Doublet chemotherapy vs. single-agent therapy with 5FU in elderly patients with metastatic colorectal cancer. a meta-analysis.

BACKGROUND: The clinical benefit of first-line doublet chemotherapy (including oxaliplatin or irinotecan) compared to single-drug therapy (5FU) in elderly patients (>70 or >75 years old) with metastatic colorectal cancer (MCRC) is controversial. Therefore, we undertook a meta-analysis of all published phase III studies. MATERIAL AND METHODS: We performed a PubMed search using keywords metastatic colorectal cancer, phase III studies, oxaliplatin, irinotecan, survival. We also screened Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) proceedings. Few studies have been published corresponding to our inclusion criteria. The efficacy outcomes were overall survival (OS) and progression-free survival (PFS). Toxicity was also examined when available. Hazard ratios (HRs) with their 95 % confidence intervals (CI) were collected from the studies and pooled. By convention, HRs <1 corresponded to a better outcome for doublets. p values <0.05 were considered statistically significant. A fixed-effect model was used. We used Comprehensive Meta-Analysis Software (Biostat, Englewood, NJ, USA). RESULTS: This meta-analysis (MA) included five original studies (Mitry and Venderbosch for CAIRO both assessing irinotecan, De Gramont and Seymour for FOCUS2 and Ducreux assessing oxaliplatin) and an already published MA (Folprecht) of four trials comparing FOLFIRI with 5FU (Saltz, Douillard, Köhne and Seymour). Our MA included 1225 patients (70 % men). For age, we chose a cut-off of 70 years for oxaliplatin and a cut-off of 75 years for irinotecan. The performance status (PS) score was 0-1 in about 90 % of patients except for the studies by Mitry and Seymour FOCUS2 which both included 30 % of PS2 patients. Overall, doublet chemotherapy, compared to 5FU alone, did not improve OS (HR = 1.00; CI: 0.89-1.13) but significantly improved PFS (HR = 0.82; CI: 0.72-0.93). When assessed separately, FOLFIRI and FOLFOX both significantly improved PFS (HR = 0.83; 0.68-1.00 and HR = 0.81; 0.68-0.97, respectively). The main grade 3-4 toxicities for FOLFIRI were diarrhoea, nausea, vomiting and neutropenia, which occurred significantly more often than with 5FU alone. CONCLUSION: Addition of oxaliplatin or irinotecan to 5FU in metastatic CRC significantly improved PFS in elderly patients more than 70 years old but was associated with an increased risk of toxicity as shown for irinotecan.

Prevention by daily soluble aspirin of colorectal adenoma recurrence: 4-year results of the APACC randomised trial.

BACKGROUND: Aspirin inhibits colorectal carcinogenesis. In a randomised double-blind placebo-controlled trial, daily soluble aspirin significantly reduced recurrence of colorectal adenomas at 1-year follow-up. In this study the results of daily intake of low-dose aspirin on polyp recurrence at 4-year follow-up are presented. METHODS: 272 patients (naive for chronic aspirin use) with colorectal adenomas were randomly assigned to treatment with lysine acetylsalicylate 160 mg/day (n=73) or 300 mg/day (n=67) or placebo (n=132) for 4 years. The primary endpoints were adenoma recurrence and adenomatous polyp burden at year 4, comparing aspirin at either dose with placebo. The same endpoints were also assessed at year 1 or 4 (last colonoscopy performed for each patient). RESULTS: At the final year 4 colonoscopy the analysis included 185 patients (55 receiving aspirin 160 mg/day, 47 aspirin 300 mg/day and 83 placebo). There was no difference in the proportion of patients with at least one recurrent adenoma between patients receiving aspirin at either dose and those treated with placebo (42/102 (41%) vs 33/83 (40%); NS) or in the adenomatous polyp burden (3.1 ± 5.8 mm vs 3.4 ± 6.2 mm; NS). Also, the proportion of patients with at least one advanced recurrent adenoma did not differ (10/102 [corrected] (10%) in the aspirin group vs 7/83 (8.4%) [corrected] in the placebo group; NS). CONCLUSION: Daily low-dose aspirin decreased adenoma recurrence significantly at 1 year but not at year 4. This discrepancy might be explained by a differential effect of aspirin according to the natural history of the polyp. TRIAL REGISTRATION NUMBER: NCT 00224679.

Cyclooxygenase-2 expression and recurrence of colorectal adenomas: effect of aspirin chemoprevention.

