Non-pegylated liposomal doxorubicin (NPLD, Myocet®) + carboplatin in patients with platinum sensitive ovarian cancers: A ARCAGY-GINECO phase IB-II trial.

BACKGROUND: Carboplatin and pegylated liposomal doxorubicin combination is a standard regimen in platinum-sensitive recurrent ovarian cancer patients. The pegylated liposomal doxorubicin shortage from 2011 to 2013 urged assessment of the efficacy and tolerance of non-pegylated liposomal doxorubicin in combination with carboplatin. METHODS: MYCA was a multicenter 2-step phase Ib-II single arm trial meant to assess the safety and efficacy of carboplatin AUC 5 mg/min.mL combined with non-pegylated liposomal (dose escalation from 40 to 50 mg/m2 during phase Ib step; and 50 mg/m2 during phase II step), every 4 weeks in patients with platinum-sensitive relapse. The primary objective was disease control rate (DCR) at 12 months. RESULTS: From 2012 to 2014, 87 patients were enrolled. They were treated as second (78%) or third line (22%) treatment. Total of 67 patients (78%) completed 6 cycles. G-CSF support was prescribed to 58% patients. The DCR at 12 months was 30.0% (95% CI, 20.3-39.7); the median PFS was 10.0 months (95% CI, 8.6-11.0). The median overall survival was 28.1 months (95% CI, 22.3-32.5); and the objective response rate was 58% (95% CI, 47-68). Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 17%, 13% and 1%, respectively; febrile neutropenia in 6%. One patient who did not receive GCSF support died from febrile neutropenia. CONCLUSION: Non-pegylated liposomal doxorubicin-carboplatin combination exhibits an acceptable safety profile, with GCSF prophylaxis. Acknowledging the lack of direct comparison, efficacy in terms of 12 month DCR was comparable with standard treatments.

Dose intensity and toxicity associated with Taxotere formulation: a retrospective study in a population of breast cancer patients treated with docetaxel as an adjuvant or neoadjuvant chemotherapy.

Docetaxel is an antineoplastic drug from the taxane family that inhibits tubulin polymerization. Its brand name is Taxotere. In mid-2010, the formulation of Taxotere changed from a two-vial preparation needing a predilution (T2V) to a one-vial ready-to-use preparation (T1V). The aim of this study was to compare the toxicity profile of these two formulations. This retrospective observational and monocentric study included all patients who received Taxotere-based chemotherapy (100 mg/m) as an adjuvant or a neoadjuvant treatment for localized breast cancer, following initial treatment with anthracycline-based chemotherapy. Patients received either T2V or T1V Taxotere depending on the period of treatment. The main endpoint was the ratio of the dose of Taxotere received to that scheduled (R=docetaxel dose received/docetaxel dose scheduled). The secondary endpoint was tolerance. A total of 97 patients were included: 39 in the T2V group and 58 in the T1V group. The ratio of docetaxel received/docetaxel scheduled was significantly lower in the T1V than in the T2V group (0.83 vs. 0.95, respectively; P=0.028). A higher proportion of patients did not receive the totality of the scheduled dose in the T1V than in the T2V group (28 vs. 8%, respectively; P=0.03). Furthermore, the proportion of patients experiencing cutaneous toxicity was significantly higher in the T1V than in the T2V group (50 vs. 15%, respectively; P<0.001) as well as for neurological toxicity (31 vs. 15%, respectively; P=0.03). The frequency of grade 3 toxicities was higher in the T1V than in the T2V group (50 vs. 8%, P=0.016). The frequency of idiosyncratic toxicities was not affected by the change of formulation (4.7 vs. 5.4%, P=0.98). This study shows that patients treated with the T1V formulation received a significantly smaller dose of Taxotere than patients treated with T2V. In this small retrospective study, no conclusions can be drawn as to why a change in formulation would be associated with differences in dose tolerance. However, it does encourage caution and need for clinical data analysis when adopting even minor changes in the formulation of well-known anticancer drugs.

FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.

BACKGROUND: Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer. METHODS: We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival. RESULTS: The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001). CONCLUSIONS: As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; ClinicalTrials.gov number, NCT00112658.).

WITHDRAWN: Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease.

BACKGROUND: Randomized trials have demonstrated that adding a drug to a single-agent or to a two-agent regimen increased the tumor response rate in patients with advanced non-small cell lung cancer (NSCLC), although its impact on survival remains controversial. OBJECTIVES: To evaluate the clinical benefit of adding a drug to a single-agent or two-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC. SEARCH METHODS: There were no language restrictions. Searches of MEDLINE and EMBASE were performed using the search terms non-small cell lung carcinoma/drug therapy, adenocarcinoma, large-cell carcinoma, squamous-cell carcinoma, lung, neoplasms, clinical trial phase III, and randomized trial. Manual searches were also performed to find conference proceedings published between January 1982 and June 2006. SELECTION CRITERIA: Data from all randomized controlled trials performed between 1980 and 2006 (published between January 1980 and June 2006) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, one-year survival rate, and toxicity rate were calculated using the fixed-effect model. Pooled median ratios (MRs) for median survival also were calculated using the fixed-effect model. ORs and MRs lower than unity (< 1.0) indicate a benefit of a doublet regimen compared with a single-agent regimen (or a triplet regimen compared with a doublet regimen). MAIN RESULTS: Sixty-five trials (13601 patients) were eligible. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR 0.42, 95% confidence interval [CI] 0.37 to 0.47, P < 0.001) and one-year survival (OR 0.80, 95% CI 0.70 to 0.91, P < 0.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI 0.79 to 0.89, P < 0.001). An increase also was observed in the tumor response rate (OR 0.66, 95% CI 0.58 to 0.75, P < 0.001) in favor of the triplet regimen, but not for one-year survival (OR 1.01, 95% CI 0.85 to 1.21, P = 0.88). The median survival ratio was 1.00 (95% CI 0.94 to 1.06, P = 0.97). AUTHORS' CONCLUSIONS: Adding a second drug improved tumor response and survival rate. Adding a third drug had a weaker effect on tumor response and no effect on survival.

5-fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) as second-line chemotherapy in patients with metastatic pancreatic adenocarcinoma.

BACKGROUND: To evaluate the efficacy and toxicity of irinotecan and oxaliplatin plus 5-fluorouracil (FU) and leucovorin (FOLFIRINOX) as second-line therapy in metastatic pancreatic adenocarcinoma (MPA). PATIENTS AND METHODS: We retrospectively analyzed the medical records of 27 patients with MPA treated with FOLFIRINOX as second-line therapy between January 2003 and November 2009 in our hospital. The recommended schedule was oxaliplatin 85 mg/m(2) on day 1 + irinotecan 180 mg/m(2) on day 1 + leucovorin 400 mg/m(2) on day 1 followed by FU 400 mg/m(2) as a bolus on day 1 and 2,400 mg/m(2) as 46-hour continuous infusion biweekly. RESULTS: The median age of the 27 patients (13 males and 14 females) was 63 years (45-83). All patients had progressive disease after first-line chemotherapy by gemcitabine. A total of 167 cycles were administered, with a median number of 6 cycles (1-29) per patient. One toxic death occurred (sepsis). Tolerance of treatment was acceptable, and the relative dose density delivered per patient was 92.8% for oxaliplatin, 89.1% for irinotecan and 96.4% for FU. Grade 3-4 neutropenia occurred in 55.6% of the patients, including 1 febrile neutropenia. The other toxicities were manageable. Regarding efficacy, 22 of the 27 patients were evaluable (WHO and RECIST criteria). Five patients had partial responses and 12 stable disease, resulting in an overall disease control rate of 63%. Median time to progression was 5.4 months (0.7-25.48), and median event-free survival was 3 months (0.5-24.9). Median overall survival was 8.5 months (0-26). A clinical benefit was reported for 55% of the patients. CONCLUSIONS: These results confirmed the good safety profile and the efficacy of the FOLFIRINOX regimen as second-line treatment of MPA.

