[Show abstract][Hide abstract] ABSTRACT: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials.
STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies.
The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013.
STRATEGIC-1 is registered at Clinicaltrials.gov: NCT01910610 , 23 July, 2013. STRATEGIC-1 is registered at EudraCT-No.: 2013-001928-19, 25 April, 2013.
BMC Cancer 12/2015; 15(1):496. DOI:10.1186/s12885-015-1503-7 · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer (CRC) is a growing cause of mortality in developing countries warranting investigation into its etiopathogenesis and earlier diagnosis. Here, we investigated the fecal metabolic phenotype of patients with advanced colorectal neoplasia and controls using 1H-nuclear magnetic resonance (NMR) spectroscopy and multivariate modeling. Wif-1 methylation levels in stools, serum and urine and seven fecal dominant and subdominant bacterial populations were quantified and correlated to metabolic profile of each patients. The predictivity of the model was 0.507 (Q2Y) and the explained variance was 0.755 (R2Y). Patients with advanced colorectal neoplasia demonstrated increased fecal concentrations of four short-chain fatty acids (valerate, acetate, propionate and butyrate) and decreased signals relating to β-glucose, glutamine and glutamate. The predictive accuracy of the multivariate 1H-NMR model was higher than guaiac-fecal occult blood test and Wif-1 methylation test for predicting advanced colorectal neoplasia. Correlation analysis between fecal metabolites and bacterial profiles revealed strong associations between Faecalibacterium prausnitzii and Clostridium leptum species with short-chain fatty acids concentration and inverse correlation between Faecalibacterium prausnitzii and glucose. These preliminary results suggest that fecal metabonomics may potentially have a future role in non-invasive colorectal screening program and may contribute to our understanding of the role of these dysregulated molecules in the cross-talk between the hosts and its bacterial microbiota.
Journal of Proteome Research 07/2015; DOI:10.1021/acs.jproteome.5b00277 · 5.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Systemic therapy is the standard care for patients with unresectable advanced colorectal cancer (CRC), but salvage surgery of metastatic disease should be considered in the case of adequate tumor shrinkage. Several drugs and combinations are now available for use in treating patients with advanced CRC, but the optimal sequence of therapy remains unknown. Moreover, the administration of antitumor therapy can be modulated by periods of maintenance or treatment breaks rather than delivered as full therapy until disease progression or unacceptable toxicity, followed by reintroduction of prior full therapy when required, before switching to other drugs. Consequently, randomized strategy trials are needed to define the optimal treatment sequences. Molecular testing for Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) is mandatory but not sufficient to select appropriate patients for epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy.
[Show abstract][Hide abstract] ABSTRACT: Background: Four different antiangiogenic treatment are approved in first line advanced Renal Cell Carcinoma (RCC): sunitinib (Su), pazopanib (Pa), sorafenib (So) and bevacizumab (Be). Due to parallel development, most of them were not directly compared for efficacy and toxicities. The aim of the present study was to perform a network meta-analysis in order to compare each drug to the others for efficacy and safety outcome. Methods: As of the 31th of July 2014, two independent reviewers searched and collected data of randomized clinical trials (RCT) of first line assessing at least one approved antiangiogenic drug in advanced RCC (Su, Pa, So, Be). The study measured the following outcomes: response rate, progression-free survival (PFS), overall survival (OS), safety (CTCAE). We calculated a traditional weighted average meta-analysis and then conducted a network meta-analysis: we examined the network formed by treatments performing a linear mixed-effect model. Results: We screened 411 abstracts and selected 17 different articles corresponding to 9 RCT including 5,050 patients Treatment arms were: 3 Su, 2 Pa, 2 So, 1 Be, 3 Be+Interferon alpha (INF2A), 2 Placebo (Pl), 4 INF2A. Efficacy meta-analysis showed significantly improvement of PFS (HR = .6; IC95% .55-.65) and OS (HR = .87; IC95% .80-.95) compared to Pl or INF2A. Network meta-analysis showed: significantly better 6-month PFS for Su or Pa compared to So (OR = 1.6; IC95% 1.1-2.4 and 1.4; IC95% 1.0-2.1, respectively) or Be+IFN (OR = 1.4; IC95% 1.0-1.9 and 1.2; IC95% 0.9-1.8, respectively); no difference between antiangiogenics for drug-related toxicity discontinuation, all grade toxicity for hypertension, diarrhea, and weight loss (Su, Pa, So); significantly more treatment discontinuation with Be+IFN (vs Su, Pz, or So), less all grade fatigue for Pa vs (Su, So or Be+IFN), more all grade anemia for Su vs (Pa, So, or Be+IFN). Conclusions: This meta-analysis confirms benefits of first line antiangiogenic in advanced RCC both for PFS and OS. Network meta-analysis suggests better 6-month PFS for Su or Pa compared to Be+IFN or So, and different safety profiles that may help clinicians to better individualize treatment.