BACKGROUND: Low-dose aspirin reduces the incidence of colorectal cancer and recurrence of adenomas. Cyclooxygenase-2 (COX-2), one of its main target enzymes, is reportedly over-expressed in colorectal adenomas. AIM: To assess COX-2 expression, in relation to adenoma recurrence and the protective effect of aspirin, in a large series of colorectal adenomas, recruited from a double-blind randomised controlled trial comparing recurrences after low-dose aspirin or placebo. METHODS: Follow-up colonoscopies were performed after 1 and 4 years to assess adenoma recurrence. COX-2 expression was assessed by immunohistochemistry for each adenoma obtained at baseline colonoscopy, separately for epithelium, deep stroma and overall. Architecture, grade of dysplasia, K-ras mutation, p53 and cyclin D1 expression were studied. RESULTS: COX-2 expression could be assessed in 219 adenomas from 136 PATIENTS: 128 adenomas (58%) from 59 patients strongly expressed COX-2. Strong COX-2 expression predominated in adenomas larger than 10 mm (84/129 vs 44/90; p=0.02) and in adenomas showing high-grade dysplasia (22/29 vs 104/188; p=0.04). Deep stromal but not epithelial initial expression of COX-2 predicted adenoma recurrence in the whole population (30/72 patients or 42% strongly expressed deep stromal COX-2 compared with 16/64 or 25% without recurrent adenoma; p=0.04). The protective effect of aspirin was mainly observed in patients in whom COX-2 initial expression was low (RR for recurrence in patients taking aspirin with low COX-2 expression: 0.59; 95% CI 0.39 to 0.90; p=0.02). There was no significant effect of aspirin at the end of the trial. CONCLUSION: Over-expression of COX-2 was frequent and predominated in large and high-grade dysplasia adenomas. Deep stromal but not epithelial initial expression of COX-2 predicted recurrence of adenomas. Aspirin did not act preferentially on patients whose initial adenomas strongly expressed COX-2.

Duration of adjuvant chemotherapy for patients with non-metastatic colorectal cancer.

BACKGROUND: Surgery of primary tumour is the backbone of colorectal cancer treatment (CRC). But in stage III cancer, metastatic or local relapse is often observed (50%). So, adjuvant treatment is always considered in this setting. The best treatment duration of hypothetic disease is not easy to define. Adjuvant chemotherapy for CRC actually lasts 6 months. The choice of optimal duration is based upon old studies using 5-fluorouracil (5FU). During the last ten years, results of major randomized controlled studies (RCTs) comparing different durations of treatments and different schedules in adjuvant setting were published. Several studies compared a 6-month chemotherapy with a longer treatment. Conversely, a single study by Chau et al compared a 6 month chemotherapy with continuous treatment lasting 3 months. But the optimal duration of these chemotherapies could be challenged. Even though the optimal duration of chemotherapy in CRC is a major issue, it has never been answered adequately. OBJECTIVES: To evaluate the optimal duration of adjuvant treatment, we performed a meta-analysis of all RCTs comparing two durations of adjuvant treatment, 6 months versus 9 to 12 months. SEARCH STRATEGY: Publications were identified from PubMed (February 28th, 2009), Embase, and the Cochrane Database of Clinical Controlled Trials (CENTRAL) in the Cochrane Library 2009 issue 1. Reviews and books were also scrutinized. Abstracts were reviewed from ASCO annual meetings proceedings from 1998 to 2009. SELECTION CRITERIA: Patients with surgically resected colorectal cancer with high risk of recurrence. DATA COLLECTION AND ANALYSIS: Several RCTs compared shorter versus longer durations of chemotherapy, 6 studies for overall survival (OS) and 7 studies for relapse free survival (RFS), for a total of 10326 patients, mean age 63.1 years, including 9826 colon and 500 rectum cancers. MAIN RESULTS: Treatments were always based on 5-FU. Two studies were excluded, an epidemiological study and a study comparing continuous treatment during 3 months with conventional chemotherapy during 6 months. The later because it compared 2 durations less than or equal to 6 months. Shorter duration of chemotherapy (3-6 months) compared with longer duration (9-12 months) was not associated to poorer RFS (RR =0.96, 95% CI : 0.90-1.02) and OS (RR = 0.96 ; 95% CI : 0.91-1.02). AUTHORS' CONCLUSIONS: The present meta-analysis confirmed that adjuvant chemotherapy of CRC should not last for more than 6 months. Prolonged duration would result in lower benefit to risk ratio. However, the results do not make it possible to favour either 3 or 6 month durations. They should help design a future RCT comparing different durations of continuous treatment.