Real-World Experience of Bevacizumab as First-Line Treatment for Ovarian Cancer: The GINECO ENCOURAGE Cohort of 468 French Patients.

Introduction: Bevacizumab-containing therapy is considered a standard-of-care front-line option for stage IIIB-IV ovarian cancer based on results of randomized phase 3 trials. The multicenter non-interventional ENCOURAGE prospective cohort study assessed treatment administration and outcomes in the French real-world setting. Patients and Methods: Eligible patients were aged ≥ 18 years with planned bevacizumab-containing therapy for newly diagnosed ovarian cancer. The primary objective was to assess the safety profile of front-line bevacizumab in routine clinical practice; secondary objectives were to describe patient characteristics, indications/contraindications for bevacizumab, treatment regimens and co-medications, follow-up and monitoring, progression-free survival, and treatment at recurrence. In this non-interventional study, treatment was administered as chosen by the investigator and participation in the trial had no influence on the management of the disease. Results: Of 1,290 patients screened between April 2013 and February 2015, 468 were eligible. Most patients (86%) received bevacizumab 15 mg/kg every 3 weeks or equivalent, typically with carboplatin (99%) and paclitaxel (98%). The median duration of bevacizumab was 12.2 (range 0-28, interquartile range 6.9-14.9) months; 8% of patients discontinued bevacizumab because of toxicity. The most common adverse events were hypertension (38% of patients), fatigue (35%), and bleeding (32%). There were no treatment-related deaths. Most physicians (90%) reported blood pressure measurement immediately before each bevacizumab infusion and almost all (97%) reported monitoring for proteinuria before each bevacizumab infusion. Median progression-free survival was 17.4 (95% CI, 16.4-19.1) months. The 3-year overall survival rate was 62% (95% CI, 58-67%). The most commonly administered chemotherapies at recurrence were carboplatin and pegylated liposomal doxorubicin. Discussion: Clinical outcomes and tolerability with bevacizumab in this real-life setting are consistent with randomized trial results, notwithstanding differences in the treated patient population and treatment schedule. Clinical Trial Registration:ClinicalTrials.gov, Identifier NCT01832415.

Single-arm phase II trial to evaluate efficacy and tolerance of regorafenib monotherapy in patients over 70 with previously treated metastatic colorectal adenocarcinoma FFCD 1404 - REGOLD.

BACKGROUND: Regorafenib significantly increases overall survival (OS) in patients with metastatic colorectal cancer previously treated but gives toxicities. OBJECTIVES: to assess the efficacy and safety of regorafenib at it's approved dose in the older population. PATIENTS AND METHODS: This multicenter single-arm phase II enrolled patients ≥70 years old after the failure of fluoropyrimidine-based chemotherapy, anti-VEGF, and anti-EGFR treatment. The primary endpoint was disease control rate (DCR) 2 months after initiation of regorafenib (160 mg/day, 3 weeks on/1 week off). RESULTS: Forty-three patients were enrolled, with a median age of 77 years. The 2 months DCR was 31.4% in the 35 evaluable patients. For the 42 patients that received at least one dose of regorafenib, median progression-free survival and OS were 2.2 and 7.5 months. The median time to autonomy degradation and quality of life degradation was 3.1 and 3.2 months, respectively. A grade 3-4 treatment-related adverse events was observed in 35/42 patients, notably: fatigue (45.2%), hand-foot skin reaction (19.0%), hypertension (21.4%), and diarrhea (7.1%). There is a trend to achieve DCR in patients ≤80 years and a trend to discontinue the study due to toxicity in patients with ECOG ≥1, over 80 years and with impaired baseline autonomy. CONCLUSION: Treatment with regorafenib in pretreated patients ≥70 years is feasible and demonstrate similar efficacy that was observed in previous studies in young patients. Fatigue is the most frequent severe adverse event. However, caution should be taken for older patients with ECOG ≥1, over 80 years, and with impaired baseline autonomy.