[Show abstract][Hide abstract] ABSTRACT: Background: Because of weak solubility in water, many cytotoxics are dissolved in ethanol. FDA recently raised alert noticing that patients could be intoxicated after their treatments. The main alcohol-containing chemotherapy drugs are gemcitabine (Gem), paclitaxel (Pac) and docetaxel (Doc). We explored prospectively blood alcohol levels in pts treated with Gem, Pac or Doc. Methods: Alcohol concentration was determined by peripheral blood sample before chemotherapy infusion (T0), at the end (T1) and 30 min later (T2) in three different prospective cohorts (Gem, Pac, Doc) in a single institution. Bioelectrical impedance analysis was performed to estimate fluid volume in order to calculate theoretical alcohol level. Clinical impact was evaluated through psychometric tests (Zazzo attention test, Stroop test) before and at the end of chemotherapy infusion. Results: 60 consecutive patients were included in our study (M/F 29/31) (Gem n = 21, Pac n = 19, Doc n = 21). Median age was 63.8 yrs (35-88). Median Gem infusion duration (ID) was 100 minutes. Median alcohol administration was 20.5 g (11.6-26). T0 alcohol concentration was 0 g/l, T1 0.32 g/l (0.1-0.65), T2 0.17g/l (0.1-0.4).Median Pac ID was 96 minutes. Median alcohol administration was 9.5 g (6.9-10.5). T0 alcohol concentration was 0 g/l, T1 0.1 g/l, T2 0.1 g/l. Median Doc ID was 90 minutes. Median alcohol administration was 2.8 g (1.8-4). T0 alcohol concentration was 0 g/l, T1 0.1 g/l, T2 0.1 g/l. Concerning Zazzo test, a significant decrease in attention abilities were shown after gemcitabine infusion, compared with taxanes (p = .001). Conclusions: Patients should be clearly informed concerning alcohol infusion during chemotherapy, and that abilities may be impaired. They should be monitored during 1 hour after gemcitabine infusion before leaving care unit.