Microsatellite instability does not predict the efficacy of chemotherapy in metastatic colorectal cancer. A systematic review and meta-analysis.

BACKGROUND: Microsatellite Instability (MSI) status is a good prognostic factor for colorectal cancer (CRC) but its predictive value for chemosensitivity remains controversial. A previous meta-analysis (MA) in the adjuvant setting showed that MSI-high (H) status did not predict the efficacy of chemotherapy. The predictive value of MSI status on the effect of metastatic chemotherapy was investigated by MA. PATIENTS AND METHODS: Studies were identified by electronic search through PubMed, Embase and ASCO proceedings online databases, using several key words (colorectal cancer, chemotherapy, microsatellite instability). For each study, the ratio of response rate (RR), complete (CR) and partial response (PR) divided by stable disease and progression was calculated. From 190 articles and 100 abstracts, only eight independent studies were selected. The data were analysed with a random-effect model (due to heterogeneity between studies) using EasyMA software. Statistical calculations were performed on six studies representing 964 patients (mean age 63 years; 91 MSI-H; 873 microsatellite stable (MSS) tumours). A total of 287 patients received 5-fluorouracil (5FU)-based chemotherapy, whereas 678 patients received combinations of 5FU or capecitabine with oxaliplatin and/or irinotecan. RESULTS: No benefit of metastatic chemotherapy in terms of RR for MSI-H patients compared with MSS patients was found. The global hazard ratio (HR) for RR was 0.82 (95% confidence interval, CI: 0.95; 0.65-1.03; p=0.09). CONCLUSION: MSI status does not predict the effect of chemotherapy which is similar in MSI-H and MSS metastatic CRC tumours.

Effects of statins on bone mineral density: a meta-analysis of clinical studies.

CONTEXT: Statins inhibit HMG-CoA reductase, preventing synthesis of mevalonate but also of isoprenoids, which affect osteoclast activity. Amino-bisphosphonates share this effect. In vitro and in vivo, statins show convincing anabolic and anti-resorptive bone effects. However, in a clinical meta-analysis (MA), they did not prevent hip fractures. OBJECTIVE AND DESIGN: Our meta-analysis studied the impact of statins on bone mineral density (BMD) at various sites and compared the effects of lipophilic and more hydrophilic statins. DATA SOURCES: Our PubMed and Embase queries using two keywords (statins, BMD) were updated to October 2006. DATA COLLECTION: Two readers independently collected BMDs from studies. DATA SYNTHESIS: Twenty-one studies, mostly observational (three randomized controlled trials and one pseudo-randomized study), were assessed. Two studies were excluded (no control groups). Three studies could not be analyzed. The sixteen studies analyzed mainly included postmenopausal osteopenic women (2971 patients under statins). Statins significantly increased BMD at total hip (TH) and femoral neck (FN). Effect sizes (ESs) were modest: 0.21 at TH (95% confidence interval [CI]: 0.16-0.25) and 0.20 at FN (CI: 0.08-0.28). Among women, statins acted similarly (ES: 0.20 for TH and 0.18 for FN; CI: 0.14-0.25 and 0.06-0.31 respectively); lipophilic statins (simvastatin, lovastatin) almost entirely caused this effect, at both TH (ES: 0.20; CI: 0.15-0.26) and FN (ES: 0.22; CI: 0.06-0.37). CONCLUSION: Our findings of modest but statistically significant beneficial effects of statins on hip BMD should promote large double-blind randomized controlled trials on their bone effects, in view of their major beneficial cardiovascular effects with excellent safety profile.

Expression of ghrelin in fundus is increased after gastric banding in morbidly obese patients.

