FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI in patients with resectable metastatic colorectal cancer (MIROX): a pragmatic approach to chemotherapy timing with perioperative or postoperative chemotherapy from an open-label, randomized phase III trial.

BACKGROUND: Perioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative. PATIENTS AND METHODS: In this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m(2)) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m(2)) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m(2)). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fong's prognostic score. The primary end point was 2-year disease-free survival (DFS). RESULTS: A total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7-FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7-FOLFIRI. CONCLUSIONS: FOLFOX7-FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing. CLINICAL TRIALS NUMBER: NCT00268398.

Randomized phase II trial of irinotecan and bevacizumab as neo-adjuvant and adjuvant to temozolomide-based chemoradiation compared with temozolomide-chemoradiation for unresectable glioblastoma: final results of the TEMAVIR study from ANOCEF†.

BACKGROUND: Prognosis of unresectable glioblastoma (GB) remains poor, despite temozolomide (TMZ)-based chemoradiation. Activity of bevacizumab (BEV) and irinotecan (IRI) has been reported in recurrent disease. We evaluated BEV and IRI as neo-adjuvant and adjuvant treatment combined with TMZ-based chemoradiation for unresectable GB. PATIENTS AND METHODS: Patients with unresectable GB, age 18-70, IK ≥50 were eligible. The experimental arm (BEV/IRI) consisted of neo-adjuvant intravenous BEV, 10 mg/kg, and IRI, 125 mg/m(2), every 2 weeks for four cycles before radiotherapy (RT) (60 Gy), concomitant oral TMZ, 75 mg/m(2)/day, and BEV, 10 mg/kg every 2 weeks. Adjuvant BEV and IRI were given every 2 weeks for 6 months. The control arm consisted of concomitant oral TMZ, 75 mg/m(2)/day during RT, and 150-200 mg/m(2) for 5 days every 28 days for 6 months. The use of BEV was allowed at progression in the control arm. RESULTS: Patients (120) were included from April 2009 to January 2011. The working hypothesis was that treatment would increase the progression-free survival at 6 month (PFS-6) from 50% to 66%. The primary objective was not achieved, and only 30 out of 60 patients were alive without progression at 6 months (50.0% [IC95% (36.8; 63.1)] in the BEV/IRI arm when 37 out of 60 patients were required according to the Fleming decision rules. PFS-6 was 7.1 months in BEV/IRI versus 5.2 months in the control arm. The median overall survival was not different between the two arms (11.1 months). Main toxicities were three fatal intracranial bleedings, three bile duct or digestive perforations/infections (1 fatal), and six thrombotic episodes in the BEV/IRI arm, whereas there was one intracranial bleeding, two bile duct or digestive perforations/infections (1 fatal), and one thrombotic episode in the control arm. CONCLUSIONS: Neo-adjuvant and adjuvant BEV/IRI, combined with TMZ-radiation, is not recommended for further evaluation in the first-line treatment of unresectable GB. CLINICAL TRIAL REGISTRATION: Clinical trial registered under EUDRACT number 2008-002775-28 (NCT01022918).

FOXP3 expression in cancer cells and anthracyclines efficacy in patients with primary breast cancer treated with adjuvant chemotherapy in the phase III UNICANCER-PACS 01 trial.

BACKGROUND: Predictive markers of response to chemotherapy are lacking in breast cancer patients. Forkhead Box Protein 3 (FOXP3) is an anti-oncogene whose absence in cancer cells could confer resistance to DNA damaging agent. So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival (OS) benefit over anthracyclines alone, in patients with FOXP3-negative tumors. PATIENTS AND METHODS: Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel (Taxotere) to anthracyclines in patients with localized breast cancer. Kaplan-Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in tumor cells. RESULTS: Four hundred and five tumors were found to express FOXP3 (37%). FOXP3 expression in breast cancer cells was associated with better OS (P = 0.003). Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in breast cancer cells is independently associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy, but not in patients treated with sequential anthracycline-taxane. Moreover, in vitro experiments showed that FOXP3 induction in breast cancer cell lines using histone deacetylase inhibitor enhances anthracyclines efficacy. CONCLUSION: FOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer.

