The ACCORD 12 trial investigated the value of two different preoperative chemoradiotherapy (CT-RT) regimens in T3-4 Nx M0 resectable rectal cancer. Clinical results are reported after follow-up of 3 ...years.
Between November 2005 and July 2008, a total of 598 patients were randomly assigned to preoperative CT-RT with CAP45 (45-Gy RT for 5 weeks with concurrent capecitabine) or CAPOX50 (50-Gy RT for 5 weeks with concurrent capecitabine and oxaliplatin). Total mesorectal excision was planned 6 weeks after CT-RT. The primary end point was sterilization of the operative specimen, which was achieved in 13.9% versus 19.2% of patients, respectively (P = .09). Clinical results were analyzed for all randomly assigned patients according to the intention-to-treat principle.
At 3 years, there was no significant difference between CAP45 and CAPOX50 (cumulative incidence of local recurrence, 6.1% v 4.4%; overall survival, 87.6% v 88.3%; disease-free survival, 67.9% v 72.7%). Grade 3 to 4 toxicity was reported in four patients in the CAP45 group and in two patients in the CAPOX50 group. Bowel continence, erectile dysfunction, and social life disturbance were not different between groups. In multivariate analysis, the sterilization rate (Dworak score) of the operative specimen was the main significant prognostic factor (hazard ratio, 0.32; 95% CI, 0.21 to 0.50).
At 3 years, no significant difference in clinical outcome was achieved with the intensified CAPOX regimen. When compared with other recent randomized trials, these results indicate that concurrent administration of oxaliplatin and RT is not recommended.
Various critical events, liver related or not, occur in patients with compensated cirrhosis, but their respective burden remains to be prospectively assessed. The aim of this prospective cohort study ...involving 35 French centers was to capture the whole spectrum of complications occurring in compensated viral cirrhosis (VC) using competing risks analyses. Inclusion criteria were: histologically proven cirrhosis resulting from hepatitis C virus (HCV) or hepatitis B virus (HBV); Child‐Pugh A; and no previous hepatic complications. The cohort was considered as a multistate disease model, cumulative incidences (CumIs) of events were estimated in a competing risks framework. A total of 1,654 patients were enrolled from 2006 to 2012 (HCV, 1,308; HBV, 315; HCV‐HBV, 31). During a median follow‐up of 34 months, at least one liver nodule was detected in 271 patients, confirmed as hepatocellular carcinoma (HCC) in 128 (4‐year cumI: 10.5%) and cholangiocarcinoma in 3. HCC incidence was higher in HCV (4‐year cumI: 11.4% vs. 7.4%; P = 0.05). HCC fulfilled Milan criteria in 79.3%, leading to curative treatment in 70.4%. Liver decompensation occurred more frequently in HCV patients (4‐year cumI: 10.8% vs. 3.6%; P = 0.0004). Virological eradication/control was achieved in 34.1% of HCV and 88.6% of HBV patients and was associated with a marked decrease in HCC, decompensation, and bacterial infection incidences. Survival was shorter in HCV patients (4‐year cumI: 91.6% vs. 97.2%; P = 0.0002). Death (n = 102; missing data: 6) was attributed to liver disease in 48 (47%; liver cancer: n = 18; miscellaneous, n = 30) and extrahepatic causes in 48 (47%; bacterial infection: n = 13; extrahepatic cancers: n = 10; cardiovascular events: n = 5; miscellaneous, n = 20). Conclusion: After 3 years of follow‐up, extrahepatic events still explained half of deaths in patients with compensated VC. A strong decrease in complications was linked to virological eradication/control. (Hepatology 2015;62:737–750)
To evaluate the efficacy of irradiation of internal mammary nodes (IMN) on 10-year overall survival in breast cancer patients after mastectomy.
This multicenter phase 3 study enrolled patients with ...positive axillary nodes (pN+) or central/medial tumors with or without pN+. Other inclusion criteria were age <75 and a Karnofsky index ≥70. All patients received postoperative irradiation of the chest wall and supraclavicular nodes and were randomly assigned to receive IMN irradiation or not. Randomization was stratified by tumor location (medial/central or lateral), axillary lymph node status, and adjuvant therapy (chemotherapy vs no chemotherapy). The prescribed dose of irradiation to the target volumes was 50 Gy or equivalent. The first 5 intercostal spaces were included in the IMN target volume, and two-thirds of the dose (31.5 Gy) was given by electrons. The primary outcome was overall survival at 10 years. Disease-free survival and toxicity were secondary outcomes.
T total of 1334 patients were analyzed after a median follow-up of 11.3 years among the survivors. No benefit of IMN irradiation on the overall survival could be demonstrated: the 10-year overall survival was 59.3% in the IMN-nonirradiated group versus 62.6% in the IMN-irradiated group (P=.8). According to stratification factors, we defined 6 subgroups (medial/central or lateral tumor, pN0 only for medial/central or pN+, and chemotherapy or not). In all these subgroups, IMN irradiation did not significantly improve overall survival.