BACKGROUND: Ghrelin, a 28 amino-acid acylated orexigenic peptide secreted by the stomach, acts on the hypothalamic arcuate nucleus which stimulates feeding behavior. Serum ghrelin level increases during fasting and decreases after a meal. Serum ghrelin is low in obese patients.Whether ghrelin is implicated in weight loss in obese patients after laparoscopic adjustable gastric banding (LAGB) is still debated. In this study, we assessed serum ghrelin level and gastric fundus expression before and 1 year after LAGB. METHODS: Gastric fundus expression of ghrelin was assessed by immunohistochemistry using a rabbit anti-human ghrelin antibody simultaneously with serum total ghrelin levels (RIA) in 13 obese patients (2 men and 11 women) after an overnight fast, before LAGB and 1 year after. Immunostaining was "blindly" analyzed by a single pathologist, measuring the density of stained fundic cells near muscularis mucosa. RESULTS: Mean age of the 13 patients was 41 years, and mean baseline BMI was 46 kg/m2. Pre- and post-LAGB gastric expression of ghrelin was analyzable in 11 patients. It was always identified, mostly with moderate or intense staining. Mean density of stained cells significantly increased 1 year after LAGB: 31/mm2 (21-38) before vs 38/mm2 (27-57) after surgery (P<0.01). This increase did not correlate with changes in BMI, nor did pre- or postoperative gastric expression of ghrelin correlate with the corresponding serum values. CONCLUSION: We showed for the first time that ghrelin expression assessed by immunohistochemistry was present in the fundus of all 11 obese patients and that it was significantly increased 1 year after LAGB, which would exclude a pathogenetic role of ghrelin in weight loss after LAGB.

Serum procalcitonin in uncomplicated falciparum malaria: a preliminary study.

BACKGROUND: Procalcitonin (PCT) has been found elevated in complicated forms of Plasmodium falciparum malaria. Its usefulness has almost never been assessed in uncomplicated falciparum malaria. METHOD: We assessed diagnostic and prognostic value of PCT in a prospective series of 25 adults with uncomplicated P. falciparum malaria. Patients originated mainly from western Africa and were infected during a stay back in their native country (19 semi-immune and 6 non-immune subjects; 11 had not received any chemoprophylaxis). RESULTS: Parasitaemia ranged from 0.01 to 3%. Eighteen patients had their first PCT determined at admission or within 24h thereafter (mean +/- SD: 3.0 +/- 4.6 ng/ml; range: 0.1-19.7). PCT was higher than 0.5 ng/ml in 14 patients (78%), higher than 2 ng/ml in 7 (39%). PCT correlated with parasitaemia (r = 0.53; p = 0.027), not with C-reactive protein (CRP). Delay between first symptoms and diagnosis was much longer among patients with PCT higher than 2 ng/ml than among those with a lower PCT. CONCLUSION: PCT was often elevated in uncomplicated malaria, especially when delay between first symptoms and diagnosis was long or parasitaemia was high (prognostic marker).

Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis.

We performed a meta-analysis of all 87 published studies linking intratumoral microvessel density (MVD), reflecting angiogenesis, to relapse-free survival (RFS) and overall survival (OS). With median MVD as cutoff, MVD impact was measured by risk ratio (RR) between the two survival distributions. Seventeen studies did not mention survival data or fit inclusion criteria. Twenty-two were multiple publications of the same series, leaving 43 independent studies (8936 patients). MVD was assessed by immunohistochemistry, using antibodies against factor VIII (27 studies; n = 5262), CD31 (10 studies; n = 2296), or CD34 (8 studies; n = 1726). MVD might be a better prognostic factor when assessed by CD31 or CD34 versus factor VIII (P = 0.11). For RFS, statistical calculations were performed in 25 studies (6501 patients). High MVD significantly predicted poor survival [RR = 1.54 for RFS and OS with the same 95% confidence interval (CI), 1.29-1.84]. Twenty-two studies analyzed separately lymph node-negative patients (n = 3580), for whom predictors of poor survival are requested. This latter meta-analysis included 15 studies for RFS (2727 patients) and 11 for OS (1926 patients). High MVD significantly predicted poor survival [RR = 1.99 for RFS (95% CI, 1.33-2.98) and RR = 1.54 for OS (95% CI, 1.01-2.33)]. Between-study variations could result from patient selection criteria, techniques to stain and count microvessels, and cutoff selection. MVD was a significant although weak prognostic factor in women with breast cancer. Standardization of MVD assessment is needed.

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.

Low dose aspirin, COX-inhibition and chemoprevention of colorectal cancer.