Population pharmacokinetics and pharmacogenetics of imatinib in children and adults.

PURPOSE: The aim of this study was to explore the effect of several demographic, biological, and pharmacogenetic covariates on the disposition of imatinib and its main metabolite (CGP74588) in both adults and children. EXPERIMENTAL DESIGN: Thirty-three children with solid malignancies included in a phase II exploratory study and 34 adults with gastrointestinal stromal tumors received 340 mg/m(2) and 400 mg imatinib, respectively. Plasma imatinib and CGP74588 concentrations observed on day 1 and at steady-state were analyzed by a population pharmacokinetic method (NONMEM) to evaluate the effect of age, body weight, age, sex, albuminemia, plasma alpha1-acid glycoprotein (AGP), and eight polymorphisms corresponding to ABCB1, ABCG2, CYP3A4, CYP3A5, and AGP (pharmacogenetic data available for 46 of 67 patients). RESULTS: Analysis of the whole data set in 67 patients showed that apparent clearance (CL/F) of imatinib was positively correlated with body weight and albuminemia and negatively with AGP. By considering these three covariates, the interindividual variability on CL/F decreased from 47% to 19%. The apparent clearance of CGP74588 was similarly dependent on both body weight and AGP and significantly lower (30% reduction) at steady-state. By adding genotype status to the final covariate imatinib model, a 22% reduction in CL/F was observed in heterozygous compared with wild-type patients corresponding to ABCG2 c.421C>A (P<0.05). CONCLUSIONS: By considering morphologic and biological covariates, a unique covariate model could be used to accurately describe imatinib pharmacokinetics in patients ages 2 to 84 years. Morphologic and biological characteristics have a stronger influence than pharmacogenetics on imatinib pharmacokinetics.

[Management of biliary tract carcinomas]. / Prise en charge thérapeutique des cancers des voies biliaires et de la vésicule biliaire.

Biliary tract carcinomas are rare tumours, counting for less than 5% of cancer. Biliary tract carcinomas comprise gallbladder carcinoma and cholangiocarcinoma, which arise from the intrahepatic or extrahepatic bile ducts. These tumours have a poor prognosis, with a median survival of 6 months for advanced disease. Surgical resection is the only potentially curative therapy. Adjuvant treatement by chemotherapy, radiotherapy or radio-chemotherapy might be an option after surgery, however no standard therapy is define. For advanced disease, despite progress of palliative chemotherapy, there is no standard therapy.

Safety of repeated administrations of ixabepilone given as a 3-hour infusion every other week in combination with irinotecan in patients with advanced malignancies.

Epothilones are active tubulin-interacting agents that warrant combinations in clinical studies. This phase I combination study explored ixabepilone administered as a 3-h infusion followed by a 90-minute infusion irinotecan, on days 1 and 14 of every 28-day cycle. Forty-one patients received doses of ixabepilone and irinotecan ranging from 15-30 mg/m(2) and 120-180 mg/m(2) every 2 weeks for a total of 173 cycles, respectively. Dose limiting toxicities reported at doses 25 mg/m(2) ixabepilone and 180 mg/m(2) irinotecan consisted of acute grade 3 diarrhoea and asthenia, eventually associated with neutropenia and sepsis, and/or delayed grade 3 peripheral neuropathy. Therefore, the recommended doses were 20 mg/m(2) ixabepilone and 180 mg/m(2) irinotecan. At this dose level, acute side effects were neutropenia, anaemia, nausea-vomiting, diarrhoea, asthenia, and alopecia. Delayed neuropathy was mostly restricted to reversible grade I-II. Pharmacokinetic data suggested no drug-drug interaction. Five objective responses were observed in four patients with lung cancer and one unknown primary epidermoid carcinoma patient. In conclusion, toxicity including peripheral neuropathy was manageable at the recommended doses of 20 mg/m(2) ixabepilone combined with 180 mg/m(2) irinotecan on days 1 and 14 every 28 days. Promising antitumour activity was observed in patients with platinum-pretreated lung cancer.