Tolerability of anti-tuberculosis treatment and HIV serostatus.

SETTING: Tuberculosis (TB) is frequent in human immunodeficiency virus (HIV) infected patients, but its treatment is hampered by adverse events and paradoxical reactions. OBJECTIVE: To examine the impact of HIV infection and other factors on the risk and spectrum of adverse events related to anti-tuberculosis treatment in a prospective cohort study conducted between January 2003 and August 2004. RESULTS: Of 105 patients treated for TB, 30 were HIV-infected. The overall incidence of adverse events was 122.5 +/- 18.5 per 100 patient-years (py) and the incidence of severe adverse events was 45.2 +/- 11.3/100 py. Age >50 years (OR 2.2, 95%CI 1.01-4.8, P = 0.046) and HIV infection (OR 3.9, 95%CI 2.1-7.5, P < 0.001) were independently associated with a higher risk of adverse events. Hepatitis (30.5/100 py) and neuropathy (28.6/100 py) were the most frequent adverse events. Hepatitis C virus infection was associated with hepatitis (OR 4.2, 95%CI 1.2-15.0, P = 0.028) and neuropathy with HIV infection (OR 3.8, 95%CI 1.1-13.7, P = 0.040). CONCLUSION: Adverse reactions to anti-tuberculosis drugs are frequent. HIV infection and age >50 years are factors associated with such reactions, while hepatitis C virus infection is a risk factor for hepatitis.

Correlation between radio-induced lymphocyte apoptosis measurements obtained from two French centres.

PURPOSE OF THE RESEARCH: In the era of modern treatment delivery, increasing the dose delivered to the target to improve local control might be modulated by the patient's intrinsic radio-sensitivity. A predictive assay based on radio-induced lymphocyte apoptosis quantification highlighted the significant correlation between CD4 and CD8 T-lymphocyte apoptosis and grade 2 or 3 radiation-induced late toxicities. By conducting this assay at several technical platforms, the aim of this study was to demonstrate that radio-induced lymphocyte apoptosis values obtained from two different platforms were comparable. MATERIALS AND METHODS: For 25 patients included in the PARATOXOR trial running in Dijon the radio-induced lymphocyte apoptosis results obtained from the laboratory of Montpellier (IRCM, Inserm U1194, France), considered as the reference (referred to as Lab 1), were compared with those from the laboratory located at the Institut de cancérologie de Lorraine (ICL, France), referred to as Lab 2. Different statistical methods were used to measure the agreement between the radio-induced lymphocyte apoptosis data from the two laboratories (quantitative data). The Bland-Altman plot was used to identify potential bias. RESULTS: All statistical tests demonstrated good agreement between radio-induced lymphocyte apoptosis values obtained from both sites and no major bias was identified. CONCLUSIONS: Since radio-induced lymphocyte apoptosis values, which predict tolerance to radiotherapy, could be assessed by two laboratories and showed a high level of robustness and consistency, we can suggest that this assay be extended to any laboratories that use the same technique.

A phase I dose escalation study using simultaneous integrated-boost IMRT with temozolomide in patients with unifocal glioblastoma.