In patients treated with 2-dimensional techniques, we failed to demonstrate a survival benefit for IMN irradiation. This study cannot rule out a moderate benefit, especially with more modern, conformal techniques applied to a higher risk population.
Neoadjuvant chemoradiotherapy is considered a standard approach for T3-4 M0 rectal cancer. In this situation, we compared neoadjuvant radiotherapy plus capecitabine with dose-intensified radiotherapy ...plus capecitabine and oxaliplatin.
We randomly assigned patients to receive 5 weeks of treatment with radiotherapy 45 Gy/25 fractions with concurrent capecitabine 800 mg/m(2) twice daily 5 days per week (Cap 45) or radiotherapy 50 Gy/25 fractions with capecitabine 800 mg/m(2) twice daily 5 days per week and oxaliplatin 50 mg/m(2) once weekly (Capox 50). The primary end point was complete sterilization of the operative specimen (ypCR).
Five hundred ninety-eight patients were randomly assigned to receive Cap 45 (n = 299) or Capox 50 (n = 299). More preoperative grade 3 to 4 toxicity occurred in the Capox 50 group (25 v 1%; P < .001). Surgery was performed in 98% of patients in both groups. There were no differences between groups in the rate of conservative surgery (75%) or postoperative deaths at 60 days (0.3%). The ypCR rate was 13.9% with Cap 45 and 19.2% with Capox 50 (P = .09). When ypCR was combined with yp few residual cells, the rate was respectively 28.9% with Cap 45 and 39.4% with Capox 50 (P = .008). The rate of positive circumferential rectal margins (between 0 and 2 mm) was 19.3% with Cap 45 and 9.9% with Capox 50 (P = .02).
The benefit of oxaliplatin was not demonstrated and this drug should not be used with concurrent irradiation. Cap 50 merits investigation for T3-4 rectal cancers.
We examined whether 66 germline single‐nucleotide polymorphisms (SNPs) in 10 candidate genes would predict clinical outcome in 316 patients with resectable locally advanced rectal cancer (LARC) ...enrolled in the ACCORD‐12 phase III trial who were randomly treated with preoperative radiotherapy plus capecitabine (CAP45; n = 155) or dose‐intensified radiotherapy plus capecitabine and oxaliplatin (CAPOX50; n = 161). The primary endpoint was tumor response according to the Dworak score. Multivariate logistic regression models adjusted on treatment arm and T stage determined the SNPs prognostic and predictive values for tumor response. In univariate analysis, five SNPs in ERCC2, XPA, MTHFR and ERCC1 were associated with the Dworak score in the CAPOX50 arm. In the overall population, interaction with treatment arm was significant for ERCC2 rs1799787 (pinteraction = 0.05) and XPA rs3176683 (pinteraction = 0.008), suggesting a predictive effect for response to oxaliplatin‐based chemoradiotherapy (CRT). All but XPA rs3176683 had a prognostic effect on tumor response. In a multivariate model, interaction remained significant for XPA rs3176683 (OR 7.33, 95% CI 1.40–38.23, pinteraction = 0.018) and the prognostic effect significant for ERCC2 rs1799787 (OR 0.55, 95%CI 0.32–0.93, p = 0.027) and ERCC1 rs10412761 (OR 0.57, 95%CI 0.34–0.98, p = 0.042). Patients with the T/G haplotype of rs1799787 and rs10412761 had a 60% decrease in odds of response (p < 0.001). None of the five SNPs were associated with toxicity, overall and disease‐free survival. These data suggest that genetic variation in DNA repair genes influences response to preoperative CRT in LARC and identify patients who benefit from the addition of oxaliplatin to CRT.
What's new?
May germline variants in genes encoding DNA repair and detoxification enzymes predict response to preoperative capecitabine‐based chemoradiotherapy in rectal cancer? In response, the authors analyzed 66 germline variants of 10 candidate genes. Among them, ERCC1 rs10412761 and ERCC2 rs1799787 are associated with tumor response in patients treated with preoperative capecitabine‐based chemoradiotherapy. For the first time, they described a predictive effect of XPA rs3176683 that may identify patients who benefit from adding oxaliplatin to capecitabine‐based chemoradiotherapy.
Radiotherapy has been driven by constant technological advances since the discovery of X-rays in 1895. Radiotherapy aims to sculpt the optimal isodose on the tumour volume while sparing normal ...tissues. The benefits are threefold: patient cure, organ preservation and cost-efficiency. The efficacy and tolerance of radiotherapy were demonstrated by randomized trials in many different types of cancer (including breast, prostate and rectum) with a high level of scientific evidence. Such achievements, of major importance for the quality of life of patients, have been fostered during the past decade by linear accelerators with computer-assisted technology. More recently, these developments were augmented by proton and particle beam radiotherapy, usually combined with surgery and medical treatment in a multidisciplinary and personalized strategy against cancer. This article reviews the timeline of 100 years of radiotherapy with a focus on breakthroughs in the physics of radiotherapy and technology during the past two decades, and the associated clinical benefits.