Chemoprevention of colorectal cancer involves the long-term use of pharmacologic agents that can prevent neoplasms from developing in the large bowel. This new approach requires major funding and human investments. Among the most widely studied agents for the chemoprevention of colorectal cancer, aspirin, the NSAIDs and COX-2 inhibitors seem to be the most promising. A large number of observational epidemiological studies show that regular use of aspirin and other NSAIDs is associated with a reduction in the risk of developing both colorectal adenomas and cancer. In addition, the prodrug sulindac reduces the growth of existing polyps in familial adenomatous polyposis (FAP). However, the dose, duration of effect and length of protection seen after cessation remain to be fully established. Furthermore, in view of previous discrepancies between the results of observational studies and randomized control trials (RCTs), it is crucially important to investigate the effects of aspirin by RCTs. RCTs investigating the effect of chemopreventive agents on adenoma recurrence as an intermediate endpoint for colorectal cancer is a more feasible approach than RCTs to investigate the effect on the incidence if colorectal cancer per se. Four RCTs of the effect of aspirin on adenoma recurrence are available. Other trials are currently underway.

Similar survival rates with first-line gefitinib, gemcitabine, or docetaxel in a randomized phase II trial in elderly patients with advanced non-small cell lung cancer and a poor performance status (IFCT-0301).

OBJECTIVES: We evaluated the impact of age in a randomized phase II trial that compared three first-line drugs in elderly patients with advanced non-small cell lung cancer (NSCLC) and a poor performance status (PS). MATERIALS AND METHODS: Patients with advanced NSCLC with a PS of 2 or 3 were enrolled into a multicenter randomized trial: arm A, gefitinib; arm B, gemcitabine; and arm C, docetaxel. We performed subgroup analyses according to age. RESULTS: Between December 2004 and June 2007, 127 patients were enrolled. Analyses were performed between the two subgroups aged <70years (younger, n=56) and ≥70years (older, n=71). Patients mainly had adenocarcinoma (46% young vs. 51%: elderly), of which 62% vs. 75% had a PS of 2, respectively. Significantly more elderly patients were women and non-smokers, and there was a non-significant trend towards more PS-2 among the elderly. Progression-free survival (PFS) was 1.4months (95% CI: 1.1-1.9) for younger compared to 2.3months (95% CI: 2.1-2.9) for elderly patients. Overall survival (OS) was 2.0months (95% CI: 1.5-2.4) and 3.7months (95% CI: 2.4-4.8), respectively. Toxicity did not differ between younger and older patients. NSCLC was better controlled in elderly patients after three cycles of monotherapy compared to younger patients (p=0.034). When adjusted for stratification criteria, age was the main prognostic factor for PFS. Adjusted HRs for PFS was 0.57 (95% CI: 0.38-0.85) for the elderly compared to patients aged <70years (p=0.004). CONCLUSIONS: Older patients had a decreased risk of progression/death compared to younger patients. Single-agent chemotherapy can be considered for patients aged ≥70years with a PS of 2.

Systematic review and bivariate/HSROC random-effect meta-analysis of immunochemical and guaiac-based fecal occult blood tests for colorectal cancer screening.

BACKGROUND: Current literature evidences higher accuracy of immunological (iFOBT) vis-à-vis guaiac-based (gFOBT) fecal occult blood tests for colorectal cancer (CRC) screening. Few well-designed head-to-head comparisons exist. AIM: This meta-analysis assesses the performances of two iFOBTs compared with an established gFOBT using colonoscopy as the gold standard. METHODS: We mobilized a bivariate and a hierarchical summary receiver operating characteristic (HSROC) model. Positive likelihood ratio (LR) and negative likelihood ratio (LR) and diagnostic odds ratios were back-calculated. We constructed bivariate credibility ellipses in the HSROC space and calculated areas under the curve to obtain a global measure of test performance. Estimates are presented at 95% credibility levels. RESULTS: We included and analyzed 21 studies. OC-Sensor was the best test for CRC screening, with high sensitivity (0.87; 95% credibility interval: 0.73-0.95) and specificity (0.93; 95% credibility interval: 0.84-0.96), optimal LR (12.01) and LR (0.14), and a high diagnostic odds ratio (88.05). Bivariate credibility ellipses showed OC-Sensor's dominance over Hemoccult (sensitivity: 0.47; 95% credibility interval: 0.37-0.58; specificity: 0.93; 95% credibility interval: 0.91-0.95). CONCLUSION: Our findings support the use of OC-Sensor for CRC detection. The diagnostic estimates obtained may be extended to derive model parameters for economic decision models and to offer insight for future clinical and public health decision making. Our findings could influence the future of FOBTs within the CRC screening arsenal.