[Medico-economic benefits of subcutaneous formulations of trastuzumab and rituximab in day hospitalisation (SCuBA Study)]. / Bénéfices médicoéconomiques des formes sous-cutanées de trastuzumab et de rituximab en hospitalisation de jour (étude SCuBA).

INTRODUCTION: New pharmaceutical forms of trastuzumab and rituximab which can be administered by the subcutaneous route have been developed recently. For day hospitalisation units, these can be used in simpler treatment protocols than previous intravenous formulations. The objective of this study was to evaluate the medical and economic consequences of switching to subcutaneous formulations of trastuzumab and rituximab. METHODS: Thirty-six day care units in 30 hospitals or clinics participated in this observational study. Data were collected on the capacity of the units, the number of chemotherapy sessions implemented, the duration of occupation of a chair and the production capacity of the unit pharmacy. The number of additional sessions made possible by the use of subcutaneous forms in 2016 was determined and the associated gain in earnings calculated using national tariffs. RESULTS: Compared to the intravenous route, the mean duration of occupation of a chair was reduced by 56.1 % for a session of subcutaneous trastuzumab and by 73.8 % for a session of subcutaneous rituximab. The mean number of additional sessions made possible by the use of subcutaneous treatments was 242 [168-316] sessions by year by unit, corresponding to 2.7 % [1.9 %-3.4 %] of the total number of chemotherapy sessions in the unit. The corresponding gain in annual earnings was € 111 388. DISCUSSION: Switching the route of administration from the intravenous to the subcutaneous route is a useful strategy to address the increase in activity of day hospitalisation units. This allows an increase of 2.7 % in the total number of chemotherapy sessions in the unit. In most of the participating units, there was room for further optimization of activity, potentially to reach 4.2 % of the total number of sessions.

Stents for palliation of obstructive metastatic colon cancer: impact on management and chemotherapy administration.

HYPOTHESIS: The more rapid and less complicated recovery after palliative stent insertion compared with surgery may theoretically facilitate the early administration of chemotherapy. DESIGN: A retrospective study. SETTING: University tertiary care referral center. PATIENTS: From January 1, 1996, to September 15, 2005, 58 patients with obstructing colon cancer and nonresectable synchronous metastases were treated with self-expanding colonic metallic stent (SEMS) (n = 31) or surgery (n = 27). MAIN OUTCOME MEASURES: Comparison of the use of SEMS and emergency surgery as palliative measures to treat obstructing colon cancer with special reference to time to chemotherapy administration and survival. RESULTS: Mortality and morbidity were comparable between the 2 groups. Median hospital stay was shorter after SEMS insertion than after surgery (median, 8.0 vs 13.5 days, respectively; P < .01). Incidence of stoma creation was lower in patients treated with SEMS than in patients treated with surgery (6% vs 37%, respectively; P = .02). The median time to chemotherapy administration was shorter after SEMS insertion than after surgery (14.0 vs 28.5 days, respectively; P = .002). Three patients with SEMS and 0 patients in the surgical group underwent a curative colonic and hepatic resection after downstaging by chemotherapy (P = .27). Two patients (6%) with SEMS and undergoing chemotherapy had a tumor perforation requiring emergency surgery. There was no difference in survival between the 2 groups (median survival, 13.7 months for SEMS vs 11.4 months for surgery; P = .19). CONCLUSIONS: Insertion of SEMS should be the first step to treat obstructing colon cancer with nonresectable synchronous metastases because it allows chemotherapy to be administered earlier, may increase the resectability rate of metastases, and favorably impacts survival. The risk of tumor perforation while receiving chemotherapy requires attention.

Pharmacokinetic-pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors.

