Impact of the addition of bevacizumab, oxaliplatin, or irinotecan to fluoropyrimidin in the first-line treatment of metastatic colorectal cancer in elderly patients.

INTRODUCTION: The clinical benefit of double-front-line therapy (including oxaliplatin or irinotecan or bevacizumab plus 5-fluorouracil (5FU) or capecitabine) compared to monotherapy (5FU or capecitabine) in elderly (> 70 years) patients with metastatic colorectal cancer (MCRC) is controversial. We performed a meta-analysis of published randomized studies. MATERIALS AND METHODS: The selection of the studies was carried out using PubMed with the following keywords: "metastatic colorectal cancer," "elderly," "oxaliplatin," "irinotecan," "bevacizumab," "survival." The efficacy endpoints were overall survival (OS) and progression-free survival (PFS). Hazard ratios (HRs) with their 95% confidence intervals (CIs) were collected from the studies and pooled. By convention, an HR < 1 was a result in favor of biotherapy. RESULTS: This meta-analysis (MA) included ten studies: three assessing irinotecan (FFCD 2001-02, CAIRO, and an already published MA by Folprecht), three assessing oxaliplatin (FOCUS2, FFCD 2000-05, and a published study by De Gramont), and four assessing bevacizumab (PRODIGE-20, AVEX, AGITG-MAX, and "AVF2192g" by Kabbinavar). Our MA included 1652 patients (62% of men). Concerning age, we chose a cut-off of 70 years or a cut-off of 75 years, corresponding to the available data for each study. The performance index (PS) was 0-1 for about 90% of patients, with the exception of FFCD 2001-02 and FOCUS2 which included 30% of patients with PS2. Overall, the addition of bevacizumab to fluoropyrimidin statistically improves both OS and PFS (HR = 0.78; CI 0.63-0.96 and HR = 0.55; CI 0.44-0.67, respectively). The addition of oxaliplatin did not statistically improve OS (= 0.99; CI 0.85-1.17) but improves PFS (HR = 0.81; CI 0.67-0.97) as well as the addition of irinotecan (HR = 1.01; CI 0.84-1.22 and HR = 0.82; CI 0.68-1.00, respectively). CONCLUSION: In previously untreated elderly patients with MCRC, the addition of bevacizumab to fluoropyrimidin appears more effective in terms of OS or PFS than the addition of oxaliplatin or irinotecan.

Is There a Benefit of Addition Docetaxel, Abiraterone, Celecoxib, or Zoledronic Acid in Initial Treatments for Patients Older Than 70 Years With Hormone-sensitive Advanced Prostate Cancer? A Meta-analysis.

BACKGROUND: Results from large randomized controlled trials combining docetaxel, abiraterone, celecoxib, or bisphosphonates with androgen deprivation therapy (ADT) in hormone-sensitive prostate cancer have emerged. However, in our knowledge, few data are available in patients older than 70 years. Therefore, we undertook a meta-analysis of all published phase III studies. MATERIALS AND METHODS: We performed a PubMed search using the keywords: "hormone sensitive prostate cancer," "phase III studies," "docetaxel," "abiraterone," "celecoxib," and "bisphosphonates." We also screened American Society of Clinical Oncology and European Society for Medical Oncology proceedings. Combination therapies were compared with ADT alone. The efficacy outcomes were overall survival (OS) and progression-free survival (PFS). Hazard ratios (HRs) with their 95% confidence intervals (CIs) were collected from the studies and pooled. A hazard ratio of less than 1.00 favored the combination group. RESULTS: This meta-analysis included 8 studies: 3 assessed docetaxel (CHAARTED, STAMPEDE arm E and C), 2 others assessed abiraterone (LATITUDE and STAMPEDE arm G); 2 others assessed celecoxib (STAMPEDE arm D and F), and the last one assessed zoledronic acid alone (STAMPEDE arm B). Our meta-analysis included 2264 patients (86% with metastases). Concerning age, we chose a cutoff of 70 years, corresponding to the available data for each study. The performance index was 0 to 1 for about 90% of patients. Overall, in patients > 70 years old, the addition of docetaxel statistically improved PFS (HR, 0.51; 95% CI, 0.42-0.61) but not OS (HR, 0.86; 95% CI, 0.69-1.07). The addition of abiraterone to ADT also statistically improved PFS (HR, 0.49; 95% CI, 0.37-0.64) but not OS (HR, 0.85; 95% CI, 0.67-1.08), as well as the addition of celecoxib (HR, 0.67; 95% CI, 0.53-0.85 and HR, 0.95; 95% CI, 0.73-1.25, respectively). The addition of zoledronic acid did not improve PFS or OS (HR, 0.78; 95% CI, 0.61-1.00 and HR, 0.99; 95% CI, 0.71-1.38, respectively). CONCLUSIONS: The addition of docetaxel, abiraterone, or celecoxib to ADT significantly increased PFS in older men with hormone-sensitive advanced prostate cancer. However, the benefit in OS is not statistically significant. Further studies are needed to define the best first-line strategy in this subgroup.