[Show abstract][Hide abstract] ABSTRACT: Adjuvant chemotherapy’s role after radical prostatectomy (RP) remains controversial in localized high-risk prostate cancer (HRPC). This phase II trial assessed the combination of weekly paclitaxel (WP) with androgen deprivation therapy (ADT) in this population. Methods: All eligible patients (pts) had undergone a laparoscopic RP with pelvic lymph node dissection for a localized HRPC defined with ≥1 of the following criteria: T3b-T4 post-operated Gleason score (GS) ≥8, PSA≥ 20 ng/mL, pN+, in Henri Mondor Hospital. Pts were randomly assigned to either triptoreline 11.25mg every 3 months during 3 years and 8 cycles of WP 100 mg/ m2 (WP arm, n=21) or triptoreline alone (ADT arm, n=26). The primary endpoint is disease free survival (DFS); events=PSA relapse, clinical and radiographic relapse, death. The planned number of pts was 152. Toxicity results indicated a good tolerability with neutropenic fever in 4.3% (n=1), and no negative impact on QoL in the WP arm (Ploussard, Prostate Cancer Prostatic Dis. 2010). Here we report 8-year DFS and overall survival (OS) results. Results: Between February 2005 and October 2007, 47 pts were enrolled. This trial was terminated prematurely because of slow accrual. After a mean follow-up of 8.4 y, we identified a PSA relapse in 25 pts (53%) and castrate-resistant prostate cancer occurred in 6 pts. No statistically difference was found in terms of either biochemical or clinical DFS (bDFS, cDFS) and OS: 8-year bDFS rate: 50% [n=11/22] in the WP arm vs 46% [n=12/26] in the ADT arm (p=0.79); 8-year cDFS rate: 95.4% [n=21/22] in the WP arm vs 88.5% [n=23/26] in the ADT arm (p=0.38). The 8-year OS rate is 90.9% (n=20/22) and 84.6% (n=22/26) respectively with no difference between treatment arms (p=0.51). No clinical, histological or biological variable demonstrated a difference in either 8-year bDFS, cDFS or OS rate. Conclusions: Provided that this trial is probably underpowered to detect a DFS benefit, adjuvant weekly paclitaxel after RP was not associated with any significant reduction in the risk of biological relapse or death compared to ADT alone in patients with localized HRPC. Chemotherapy should be only proposed in dedicated clinical trial for localized HRPC.
[Show abstract][Hide abstract] ABSTRACT: Background: Association between objective response rate (ORR), disease control rate (DCR) and progression free survival (PFS) remains controversial in renal cell carcinoma treated with first line antiangiogenics for advance disease. Methods: Following PRISMA guidelines, as of July,1, 2014, two independent reviewers systematically searched in MEDLINE and collected data from all published trials evaluating at least one antiangiogenic drug for advanced RCC (1st line or after cytokine only). Trials were included if it contains data about ORR, DCR and median PFS (mPFS). The association between ORR, DCR and mPFS was investigated by linear regression analysis weighted by sample size. Results: After screening 1,608 reports, we identified 33 eligible trials (19 randomised trials): 9 phase III, 21 phase II, 2 phase I-II and 1 phase I, involving 8965 pts and 57 treatment arms (35 monotherapy, 22 combination treatment). The median ORR and DCR were 27% (range 0-59) and 77% (22-93), respectively. mPFS and median overall survival (mOS) were 8.9 mo (2.8-16.8) and 23.5 mo (15.2-36.5), respectively. ORR and DCR significantly correlated with mPFS (p<001 and 0.004 respectively) with a better explicative power for the model including ORR (Adjusted R²: 47% for ORR and 16% for DCR). The regression coefficient was 0.15 for ORR, meaning that for or each 10% increase in ORR, PFS improved by 1.5 months. Conclusions: Our model suggests that ORR and DCR correlate with PFS in 1stline antiangiogenic trials in advanced RCC. ORR could be an interesting surrogate marker of PFS in future trials with antiangiogenics in RCC.
Total nb of trials 33
Total nb of treatment arms 57
Total nb. of pts 8965
Median nb. of pts per trial (range) 91 (18-557)
Total nb of randomly arms 40
Total nb of randomized trials 19
Phase (III/II/I-II/I) 9/21/2/1
Nb of monotherapy / combination regimen 35 / 22
Pts with good MSKC, median % (range) 34 (6-55)
Pts with intermediate MSKC, median % (range) 56 (39-92)
Pts with poor MSKC, median % (range) 7 (0-26)
Male pts, median % (range) 71,5 (44-85)
Median age (range) 61 (18-89)
% no antiangiogenics pretreated pts 84
% prior nephrectomy 87
[Show abstract][Hide abstract] ABSTRACT: Several bacterial species have been implicated in the development of colorectal carcinoma (CRC), but CRC-associated changes of fecal microbiota and their potential for cancer screening remain to be explored. Here, we used metagenomic sequencing of fecal samples to identify taxonomic markers that distinguished CRC patients from tumor-free controls in a study population of 156 participants. Accuracy of metagenomic CRC detection was similar to the standard fecal occult blood test (FOBT) and when both approaches were combined, sensitivity improved > 45% relative to the FOBT, while maintaining its specificity. Accuracy of metagenomic CRC detection did not differ significantly between early- and late-stage cancer and could be validated in independent patient and control populations (N = 335) from different countries. CRC-associated changes in the fecal microbiome at least partially reflected microbial community composition at the tumor itself, indicating that observed gene pool differences may reveal tumor-related host–microbe interactions. Indeed, we deduced a metabolic shift from fiber degradation in controls to utilization of host carbohydrates and amino acids in CRC patients, accompanied by an increase of lipopolysaccharide metabolism.