PURPOSE: This study explored factors affecting the pharmacokinetic variability of imatinib and CGP 74588, and the pharmacokinetic-pharmacodynamic correlations in patients with advanced gastrointestinal stromal tumors. EXPERIMENTAL DESIGN: Thirty-five patients with advanced gastrointestinal stromal tumors received 400 mg of imatinib daily. Six blood samples were drawn: before intake, during 1- to 3- and 6- to 9-hour intervals after intake on day 1, and before intake on days 2, 30, and 60. Plasma imatinib and CGP 74588 concentrations were quantified by reverse-phase high-performance liquid chromatography coupled with tandem mass spectrometry, and analyzed by the population pharmacokinetic method (NONMEM program). The influence of 17 covariates on imatinib clearance (CL) and CGP 74588 clearance (CLM/fm) was studied. These covariates included clinical and biological variables and occasion (OCC = 0 for pharmacokinetic data corresponding to the first administration, or OCC = 1 for the day 30 or 60 administrations). RESULTS: The best regression formulas were: CL (L/h) = 7.97 (AAG/1.15)(-0.52), and CLM/fm (L/h) = 58.6 (AAG/1.15)(-0.60) x 0.55(OCC), with the plasma alpha1-acid glycoprotein (AAG) levels indicating that both clearance values decreased at a higher AAG level. A significant time-dependent decrease in CLM/fm was evidenced with a mean (+SD) CGP 74588/imatinib area under the curve (AUC) ratio of 0.25 (+/-0.07) at steady state, compared with 0.14 (+/-0.03) on day 1. Hematologic toxicity was correlated with pharmacokinetic variables: the correlation observed with the estimated unbound imatinib AUC at steady-state (r = 0.56, P < 0.001) was larger than that of the total imatinib AUC (r = 0.32, NS). CONCLUSIONS: The plasma AAG levels influenced imatinib pharmacokinetics. A protein-binding phenomenon needs to be considered when exploring the correlations between pharmacokinetics and pharmacodynamics.

Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease.

BACKGROUND: Randomized trials have demonstrated that adding a drug to a single-agent or to a two-agent regimen increased the tumor response rate in patients with advanced non-small cell lung cancer (NSCLC), although its impact on survival remains controversial. OBJECTIVES: To evaluate the clinical benefit of adding a drug to a single-agent or two-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC. SEARCH STRATEGY: There were no language restrictions. Searches of MEDLINE and EMBASE were performed using the search terms non-small cell lung carcinoma/drug therapy, adenocarcinoma, large-cell carcinoma, squamous-cell carcinoma, lung, neoplasms, clinical trial phase III, and randomized trial. Manual searches were also performed to find conference proceedings published between January 1982 and June 2006. SELECTION CRITERIA: Data from all randomized controlled trials performed between 1980 and 2006 (published between January 1980 and June 2006) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, one-year survival rate, and toxicity rate were calculated using the fixed-effect model. Pooled median ratios (MRs) for median survival also were calculated using the fixed-effect model. ORs and MRs lower than unity (< 1.0) indicate a benefit of a doublet regimen compared with a single-agent regimen (or a triplet regimen compared with a doublet regimen). MAIN RESULTS: Sixty-five trials (13601 patients) were eligible. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR 0.42, 95% confidence interval [CI] 0.37 to 0.47, P < 0.001) and one-year survival (OR 0.80, 95% CI 0.70 to 0.91, P < 0.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI 0.79 to 0.89, P < 0.001). An increase also was observed in the tumor response rate (OR 0.66, 95% CI 0.58 to 0.75, P < 0.001) in favor of the triplet regimen, but not for one-year survival (OR 1.01, 95% CI 0.85 to 1.21, P = 0.88). The median survival ratio was 1.00 (95% CI 0.94 to 1.06, P = 0.97). AUTHORS' CONCLUSIONS: Adding a second drug improved tumor response and survival rate. Adding a third drug had a weaker effect on tumor response and no effect on survival.

[Pharmacokinetic-pharmacodynamics relationships of imatinib (Glivec)]. / Pharmacocinétique (PK) et pharmacodynamie (PD) de l'imatinib (Glivec).