Impact of physical activity on cancer-specific and overall survival of patients with colorectal cancer.

Background. Physical activity (PA) reduces incidence of colorectal cancer (CRC). Its influence on cancer-specific (CSS) and overall survival (OS) is controversial. Methods. We performed a literature-based meta-analysis (MA) of observational studies, using keywords "colorectal cancer, physical activity, and survival" in PubMed and EMBASE. No dedicated MA was found in the Cochrane Library. References were cross-checked. Pre- and postdiagnosis PA levels were assessed by MET. Usually, "high" PA was higher than 17 MET hour/week. Hazard ratios (HRs) for OS and CSS were calculated, with their 95% confidence interval. We used more conservative adjusted HRs, since variables of adjustment were similar between studies. When higher PA was associated with improved survival, HRs for detrimental events were set to <1. We used EasyMA software and fixed effect model whenever possible. Results. Seven studies (8056 participants) were included, representing 3762 men and 4256 women, 5210 colon and 1745 rectum cancers. Mean age was 67 years. HR CSS for postdiagnosis PA (higher PA versus lower) was 0.61 (0.44-0.86). The corresponding HR OS was 0.62 (0.54-0.71). HR CSS for prediagnosis PA was 0.75 (0.62-0.91). The corresponding HR OS was 0.74 (0.62-0.89). Conclusion. Higher PA predicted a better CSS. Sustained PA should be advised for CRC. OS also improved (reduced cardiovascular risk).

Comparison of the efficacy and safety of single-agent and doublet chemotherapy in advanced non-small cell lung cancer in the elderly: a meta-analysis.

BACKGROUND: In patients with advanced non-small cell lung cancer (NSCLC) aged more than 70 years, the benefit-to-risk ratio of doublet chemotherapy vs single-agent is not established. METHODS: We performed a meta-analysis (MA), with a PubMed query using keywords simultaneously (Randomized controlled trial, Aged, Anti-neoplastic combined chemotherapy protocols/therapeutic use, Carcinoma, Non-small cell lung/drug therapy). Abstracts from ASCO, WCLC, and ESMO proceedings were reviewed. Articles were also obtained by cross-checking references. Third-generation agents (gemcitabine, vinorelbine, paclitaxel, docetaxel) in combination with or without platinum were included. The efficacy outcomes were Overall Response Rate (ORR) and 1-Year Overall Survival (OS). We used EasyMA software and a random-effect model in case of heterogeneity. RESULTS: This MA comprised 10 studies including 2605 patients (mean age 74; 1866 men and 620 women; 654 stage IIIB and 1677 stage IV; 839 squamous cell cancers, 968 adenocarcinomas, 521 other pathological types). One-year OS (including the last trial by Abe) did not significantly improve for doublets compared with single-agents (HR 0.92; 95% Confidence Interval or CI: 0.82-1.03) whereas it improved significantly before inclusion of this last study, when the study by Quoix et al., the most favorable to doublets, was included. However, doublet chemotherapy significantly improved ORR after inclusion of Abe study (HR 1.51; 1.22-1.86; p<0.001). OS was not significantly improved, neither by doublets including platinum (HR 0.90, 0.70-1.16), nor by those without platinum (HR 0.94, 0.84-1.07). ORR, but not OS, was improved by doublets including a taxane (docetaxel and paclitaxel) (HR 1.72; 1.28-2.33) except for paclitaxel with a significant OS and ORR benefit. All-grade neutropenia thrombocytopenia and anemia were significantly more frequent with doublets than with single-agents (HR 1.26, 1.15-1.39; 1.75, 1.11-2.77 and 1.33, 1.17-1.52 respectively). Grade 3/4 thrombocytopenia and anemia but not neutropenia were significantly more frequent with doublets (HRs 2.13, 1.01-4.49 and 1.84, 1.29-2.63 respectively). CONCLUSION: Compared with single-agents, doublets significantly improved ORR but not OS. They induced significantly more frequent thrombocytopenia and anemia. The benefit-to-risk ratio of doublets in advanced NSCLC might be more favorable than that of single agents, based on ORR but not OS.

[Sarcoidosis: the involvement of anterior pituitary hormones is poorly recognized]. / Sarcoïdose : l'atteinte des hormones à dépendance antéhypophysaire est insuffisamment diagnostiquée.