Molecular Systems Biology 11/2014; 10(11). DOI:10.15252/msb.20145645 · 14.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination. Methods: Individual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti-epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R2 statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models. Results: Forty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R2, 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy. Conclusion: In modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.
[Show abstract][Hide abstract] ABSTRACT: Regorafenib (BAY 73-4506, Stivarga® Bayer HealthCare Pharmaceutical Inc) is an oral multikinase inhibitor with a distinct and wide-ranging profile of tyrosine kinase inhibition, resulting in antiangiogenic and antiproliferative properties in tumors. Single-agent regorafenib administered as a 160-mg daily dose for the first 21 days of a 28-day cycle is approved for use in patients with pretreated metastatic colorectal cancer (mCRC) and gastrointestinal stromal tumor (GIST) progressing on imatinib and sunitinib, following publication of data from the phase III CORRECT and GRID studies respectively. Regorafenib is currently under phase III investigation in patients with hepatocellular carcinoma and is in several phase II studies in patients with gastrointestinal (GI) tumors. This review describes the clinical development of regorafenib in patients with GI cancers, and highlights the key issues important for the modern day clinical pharmacist who forms part of the multidisciplinary team ensuring safe and effective delivery of the drug to the patient. This information is considered of particular importance to the clinical pharmacist for the future development of regorafenib in this treatment setting.
[Show abstract][Hide abstract] ABSTRACT: This two-arm, randomised, multicentre, open-label, phase IIIb study investigated the safety and efficacy of a 3-h catumaxomab infusion with/without prednisolone premedication to reduce catumaxomab-related adverse events. Patients with malignant ascites due to epithelial cancer received four 3-h intraperitoneal catumaxomab infusions with/without intravenous prednisolone (25 mg) premedication before each infusion. The primary safety endpoint was a composite safety score calculated from the incidence and intensity of the most frequent catumaxomab-related adverse events (pyrexia, nausea, vomiting and abdominal pain). Puncture-free survival (PuFS) was a co-primary endpoint. Time to next puncture (TTPu) and overall survival (OS) were secondary endpoints. Prednisolone premedication did not result in a significant reduction in the main catumaxomab-related adverse events. The mean composite safety score was comparable in both arms (catumaxomab plus prednisolone, 4.1; catumaxomab, 3.8; p = 0.383). Median PuFS (30 vs. 37 days) and TTPu (78 vs. 102 days) were shorter in the catumaxomab plus prednisolone arm than in the catumaxomab arm, but the differences were not statistically significant (p = 0.402 and 0.599, respectively). Median OS was longer in the catumaxomab plus prednisolone arm than in the catumaxomab arm (124 vs. 86 days), but the difference was not statistically significant (p = 0.186). The superiority of catumaxomab plus prednisolone versus catumaxomab alone could not be proven for the primary endpoint. Prednisolone did not result in a significant reduction in the main catumaxomab-related adverse events. The study confirms the safety and efficacy of catumaxomab administered as four 3-h intraperitoneal infusions for the treatment of malignant ascites.
Medical Oncology 08/2014; 31(8):76. DOI:10.1007/s12032-014-0076-7 · 2.06 Impact Factor