2008 and 2011. Follow-up ended in February 2013. INTERVENTIONS In the first randomization, 223 patients received 1000 mg/m2 weekly of gemcitabine alone and 219 patients received 1000 mg/m2 of gemcitabine plus 100 mg/d of erlotinib. In the second randomization involving patients with progression-free disease after 4 months, 136 patients received 2 months of the same chemotherapy and 133 underwent chemoradiotherapy (54 Gy plus capecitabine). MAIN OUTCOMES AND MEASURES The primary outcome was overall survival from the date of the first randomization. Secondary outcomes were the effect of erlotinib and quality assurance of radiotherapy on overall survival, progression-free survival of gemcitabine-erlotinib and erlotinib maintenance with gemcitabine alone at the second randomization, and toxic effects. RESULTS A total of 442 of the 449 patients (232 men; median age, 63.3 years) enrolled underwent the first randomization. Of these, 269 underwent the second randomization. Interim analysis was performed when 221 patients died (109 in the chemoradiotherapy group and 112 in the chemotherapy group), reaching the early stopping boundaries for futility. With a median follow-up of 36.7 months, the median overall survival from the date of the first randomization was not significantly different between chemotherapy at 16.5 months (95% CI, 14.5-18.5 months) and chemoradiotherapy at 15.2 months (95% CI, 13.9-17.3 months; hazard ratio [HR], 1.03; 95% CI, 0.79-1.34; P = .83). Median overall survival from the date of the first randomization for the 223 patients receiving gemcitabine was 13.6 months (95% CI, 12.3-15.3 months) and was 11.9 months (95% CI, 10.4-13.5 months) for the 219 patients receiving gemcitabine plus erlotinib (HR, 1.19; 95% CI, 0.97-1.45; P = .09; 188 deaths vs 191 deaths). Chemoradiotherapy was associated with decreased local progression (32% vs 46%, P = .03) and no increase in grade 3 to 4 toxicity, except for nausea. CONCLUSIONS AND RELEVANCE In this open-label, randomized trial involving patients with locally advanced pancreatic cancer with disease controlled after 4 months of induction chemotherapy, there was no significant difference in overall survival with chemoradiotherapy compared with chemotherapy alone and there was no significant difference in overall survival with gemcitabine compared with gemcitabine plus erlotinib used as maintenance therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00634725.

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].

Gemcitabine Plus Oxaliplatin (GEMOX) Combined With Cetuximab in Patients With Progressive Advanced Stage Hepatocellular Carcinoma : Results of a Multicenter Phase 2 Study

The authors conducted a phase 2 trial of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in combination with the gemcitabine plus oxaliplatin (GEMOX) regimen in patients with documented progressive hepatocellular carcinoma (HCC).

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.

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

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.

Intensive Systemic Chemotherapy Combined With Surgery for Metastatic Colorectal Cancer: Results of a Phase II Study

PURPOSE To evaluate the efficacy and tolerability of the metastatic irinotecan plus oxaliplatin (MIROX) strategy (adjuvant FOLFOX-7 followed by FOLFIRI), in patients with resectable metastatic colorectal cancer. PATIENTS AND METHODS Forty-seven patients with resectable metastases of colorectal cancer were prospectively enrolled onto this study. Treatment consisted of six cycles of leucovorin 400 mg/m(2), oxaliplatin 130 mg/m(2) in a 120-minute infusion, and fluorouracil (FU) 2,400 mg/m(2) in a 46-hour infusion, every 2 weeks (FOLFOX-7), followed by six cycles of leucovorin 400 mg/m(2), irinotecan 180 mg/m(2) in a 90-minute infusion, bolus FU 400 mg/m(2), and FU 2,400 mg/m(2) as a 46-hour infusion, every 2 weeks (FOLFIRI). Surgery was performed before chemotherapy in 25 patients and after six cycles of FOLFOX-7 in 22 patients (six cycles of FOLFIRI were administered after surgery). RESULTS All but one of the patients underwent curative surgery. Two patients refused postoperative chemotherapy. Tolerability was generally good. The main toxicities were grade 3 to 4 neutropenia (13%) and thrombocytopenia (11%); no febrile neutropenia or bleeding occurred, and there were no deaths caused by toxicity. Two pathologically confirmed complete responses and 15 partial responses were obtained with FOLFOX-7 in the 22 patients who received this regimen before surgery (overall response rate, 77%; 95% CI, 68 to 86). The median disease-free survival time was 21 months; the median overall survival has not yet been reached. The 2-year overall and disease-free survival rates were 89% and 47%, respectively. CONCLUSION The MIROX strategy is feasible and well tolerated by patients with resectable metastatic colorectal cancer. Progression-free and overall survival rates are promising, with a median of 38 months of follow-up. This strategy currently is being compared with the leucovorin and FU regimen in a phase III trial.

Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational molecular study

BACKGROUND The purpose of this study was to evaluate the combination of panitumumab and irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines-irinotecan and bevacizumab). PATIENTS AND METHODS KRAS status was first determined locally but subsequent validation of KRAS status and additional screenings (rare KRAS, NRAS, BRAF mutations and EGFR copy number) were centrally assessed. Patients received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks. RESULTS Sixty-five eligible patients were analyzed. The objective response rate (ORR) was 29.2% [95% confidence interval (95% CI) 18.2-40.3]. Median progression-free and overall survivals were 5.5 and 9.7 months, respectively. Most frequent grade 3/4 toxic effects were skin 32.3%, diarrhea 15.4% and neutropenia 12.3%. Tissue samples were available for 60 patients. For the confirmed KRAS wild-type population codon 12 or 13 mutation (n = 54), ORR was 35.2% (95% CI 22.4.1-47.9). Thirteen patients had a NRAS, a BRAF or a rare KRAS mutation, and no tumor response was observed in this subgroup when compared with 46.3% (95% CI 31.1-61.6) ORR in the subgroup of 41 patients with no identified mutation. CONCLUSION Panitumumab and irinotecan is an active third-line regimen in a well-defined population based on biomarkers. CLINICALTRIALS. GOV IDENTIFIER NCT00655499.BACKGROUND The purpose of this study was to evaluate the combination of panitumumab and irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines-irinotecan and bevacizumab). PATIENTS AND METHODS KRAS status was first determined locally but subsequent validation of KRAS status and additional screenings (rare KRAS, NRAS, BRAF mutations and EGFR copy number) were centrally assessed. Patients received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks. RESULTS Sixty-five eligible patients were analyzed. The objective response rate (ORR) was 29.2% [95% confidence interval (95% CI) 18.2-40.3]. Median progression-free and overall survivals were 5.5 and 9.7 months, respectively. Most frequent grade 3/4 toxic effects were skin 32.3%, diarrhea 15.4% and neutropenia 12.3%. Tissue samples were available for 60 patients. For the confirmed KRAS wild-type population codon 12 or 13 mutation (n = 54), ORR was 35.2% (95% CI 22.4.1-47.9). Thirteen patients had a NRAS, a BRAF or a rare KRAS mutation, and no tumor response was observed in this subgroup when compared with 46.3% (95% CI 31.1-61.6) ORR in the subgroup of 41 patients with no identified mutation. CONCLUSION Panitumumab and irinotecan is an active third-line regimen in a well-defined population based on biomarkers. ClinicalTrials.gov Identifier NCT00655499.

Simplified Prognostic Model in Patients with Oxaliplatin-Based or Irinotecan-Based First-Line Chemotherapy for Metastatic Colorectal Cancer: A GERCOR Study

BACKGROUND The present study was done to establish a prognostic model for patients and trials using an oxaliplatin-based or irinotecan-based first-line chemotherapy in metastatic colorectal cancer. PATIENTS AND METHODS Eight hundred three patients treated with FOLFOX or FOLFIRI in three prospective trials were randomly separated into learning (n = 535) and validation (n = 268) samples. Eleven baseline variables were evaluated in univariate and multivariate analysis as prognostic factors for overall survival, and a prognostic score was developed. RESULTS Independent prognostic factors identified in multivariate analysis for overall survival were performance status (PS) (p < .001), serum lactate dehydrogenase (LDH) (p < .001), and number of metastatic sites (p = .005). A prognostic score based on these three variables was found efficient (Harrells C index 0.61). This new model was improved by selecting only PS and LDH (Harrells C index 0.64). Three risk groups for death could be identified: a low-risk group (n = 184; median overall survival [OS] 29.8 months), an intermediate-risk group (n = 223; median OS 19.5 months), and a high-risk group (n = 128; median OS 13.9 months). Median survival for the low-, intermediate-, and high-risk groups were 26.8, 21.1, and 16.5 months, respectively, in the validation sample (Harrells C index 0.63). CONCLUSIONS Serum LDH level was the main prognostic factor in predicting survival, followed by WHO PS. We identified three risk groups for death depending on these two baseline parameters. This simple prognostic model can be useful for clinicians use and patient stratification in future clinical trials.