Predictive value of vascular endothelial growth factor polymorphisms for maintenance bevacizumab efficacy in metastatic colorectal cancer: an ancillary study of the PRODIGE 9 phase III trial.

Background: Several studies have reported the impact of single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes on the efficacy of bevacizumab in metastatic colorectal cancer (mCRC), but results are still inconsistent. The PRODIGE 9 phase III study compared bevacizumab maintenance versus observation alone after induction chemotherapy with FOLFIRI plus bevacizumab. Objective: We evaluated the impact of SNPs of VEGF-A, VEGF receptors (VEGFR-1, VEGFR-2), and hypoxia inducible factor-1α (HIF-1α) on tumor control duration (TCD), overall survival (OS), progression-free survival (PFS), and duration of first chemotherapy free-intervals (CFI). Patients and methods: We included 314/491 patients from PRODIGE 9 with a DNA blood sample available. Nine SNPs were genotyped on germline DNA using real-time Polymerase Chain Reaction TaqMan TM (Thermo Fisher Scientific, Waltham, MA , USA 02451). Results: In the bevacizumab arm, patients with the VEGFR-1 rs9582036 CC genotype (n = 14) had significantly longer TCD [22.4 months (95% confidence interval (CI): 14.75-not reached)] than patients with the AA or CA genotype [14.4 months (95% CI: 11.7-17.1)] (p = 0.036), whereas there was no significant difference in the observation arm. In the bevacizumab arm, no significant difference was found between the CC, and AA or CA genotype for OS [28.2 (95% CI: 18.1-42.8) versus 22.5 (95% CI: 18.6-24.6) months, p = 0.5], PFS [9.4 (95% CI: 7.2-11.3) versus 9.2 (95% CI: 8.71-10.1)], and duration of the first CFI [4.6 (95% CI: 1.6-13.3) versus 4.14 (95% CI: 0.5-29.0) months, p = 0.3]. Conclusion: Among mCRC patients treated with bevacizumab maintenance, those with the VEGFR-1 rs9582036 CC genotype experienced longer TCD. The presence of this genotype may thus predict a benefit of bevacizumab maintenance in mCRC.

Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.

INTRODUCTION: Biliary obstruction secondary to colorectal cancer liver metastases is associated with a poor prognosis especially when chemotherapy cannot be re-started. The aim of this study was to determine the survival after biliary drainage and the associated prognostic factors. METHODS: Patients from two French centers were included retrospectively after first biliary endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography drainage for biliary obstruction secondary to liver metastases of colorectal cancer, occurring during chemotherapy. RESULTS: The final analysis included 69 patients. Overall median survival was 115 days. In univariate analysis, a previous liver surgery, technical and functional success of drainage and restarted chemotherapy were significantly associated with an improved survival. Chemotherapy was restarted after a median of 27 days. When drainage was efficient, survival improved from 33 to 262days (p<0.001). In multivariate analysis, significant protective factors for survival included previous a hepatectomy (HR 0.41) and functional success of the drainage (HR 0.29). Predictive factors for death included increased lines of chemotherapy (HR 1.68) and fever before drainage (HR 2.97). CONCLUSIONS: This is the first study concerning the benefits of biliary drainage for malignant biliary obstruction during the course of chemotherapy for colorectal cancer. A successful biliary drainage leads to improved survival and allows achievement of chemotherapy for 70% of patients.

Nutritional status and quality of life of cancer patients needing exclusive chemotherapy: a longitudinal study.

BACKGROUND: The aims of this study were to report nutritional status in a large panel of patients with cancer requiring exclusive chemotherapy and to study the influence of nutritional status on their quality of life (QoL). METHODS: This work was a longitudinal cohort study performed at a French university teaching hospital. Eligible patients were individuals with a cancer needing treatment based on exclusive chemotherapy. Three work-ups were performed: i) before the administration of the first course of chemotherapy: T1, ii) before the administration of the second (for patients with 3 planned courses) or third (patients with 6 planned courses) course: T2, and iii) before the administration of the last planned course: T3. The following data were collected: general health (performance status) and nutritional status (weight, anorexia grading, albuminemia, pre-albuminemia, and C-reactive protein) and QoL. RESULTS: The nutritional status of patients with cancer was preserved. Functional impairment, the presence of anorexia, the palliative nature of the chemotherapy, and an elevated C-reactive protein dosage were independent predictive factors of a lower QoL among patients assessed at the end of chemotherapy. CONCLUSIONS: Although larger studies should corroborate these findings, clinicians may include this information in the management of patients with cancer requiring exclusive chemotherapy to identify the most vulnerable patients. TRIAL REGISTRATION: Current controlled trials NCT01687335 (registration date: October 6, 2011).