Is There a Survival Benefit of First-Line Epidermal Growth Factor Receptor Tyrosine-Kinase Inhibitor Monotherapy Versus Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer?: A Meta-Analysis.

BACKGROUND: Tyrosine-kinase inhibitors (TKIs) markedly improve progression-free survival (PFS) of patients with advanced non-small-cell lung cancer (NSCLC) mutated for epidermal growth factor receptor (EGFR). Results on overall survival (OS) are less clear-cut. We performed a publication-based meta-analysis to address further this issue. METHODS: We did a PubMed query using keywords simultaneously (lung neoplasm, tyrosine kinase inhibitors, epidermal growth factor receptor mutation, survival, and randomized controlled trials). We also searched for relevant abstracts in annual proceedings of ASCO, ESMO, and WCLC meetings. We cross-checked all references from all eligible articles. Only phase III randomized controlled trials comparing TKI monotherapy and platinum-based doublet chemotherapy in first-line treatment of metastatic or advanced NSCLC were included. We used EasyMA software to perform statistical analyses. A random effect model was used in case of heterogeneity between studies (and a fixed effect model in absence of heterogeneity). RESULTS: The eight eligible studies included 2962 patients (780 males, 2182 females, mostly Asian, median age 60 years), 2909 adenocarcinomas (98 %), 1739 mutated tumors (897 exon 19 deletion, 699 L858 mutation), 448 stage IIIB, and 2222 stage IV (75 %) tumours and 2453 never smokers (83 %). Four studies assessed gefitinib, two studies assessed erlotinib, and two studies assessed afatinib. Chemotherapies were doublets including a platinum salt. All studies included patients with EGFR mutations, but six studies included only EGFR mutated patients. OS was similar among patients who first received TKI or chemotherapy (HR 0.98, 95 % CI 0.87-1.10, fixed effect model). Conversely, compared with chemotherapy, EGFR TKIs significantly improved PFS in patients with EGFR-mutated tumours (HR 0.37, 95 % CI 0.29-0.49, random effect model). Concerning side effects, rash (RR 6.29, 95 % CI 4.05-9.77), diarrhoea (RR 3.51, 95 % CI 2.15-5.75), stomatitis (RR 3.57, 95 % CI 1.81-7.04), and interstitial lung disease (RR 6.07, 95 % CI 1.66-22.2) were significantly more frequent after TKIs. As expected, fatigue (RR 0.38, 95 % CI 0.32-0.45), nausea/vomiting (RR 0.19, 95 % CI 0.11-0.32), and haematological disorders, including thrombocytopenia (RR 0.18, 95 % CI 0.09-0.35), anaemia (RR 0.22, 95 % CI 0.15-0.33), and grade 3-4 neutropenia (RR 0.06, 95 % CI 0.04-0.08), were significantly more frequent after chemotherapy. CONCLUSION: The major discrepancy between a similar OS and a markedly improved PFS after first-line TKI compared with chemotherapy could be related to the high level of crossing-over between both groups.

Deficient mismatch repair phenotype is a prognostic factor for colorectal cancer in elderly patients.

OBJECTIVE: About 15% of colorectal adenocarcinomas have a deficient DNA mismatch repair phenotype. The frequency of deficient DNA mismatch repair tumours increases with age due to the hypermethylation of hMLH1 promoter. The study aimed to determine the prognostic value of deficient DNA mismatch repair phenotype in elderly patients. DESIGN: Mismatch repair phenotype was retrospectively determined by molecular analysis in consecutive resected colorectal adenocarcinoma specimens from patients over 75 years of age from 4 Oncology centres. RESULTS: 231 patients (median age: 81, range: 75-100) were enrolled from 2005 to 2008. Mean prevalence of deficient DNA mismatch repair phenotype was 22.5%, and 36% for patients over 85 years. Deficient DNA mismatch repair status was significantly associated with older age, female sex, proximal colon primary and high grade tumour. For stage II tumours no deficient DNA mismatch repair tumours had a recurrence at end of follow-up compared to 17% for tumours with proficient phenotype. The proficient phenotype status was significantly associated with worse age-adjusted overall survival [HR 2.60; 95% CI 1.05-6.44; p=0.039]. For stage III tumours a trend for less recurrence was observed for deficient DNA mismatch repair phenotype (16%) compared to proficient phenotype (36%). CONCLUSION: deficient DNA mismatch repair phenotype is a prognostic factor in stage II colorectal tumour in elderly patients. Our results suggest that mismatch repair phenotype should be taken in consideration for adjuvant chemotherapy decision in elderly patients.