FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study.

PURPOSE: In metastatic colorectal cancer, phase III studies have demonstrated the superiority of fluorouracil (FU) with leucovorin (LV) in combination with irinotecan or oxaliplatin over FU + LV alone. This phase III study investigated two sequences: folinic acid, FU, and irinotecan (FOLFIRI) followed by folinic acid, FU, and oxaliplatin (FOLFOX6; arm A), and FOLFOX6 followed by FOLFIRI (arm B). PATIENTS AND METHODS: Previously untreated patients with assessable disease were randomly assigned to receive a 2-hour infusion of l-LV 200 mg/m2 or dl-LV 400 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 to 3,000 mg/m2 every 46 hours every 2 weeks, either with irinotecan 180 mg/m2 or with oxaliplatin 100 mg/m2 as a 2-hour infusion on day 1. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B). RESULTS: Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI (P = .99). Median second progression-free survival (PFS) was 14.2 months in arm A versus 10.9 in arm B (P = .64). In first-line therapy, FOLFIRI achieved 56% response rate (RR) and 8.5 months median PFS, versus FOLFOX6 which achieved 54% RR and 8.0 months median PFS (P = .26). Second-line FOLFIRI achieved 4% RR and 2.5 months median PFS, versus FOLFOX6 which achieved 15% RR and 4.2 months PFS. In first-line therapy, National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia were more frequent with FOLFIRI, and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6. CONCLUSION: Both sequences achieved a prolonged survival and similar efficacy. The toxicity profiles were different.

A dose finding, safety and pharmacokinetic study of AVE1642, an anti-insulin-like growth factor-1 receptor (IGF-1R/CD221) monoclonal antibody, administered as a single agent and in combination with docetaxel in patients with advanced solid tumours.

PURPOSE: AVE1642, a humanised mAb, binds the human IGF-1R specifically and with high affinity. This study aimed to select the dose of AVE1642 alone and then combined with docetaxel 75mg/m(2) (D). MATERIAL AND METHODS: AVE1642 was administered alone at cycle (cy) 1 and then combined with D from cy2, q3w. RESULTS: A total of 27 patients received a median number of 5 cy (range, 1-10). The most common tumour types were sarcoma (18.5%), osseous tumours (11.1%) and colon cancer (11.1%). Two DLTs were reported in cy1 at dose level (DL) 18mg/kg and dose escalation was stopped. No major safety issue was observed. No anti-drug antibodies were detected. The Maximal Tolerated Dose of AVE1642 was 12mg/kg. The dose selected for further combinations is 6mg/kg, based on PK/PD data. Three objective responses, (two in sarcoma and one breast cancer) were observed but only one was confirmed. Eleven patients appeared to benefit from treatment with prolonged disease stabilisation ⩾4months. CONCLUSION: AVE1642 is well tolerated as a single agent and combined with D. The selected dose of AVE1642 combined with D is 6mg/kg. Promising activity was seen in sarcoma and breast cancer patients.

High prognostic significance of residual disease after neoadjuvant chemotherapy: a retrospective study in 710 patients with operable breast cancer.

Prognostic factors are used to help clinical decision-making in selecting the appropriate treatment for individual patients. The purpose of this retrospective study was to identify one or more factors associated with overall survival (OS) and disease-free survival (DFS), in 710 patients with operable breast cancer, subjected to neoadjuvant chemotherapy followed by surgery, radiotherapy and adjuvant treatments. At a median follow-up of 7.6 years, univariate analysis showed that pathological complete response (pCR) was significantly related to survival (p < 0.003), as well as accepted prognostic factors, as SBR and MSBR grades, hormonal receptors or node involvement at surgery, who remained significant in our study (p < 0.001). The revised Nottingham prognostic index (NPI) and related indices (BGI, MNPI and MBGI) were also significantly associated to survival (p < 0.003). In multivariate analysis, node involvement and MSBR grade remained prognostic factors for OS and DFS (p < 0.0003 and p < 0.02, respectively). The MNPI and pCR were significantly related with OS (p = 0.04) and pts with hormonal receptor-positive tumours had a better DFS than others (p = 0.004). Among all clinical and pathological parameters, axillary dissection after neoadjuvant chemotherapy is still important to determine node involvement, a major prognostic factor. Moreover, MSBR grade seemed to be more accurate and predictive of long-term outcome than the standard SBR grade. It is concluded that, outside any other 'biological' factor, residual disease in breast and nodes must be strongly considered after an induction chemotherapy so as to choose adjuvant treatment for the individual patient.

Circadian rhythm of irinotecan tolerability in mice.

The toxicity of irinotecan (CPT-11), a topoisomerase-I inhibitor largely used in cancer patients, was investigated as a function of the circadian time of its administration in mice, with mortality, body weight loss, leukopenia, neutropenia, intestinal lesions, and bone marrow cell cycle phase distribution as end points. Four experiments were performed on a total of 773 male mice standardized with 12h light/12h darkness. Irinotecan was administered daily for 4 or 10 consecutive days (D1-4 and D1-10, respectively, in different experiments) at one of six circadian stages expressed in hours after light onset (HALO). The survival curves differed significantly as a function of the dosage and circadian time of drug administration by the D1-10 schedule, with 70% survival at 7 or 11 HALO and 51% at 19 or 23 HALO (p=0.039 from log rank test). CPT-11 administration at 19 or 23 HALO resulted in (1) greatest mean body weight loss at nadir; (2) most severe colic and bone marrow lesions and/or slowest recovery; and (3) deepest neutropenia nadir and/or slowest hematologic recovery. These circadian treatment time-related differences were statistically validated. The bone marrow cell cycle data revealed a four to eight-fold larger G2-M phase arrest following irinotecan administration at 19 or 23 HALO in comparison to the other times of drug administration, apparently representative of the repair of more extensive DNA damage (p < 0.001 from ANOVA) when the medication was given at these circadian times. Overall, CPT-11 was better tolerated by mice treated during the light (animals' rest) span. The results support the administration of CPT-11 to cancer patients in the second half of the night, during sleep, in order to improve drug tolerability.

FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.

PURPOSE: In metastatic colorectal cancer, phase III studies have demonstrated the superiority of fluorouracil (FU) with leucovorin (LV) in combination with irinotecan or oxaliplatin over FU + LV alone. This phase III study investigated two sequences: folinic acid, FU, and irinotecan (FOLFIRI) followed by folinic acid, FU, and oxaliplatin (FOLFOX6; arm A), and FOLFOX6 followed by FOLFIRI (arm B). PATIENTS AND METHODS: Previously untreated patients with assessable disease were randomly assigned to receive a 2-hour infusion of l-LV 200 mg/m(2) or dl-LV 400 mg/m(2) followed by a FU bolus 400 mg/m(2) and 46-hour infusion 2,400 to 3,000 mg/m(2) every 46 hours every 2 weeks, either with irinotecan 180 mg/m(2) or with oxaliplatin 100 mg/m(2) as a 2-hour infusion on day 1. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B). RESULT: Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI (P =.99). Median second progression-free survival (PFS) was 14.2 months in arm A versus 10.9 in arm B (P =.64). In first-line therapy, FOLFIRI achieved 56% response rate (RR) and 8.5 months median PFS, versus FOLFOX6 which achieved 54% RR and 8.0 months median PFS (P =.26). Second-line FOLFIRI achieved 4% RR and 2.5 months median PFS, versus FOLFOX6 which achieved 15% RR and 4.2 months PFS. In first-line therapy, National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia were more frequent with FOLFIRI, and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6. CONCLUSION: Both sequences achieved a prolonged survival and similar efficacy. The toxicity profiles were different.

Clinical trials in paediatric oncology. Recommendations for the development of new anticancer agents.

Childhood and adolescent cancers are rare diseases. Despite the progress in treatment (more than two-thirds of all cases are cured), cancer remains the leading cause of death by disease in children older than 1 year. Access to new drugs that are more efficacious or better tolerated is therefore an important public health priority. The objective of our round table was thus to take inventory of the situation and to propose recommendations aimed at facilitating coordinated, rational and more rapid access to new treatments. The active participation of paediatric oncologists, parents, pharmaceutical companies and regulatory authorities proved not only necessary but very constructive. Pharmaceutical companies have developed very few new anticancer agents for children during the past 10 years. The round table identified current trends that appear propitious: the mobilisation of parents and patients' associations; European initiatives to encourage companies to assess drugs in children; regulatory initiatives to guide drug development; and the existence of structured clinical research networks in paediatric oncology, including for the development of early treatment. The round table recommends the following measures to improve access to new treatments for children and adolescents with cancer: 1. Conduct preclinical paediatric evaluation of all anticancer agents that begin the development process for adults (research and validation of treatment targets; pharmacological evaluation in relevant experimental models) to help choose the agents to study in children. 2. Initiate paediatric clinical development before the first application for authorization for adults is filed, when sufficient safety and tolerability data are available, that is, after the phase I trials in adults and optimally during the phase II trials. 3. Optimise paediatric clinical evaluation by defining development plans early and by reducing the duration of studies (enlargement of the early treatment research network to ensure adequate recruitment; new evaluation methods; better extrapolation of pharmacological data from adults to children for dose-finding). 4. Improve information to and participation of parents and patients in clinical research for new treatments. The prerequisite for the success of this project became rapidly clear to all the round-table participants: cooperation and partnership between specialists and other scientists from academia, parent associations, pharmaceutical companies and regulatory authorities. Only with such cooperation can progress in treatment occur and new hopes for recovery be fulfilled.

A phase II study of irinotecan in patients with advanced renal cell carcinoma.

BACKGROUND: Patients with disseminated renal cell carcinoma (RCC) have a poor outcome, and the disease is considered highly resistant to chemotherapy. Irinotecan is an active drug in the treatment of a number of neoplastic diseases and is not concerned with the multidrug-resistance phenotype of tumor cells, a common mechanism of drug inactivation and resistance in patients with RCC. Therefore, the authors tested the antitumor activity of irinotecan in patients with RCC. METHODS: Patients with disseminated RCC received irinotecan (350 mg/m(2)) every 3 weeks. The primary objective of the study was to determine the overall response rate. Two groups of patients were defined: previously treated patients (Group A) and nonpretreated patients (Group B). RESULTS: Forty-two eligible patients were recruited: Twenty-six patients (Group A) had received previous chemotherapy or immunotherapy, and 16 patients had received no previous systemic therapy (Group B). The median number of cycles received per patient was 3 cycles (range, 1-6 cycles). A dose reduction was required in only 8% of cycles. Two patients, one in each group, had minor responses. Eleven patients (42%) in Group A and 1 patient (12%) in Group B had disease stabilization. Overall, therapy was tolerated well. Grade 4 neutropenic fever occurred in 17% of patients. The 1-year overall survival rate was 61% (95% confidence interval, 42-80%) in Group A and 19% (95% confidence interval, 0-49%) in Group B. CONCLUSIONS: Irinotecan was tolerated well and had limited activity in patients with disseminated RCC at the dose and schedule used in the current study. A high percentage of disease stabilization was observed in cytokine-pretreated patients.