PURPOSE: To evaluate the maximum tolerated dose of simultaneous integrated-boost intensity-modulated radiotherapy (SIB-IMRT) associated with temozolomide in patients with glioblastoma. PATIENTS AND METHODS: Between November 2009 and January 2012, nine patients with malignant glioma were enrolled in this phase I clinical trial. Radiotherapy was delivered using fractions of 2.5Gy on the planning target volume b and of 1.9Gy on the planning target volume a. Volumes were defined as follow: gross tumour volume b: tumour taking up contrast on T1 weighted MRI images; clinical target volume b: gross tumour volume b+0.5cm (adapted to the anatomical structures) and lastly planning target volume b: clinical target volume b+0.5cm; gross tumour volume a: tumour (gross tumour volume b)+2cm and including oedema outlined on T2Flair MRI sequences; clinical target volume a gross tumour volume a+0.5cm (adapted to the anatomical structures); planning target volume a: clinical target volume a+0.5cm. Three patients were enrolled at each of the three levels of dose (70, 75 and 80Gy prescribed on the planning target volume b and 56, 60 and 60.8Gy on the planning target volume a). Radiotherapy was delivered with temozolomide according to the standard protocol. Dose-limiting toxicities were defined as any haematological toxicities at least grade 4 or as any radiotherapy-related non-haematological acute toxicities at least grade 3, according to the Common Terminology Criteria for Adverse Events, version 3.0. RESULTS: Until the last dose level of 80Gy, no patient showed dose-limiting toxicity. CONCLUSIONS: SIB-IMRT, at least until a dose of 80Gy in 32 daily fractions, associated with temozolomide is feasible and well tolerated.

[Reirradiations of head and neck cancers: state of the concept and ways of development]. / Ré-irradiations des cancers de la tête et du cou : état du concept et voies de développement.

The treatment of local recurrence or second primary developed in irradiated area in the field of head and neck carcinoma, should be planned and organized through multidisciplinary discussions. The outcome of such a clinical situations benefits from second line and advanced technology treatments. Only a few patients are amenable to salvage surgery, hence radiation therapy, combined or not with chemotherapy, takes a major role in these indications. This overview of the literature describes recent development in this field, aiming to improve local control while the sparing of organ at risk remains an important goal. Radiation therapy is currently implementing major new technologies set to improve external beam irradiation with new concepts on dose, fractionation, intensity modulated radiation therapy and stereotactic approach - as well as in brachytherapy. Apart from dedicated studies, the great heterogeneity of the treated patients should be underlined and taken into consideration. However, current data confirm the feasibility of reirradiation with acceptable local control and toxicity.

Pulmonary manifestations of leptospirosis.

BACKGROUND: Pulmonary manifestations in leptospirosis are considered a major complication and are related to a poor prognosis. We present a large series of patients with pulmonary involvement using a practical approach based on the presence of acute respiratory failure (ARF). METHODS: A retrospective study of patients with confirmed leptospirosis. RESULTS: One hundred and sixty-nine patients with a laboratory-confirmed diagnosis of leptospirosis were investigated. One hundred and thirty-four patients (36.7±14 years of age) had pulmonary involvement. Severe pulmonary involvement was defined by evidence of ARF. Univariate analysis found the following factors related to severe pulmonary leptospirosis: dyspnoea (OR=10.14, p<0.0001), pulmonary crepitations (OR=4.8, p<0.0004), abnormal chest X-ray (OR=9.88, p<0.007) with alveolar shadowing (OR=8.12, p<0.0001), oliguria/anuria (OR=5.48, p<0.0001), hepatomegaly (OR=7.11, p< 0.0001), shock (OR=8.38, p< 0.0001), ICU admission (OR=60.08, p< 0.0001), dialysis (OR=4.87, p< 0.001), mechanical ventilation (OR=216, p< 0.0001) and development of nosocomial infection (OR=21.5, p< 0.0001). The mortality rate was significantly different between severe (40%) and non-severe (5.3%) pulmonary forms (OR=11.87, p< 0.0001). Multivariate analysis found two independent factors related to severe pulmonary involvement: dyspnoea (OR=10.18, p< 0.0001) and oliguria/anuria (OR=4.87, p< 0.0009). We performed a multivariate analysis to assess independent factors related to mortality and found: mechanical ventilation requirement (OR=27.85, p< 0.0001) and AST greater than 150 IU/L (OR=4.57, p< 0.02). Haemoptysis was associated with survival (OR=0.2, p< 0.02). CONCLUSIONS: Severe pulmonary involvement in leptospirosis is associated with extensive disease involving other organs. The association of multiple factors is associated with severe forms of the disease and a high mortality rate.