Monoclonal antibodies for treating gastric cancer: promises and pitfalls.

INTRODUCTION: Gastric cancer (GC) presents dismal prognosis when diagnosed at advanced stages, standard chemotherapy having shown little efficacy. Introduction of biotherapies interfering with novel targets and signaling pathways is currently an emerging strategy. AREAS COVERED: Only two monoclonal antibodies (trastuzumab and ramucirumab) have been approved, mostly in association with cytotoxics. Conversely, testing other promising biotherapies (panitumumab, cetuximab, bevacizumab, rilotumumab) have yielded conflicting results, since encouraging early clinical trials have failed to be confirmed in larger phase-III studies. Empirical and underpowered strategies when designing combinational studies, lack of comprehensive knowledge of pharmacokinetics/pharmacodynamics (PK/PD) relationships, and underestimation of the large inter-patient variability in drug exposure levels with monoclonal antibodies, could explain the failures in developing biotherapies in gastric cancer. This review covers the achievements and limits of monoclonal antibodies in gastric cancer and proposes clues to overcome current failures. EXPERT OPINION: Trastuzumab efficacy could be improved thanks to its combination with triplet chemotherapy or with another anti-HER2 agents or in continuation during second-line chemotherapy. Concerning ramucirumab, further studies are necessary to prove its interest in first line treatment of advanced GC, to use the optimal dose in each patient-given the large inter-patients variability, and to find predictive biomarkers of efficacy.

Vascular Endothelial Growth Factor A c.*237C>T polymorphism is associated with bevacizumab efficacy and related hypertension in metastatic colorectal cancer.

BACKGROUND: No predictive marker has been yet identified for bevacizumab which is widely used in metastatic colorectal cancer. AIMS: Evaluate impact of single nucleotide polymorphisms involved in Vascular Endothelial Growth Factor pathway on efficacy and tolerance of bevacizumab. METHODS: We retrospectively included patients who were treated with bevacizumab-based chemotherapy for metastatic colorectal cancer, and for whom a deoxyribonucleic acid sample was available. Ten polymorphisms in Vascular Endothelial Growth Factor-A, his receptors and hypoxia inducible factor-1α were genotyped on germ line DNA using real-time polymerase chain reaction TaqMan(®). RESULTS: 89 patients were included. The CC genotype for rs3025039 (Vascular Endothelial Growth Factor-A c.*237C>T) was associated with a significantly better time to treatment failure (14.2 months) as compared to the CT and TT genotypes (6.0 months) in univariate (p = 0.004) and multivariate (p = 0.022; HR = 0.57; 95% CI [0.35-0.92]) analysis. Patients with at least one T allele showed worse overall survival and progression-free survival as compared to homozygous CC patients in univariate analysis (respectively p = 0.016 and p = 0.044). There was significantly more severe hypertension for the CC genotype (29.5%) compared to CT and TT genotypes (7.1%) (p = 0.022) in multivariate analysis. CONCLUSIONS: In this retrospective study, the rs3025039 polymorphism was significantly associated with time to treatment failure and hypertension in patients treated with bevacizumab-based chemotherapy.

Severe hypersensitivity pneumonitis associated with everolimus therapy for neuroendocrine tumour: a case report.

BACKGROUND: Novel therapeutic agents are currently being investigated for neuroendocrine tumour treatment. CASE PRESENTATION: We report here on the case of a patient presenting with hypersensitivity pneumonitis while being treated with everolimus, a mammalian target of rapamycin (mTOR) inhibitor. CONCLUSION: Side effects of everolimus should be familiar to clinicians, including nonspecialists, and be monitored carefully to allow for prompt management.