OBJECTIVE: Hypothalamic-pituitary locations of sarcoidosis are rare. Achieving more systematic hormonal testing could increase the screening of such patients. The objective of this study was to evaluate the impact on the detection of hypothalamic-pituitary sarcoidosis in patients hospitalized for this condition in a lung disease sensibilized department. METHODS: In hormonology department, we collected and analyzed hormonal testing, from the list of patients hospitalized for pulmonary sarcoidosis in 2007-2008. Diabetes insipidus was defined clinically. The case of patients with multiple hormone deficiencies was analyzed for the diagnosis of hypothalamic-pituitary damage. RESULTS: In a cohort of 486 patients, 158 (33%) had a hormonal abnormality. Forty-six of 158 patients (≈30%) had at least one pituitary deficiency or hyperprolactinemia: 31 adrenal insufficiency (isolated for 21), 20 gonadotrop deficiency, 14 hyperprolactinemia, 3 thyreotrop deficiency and a growth hormone deficiency. Among eight patients with association of hyperprolactinemia and hypogonadism, four have a probable diagnosis of hypothalamic-pituitary sarcoidosis, including 3 new cases. DISCUSSION: Despite a selection bias (hospital patients, more severe forms), prevalence of hormonal abnormalities was higher than expected. CONCLUSION: In the condition of this study, hypothalamic-pituitary affected 2.5% of patients with sarcoidosis in pneumologic department (4/158). Hormonal abnormalities were present in one third of hospitalized patients. The most prevalent deficiency found was corticotrope deficiency, secondary to corticosteroid therapy.

Identification and chemoprevention in subjects at moderate risk of colorectal cancer.

The risk of developing colorectal cancer (CRC) depends on both genetic factors and lifestyle-related factors. Chemoprevention's true contribution is dependent on lifetime CRC risk. There are clinical situations where chemoprevention for CRC is undoubtedly useful. There are other situations where the risk of CRC seems to be only moderately increased and in these situations, the true contribution of chemoprevention is questionable. A few specific studies assessing the effect of chemopreventive agents in these situations are available. In the present article, we will try to better define these particular situations and discuss the risk quantification and the expected chemoprevention contribution.

An anticancer strategic dilemma: to kill or to contain. The choice of the pharmaceutical industry in 2009.

For decades, the fight against cancer was based on oncolytic drugs aimed at eradicating malignant cells (killing strategy). The main flaws of this approach were its toxicity and the consequent emergence of resistance. New views on tumour biology consider tumours as complex organs involving dynamic interactions between their components. This implies the existence of dormant states and thus of a new therapeutic strategy aimed at inducing or extending tumour dormancy (containment strategy). The aim of this overview was to quantify the relative importance of these two strategies among the clinical trials (240 phase 1 and 186 phase 2 trials), launched or still in the pipeline and sponsored by the pharmaceutical industry in 2009. The most frequently targeted molecular entities are vascular endothelial growth factors (VEGFRs) (19 drugs), ErBBs (17 drugs), c-met (14 drugs), tubulin (12 drugs), IGFRs (12 drugs). The main result of this overview is that the killing strategy is still largely prevailing since 326 drugs in 2009 (77% of the drugs tested in clinical trials in 2009) referred to this strategy, whereas 100 drugs could be attributed to the containment or mixed strategies in 2009. To obtain a dynamic view of the repartition of drugs between the killing strategy and the containment or mixed strategies, the present work should be renewed every 3-4 years.

Cardiovascular toxicity of anti-angiogenic drugs.

Anti-angiogenic targeted therapies are now major tools in the management of solid tumors. Briefly, one can distinguish between monoclonal antibodies such as bevacizumab directed against vascular endothelial growth factor (VEGF) and small molecules such as those targeted against receptors with tyrosine-kinase activity. Soon after they were marketed, these drugs showed cardiovascular toxicities, such as hypertension, left ventricular systolic dysfunction, heart failure and conduction abnormalities. The most frequent cardiovascular side effect of targeted therapies is hypertension, but the most life-threatening is QT prolongation with its risk of torsade de pointe and sudden cardiac death. Since the incidence of different types of cardiovascular side effects following targeted therapies varies across studies-and despite the fact that several meta-analyses attempted to summarize available information-those side effects are still not well identified. In addition, their reversibility is not precisely known. This review aims to present and discuss the various cardiovascular toxicities of anti-angiogenic targeted therapies for cancer.