Imatinib (Glivec) is a specific inhibitor of tyrosine kinase receptor, in particular of the proto-oncogene c-kit. Proto-oncogene c-kit is expressed or mutated in stromal digestive tumors (GIST). Pharmacokinetic (PK) analysis showed that imatinib displayed linear PK in patients with advanced GIST. Imatinib is extensively metabolized by the cytochrome P450 enzyme system. Alpha-1-acid glycoprotein (AAG), a protein involved in the acute phase of inflammation, is implicated in protein binding of imatinib and seems to play a key role in imatinib PK.

Phase I and pharmacokinetic study of aplidine, a new marine cyclodepsipeptide in patients with advanced malignancies.

PURPOSE: To establish the safety, pharmacokinetic parameters, maximum-tolerated dose, and recommended dose of aplidine, a novel marine cyclodepsipeptide, in patients with advanced cancer. PATIENTS AND METHODS: Using a modified Fibonacci method, we performed a phase I and pharmacokinetic study of aplidine administered as a 24-hour intravenous infusion every 2 weeks. RESULTS: Sixty-seven patients received aplidine at a dose ranging from 0.2 to 8 mg/m(2). Dose-limiting myotoxicity corresponding to grade 2 to 3 creatine phosphokinase elevation and grade 1 to 2 myalgia and muscle weakness occurred in two of six patients at 6 mg/m(2). No cardiac toxicity was observed. Electron microscopy analysis showed the disappearance of thick filaments of myosin. Grade 3 muscle toxicity occurred in three of 14 patients at the recommended dose of 5 mg/m(2) and seemed to be more readily reversible with oral carnitine (1 g/10 kg). Therefore, dose escalation was resumed using carnitine prophylactically, allowing an increase in the recommended dose to 7 mg/m(2). Other toxicities were nausea and vomiting, diarrhea, asthenia, and transaminase elevation with mild hematologic toxicity. Aplidine displayed a long half-life (21 to 44 hours), low clearance (45 to 49 L/h), and a high volume of distribution (1,036 to 1,124 L) with high interpatient variability in plasma, whereas in whole blood, clearance ranged from 3.0 to 6.2 L/h. Minor responses and prolonged tumor stabilizations were observed in patients with medullary thyroid carcinoma. CONCLUSION: Muscle toxicity was dose limiting in this study. Recommended doses of aplidine were 5 and 7 mg/m(2) without and with carnitine, respectively. The role of carnitine will be further explored in phase II studies.

Pharmacokinetic profile of cetuximab (Erbitux) alone and in combination with irinotecan in patients with advanced EGFR-positive adenocarcinoma.

This trial assessed pharmacokinetic interactions between cetuximab and irinotecan. Patients were placed in either in group A (irinotecan 350 mg/m2/3 weeks and 400 mg/m2 cetuximab at week 2 then 250 mg/m2/week) or group B (cetuximab weekly starting week 1 then irinotecan starting week 4). Patient plasma or serum samples from each treatment arm were analysed using HPLC and ELISA. Among 14 patients, compartmental model showed no significant differences in mean plasma AUC at week 1 versus week 4 for irinotecan (44,388 versus 39,800 microg/ml/h) and cetuximab (20,441 versus 23,363 microg/ml/h), respectively. Half-lifes (standard deviations) for irinotecan were 16.02 (+/-8.41) h at week 1 and 13.99 (+/-2.14) h at week 4, and for cetuximab 106 (+/-32) at week 3 and 111 (+/-30) h at week 4. Mean concentration-versus-time profiles either alone or in combination were superimposable for cetuximab and irinotecan. From this study, we conclude that there is no evidence of pharmacokinetic interaction between irinotecan and cetuximab.

Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-analysis.