[Pulmonary manifestations of leptospirosis]. / Manifestations pulmonaires de la leptospirose.

BACKGROUND: Pulmonary manifestations in leptospirosis are considered a major complication, and are related to a poor prognosis. We present a large series of patients with pulmonary involvement using a practical approach based on the presence of acute respiratory failure (ARF). METHODS: A retrospective study of patients with confirmed leptospirosis. RESULTS: 169 patients with a laboratory-confirmed diagnosis of leptospirosis were investigated. 134 patients (36.7 + or - 14 years of age) had pulmonary involvement. Severe pulmonary involvement was defined by evidence of acute respiratory failure. Univariate analysis found the following factors related to severe pulmonary leptospirosis: dyspnoea (OR 10.14, p<0.0001), pulmonary crepitations (OR 4.8, p<0.0004), abnormal chest X Ray (OR 9.88, p<0.007) with alveolar shadowing (OR 8.12, p<0.0001), oliguria/anuria (OR 5.48, p<0.0001), hepatomegaly (OR 7.11, p<0.0001), shock (OR 8.38, p<0.0001), ICU admission (OR 60.08, p<0.0001), dialysis (OR 4.87, p<0.001), mechanical ventilation (OR 216, p<0.0001) and development of nosocomial infection (OR 21.5, p<0.0001). The mortality rate was significantly different between severe (40%) and non-severe (5.3%) pulmonary forms (OR 11.87, p<0.0001). Multivariate analysis found 2 independent factors related to severe pulmonary involvement: dyspnoea (OR 10.18, p<0.0001), and oliguria/anuria (OR 4.87, p<0.0009). We performed a multivariate analysis to assess independent factors related to mortality and found: Mechanical ventilation requirement (OR 27.85, p<0.0001) and ASAT>150 UI/L (OR 4.57, p<0.02). Haemoptysis was associated with survival (OR 0.2, p<0.02). CONCLUSION: Severe pulmonary involvement in leptospirosis is associated with extensive disease involving other organs. The association of multiples factors is associated with severe forms of the disease and a high mortality rate.

The long-term benefits of genotypic resistance testing in patients with extensive prior antiretroviral therapy: a model-based approach.

OBJECTIVES: Resistance testing in HIV disease may provide long-term benefits that are not evident from short-term data. Our objectives were to estimate the long-term effectiveness, cost and cost-effectiveness of genotype testing in patients with extensive antiretroviral exposure. METHODS: We used an HIV simulation model to estimate the long-term effectiveness and cost-effectiveness of genotype testing. Clinical data incorporated into the model were from NARVAL, a randomized trial of resistance testing in patients with extensive antiretroviral exposure, and other randomized trials. Each simulated patient was eligible for up to three sequential regimens of antiretroviral therapy (i.e. two additional regimens beyond the trial-based regimen) using drugs not available at the time of the study, such as lopinavir/ritonavir, darunavir/ritonavir and enfuvirtide. RESULTS: In the long term, projected undiscounted life expectancy increased from 132.2 months with clinical judgement alone to 147.9 months with genotype testing. Median survival was estimated at 11.9 years in the resistance testing arm vs 10.4 years in the clinical judgement alone arm. Because of increased survival, the projected lifetime discounted cost of genotype testing was greater than for clinical judgement alone (euro313,900 vs euro263,100; US$399,000 vs US$334,400). Genotype testing cost euro69,600 (US$88,500) per quality-adjusted life year gained compared with clinical judgement alone. CONCLUSIONS: In patients with extensive prior antiretroviral exposure, genotype testing is likely to increase life expectancy in the long term as a result of the increased likelihood of receiving two active new drugs. Genotype testing is associated with cost-effectiveness comparable to that of strategies accepted in patients with advanced HIV disease, such as enfuvirtide use.