CONTEXT: Randomized trials have demonstrated that adding a drug to a single-agent or to a 2-agent regimen increased the tumor response rate in patients with advanced non-small-cell lung cancer (NSCLC), although its impact on survival remains controversial. OBJECTIVE: To evaluate the clinical benefit of adding a drug to a single-agent or 2-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC. DATA SOURCES AND STUDY SELECTION: Data from all randomized controlled trials performed between 1980 and 2001 (published between January 1980 and October 2003) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC. There were no language restrictions. Searches of MEDLINE and EMBASE were performed using the search terms non-small-cell lung carcinoma/drug therapy, adenocarcinoma, large-cell carcinoma, squamous-cell carcinoma, lung, neoplasms, clinical trial phase III, and randomized trial. Manual searches were also performed to find conference proceedings published between January 1982 and October 2003. DATA EXTRACTION: Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, 1-year survival rate, and toxicity rate were calculated using the fixed-effect model. Pooled median ratios (MRs) for median survival also were calculated using the fixed-effect model. ORs and MRs lower than unity (<1.0) indicate a benefit of a doublet regimen compared with a single-agent regimen (or a triplet regimen compared with a doublet regimen). DATA SYNTHESIS: Sixty-five trials (13 601 patients) were eligible. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR, 0.42; 95% confidence interval [CI], 0.37-0.47; P<.001) and 1-year survival (OR, 0.80; 95% CI, 0.70-0.91; P<.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI, 0.79-0.89; P<.001). An increase also was observed in the tumor response rate (OR, 0.66; 95% CI, 0.58-0.75; P<.001) in favor of the triplet regimen, but not for 1-year survival (OR, 1.01; 95% CI, 0.85-1.21; P =.88). The median survival ratio was 1.00 (95% CI, 0.94-1.06; P =.97). CONCLUSION: Adding a second drug improved tumor response and survival rate. Adding a third drug had a weaker effect on tumor response and no effect on survival.

[New drugs in bronchial cancer]. / Nouveaux médicaments dans le cancer bronchique.

MODEST RESULTS TILL NOW: Despite progress in the treatment of bronchial cancer (BC) over the last 20 years, notably with platinum-based chemotherapy, results in terms of survival have been modest and prognosis of the tumor generally remains unfavorable. CLASSICAL CHEMOTHERAPY: In non-small cell BC, 5 new cytotoxic agents: vinorelbine (a new mitotic inhibitor), gemcitabine (an antimetabolic), docetaxel and paclitaxel (of the taxane family), irinotecan (DNA repair enzyme inhibitor) have shown interesting results. In small cell BC, among the new cytotoxics, only topoisomerase I inhibitors represented by irinotecan and topotecan are really interesting. Taxanes appear rather disappointing. ONGOING CLINICAL ASSESSMENT OF NEW MOLECULES: Exploration of new drugs is an absolute priority. In parallel with the development of new traditional cytotoxics (trapazamin, oxaliplatin, ALIMTA a new antifolate, UFT and epothilone); studies on agents with biological or molecular effects: thyroxin-kinase inhibitors, trastuzumab--a monoclonal antibody--a metalloprotease inhibitor and marimastat are presently ongoing.

Sunitinib in advanced pancreatic neuroendocrine tumors: latest evidence and clinical potential.

Based on preclinical data available in the RIP1-Tag2 transgenic mouse model, sunitinib is an inhibitor of angiogenesis in pancreatic neuroendocrine tumors blocking vascular endothelial growth factor receptors and platelet-derived growth factor receptors in endothelial cells and pericytes, respectively. Evidence of objective response in phase I trials justified the initiation of a large phase II/III program using sunitinib in patients with advanced/metastatic well-differentiated pancreatic neuroendocrine tumors. In the phase II study, sunitinib showed potent antitumor activity and a safe toxicity profile. In a recent double-blind placebo-controlled randomized phase III trial, sunitinib doubled the progression-free survival of patients, induced objective responses, and reduced the risk of death of patients with advanced/metastatic well-differentiated tumors. These data allowed the approval of sunitinib in several countries including Europe and the United States of America. These recent data provide hope for patients with well-differentiated pancreatic neuroendocrine tumors and will change standards of care in this disease.