The purpose of this study was to develop accurate models and nomograms to predict local recurrence, distant metastases, and survival for patients with locally advanced rectal cancer treated with ...long-course chemoradiotherapy (CRT) followed by surgery and to allow for a selection of patients who may benefit most from postoperative adjuvant chemotherapy and close follow-up.
All data (N = 2,795) from five major European clinical trials for rectal cancer were pooled and used to perform an extensive survival analysis and to develop multivariate nomograms based on Cox regression. Data from one trial was used as an external validation set. The variables used in the analysis were sex, age, clinical tumor stage stage, tumor location, radiotherapy dose, concurrent and adjuvant chemotherapy, surgery procedure, and pTNM stage. Model performance was evaluated by the concordance index (c-index). Risk group stratification was proposed for the nomograms.
The nomograms are able to predict events with a c-index for external validation of local recurrence (LR; 0.68), distant metastases (DM; 0.73), and overall survival (OS; 0.70). Pathologic staging is essential for accurate prediction of long-term outcome. Both preoperative CRT and adjuvant chemotherapy have an added value when predicting LR, DM, and OS rates. The stratification in risk groups allows significant distinction between Kaplan-Meier curves for outcome.
The easy-to-use nomograms can predict LR, DM, and OS over a 5-year period after surgery. They may be used as decision support tools in future trials by using the three defined risk groups to select patients for postoperative chemotherapy and close follow-up (http://www.predictcancer.org).
Many significant products commercialized or in the development phase, possess aromatic carbon--carbon and aromatic carbon--nitrogen bonds which can be assembled by organometallic catalyst ...cross-coupling reations. An analysis of relevant patent literature, which could be of interest for industrial and academic chemists, is proposed.
Background & Aims We performed a prospective study to investigate the effects of a sustained viral response (SVR) on outcomes of patients with hepatitis C virus (HCV) infection and compensated ...cirrhosis. Methods We collected data from 1323 patients included in the prospective Agence Nationale pour la Recherche sur le SIDA et les hépatites virales (ANRS) viral cirrhosis (CirVir) cohort, recruited from 35 clinical centers in France from 2006 through 2012. All patients had HCV infection and biopsy-proven cirrhosis, were Child–Pugh class A, and had no prior liver complications. All patients received anti-HCV treatment before or after inclusion (with interferon then with direct antiviral agents) and underwent an ultrasound examination every 6 months, as well as endoscopic evaluations. SVR was considered as a time-dependent covariate; its effect on outcome was assessed by the Cox proportional hazard regression method. We used a propensity score to minimize confounding by indication of treatment and capacity to achieve SVR. Results After a median follow-up period of 58.2 months, 668 patients (50.5%) achieved SVR. SVR was associated with a decreased incidence of hepatocellular carcinoma (hazard ratio HR compared with patients without an SVR, 0.29; 95% confidence interval CI, 0.19–0.43; P < .001) and hepatic decompensation (HR, 0.26; 95% CI, 0.17–0.39; P < .001). Patients with SVRs also had a lower risk of cardiovascular events (HR, 0.42; 95% CI, 0.25–0.69; P = .001) and bacterial infections (HR, 0.44; 95% CI, 0.29–0.68; P < .001). Metabolic features were associated with a higher risk of hepatocellular carcinoma in patients with SVRs, but not in patients with viremia. SVR affected overall mortality (HR, 0.27 compared with patients without SVR; 95% CI, 0.18–0.42; P < .001) and death from liver-related and non–liver-related causes. Similar results were obtained in a propensity score-matched population. Conclusions We confirmed a reduction in critical events, liver-related or not, in a prospective study of patients with HCV infection and compensated cirrhosis included in the CirVir cohort who achieved an SVR. We found an SVR to reduce overall mortality and risk of death from liver-related and non–liver-related causes. A longer follow-up evaluation is required to accurately describe and assess specific risk factors for complications in this population.
Gut microbiota richness and stability are important parameters in host–microbe symbiosis. Diet modification, notably using dietary fibres, might be a way to restore a high richness and stability in ...the gut microbiota. In this work, during a 6‐week nutritional trial, 19 healthy adults consumed a basal diet supplemented with 10 or 40 g dietary fibre per day for 5 days, followed by 15‐day washout periods. Fecal samples were analysed by a combination of 16S rRNA gene pyrosequencing, intestinal cell genotoxicity assay, metatranscriptomics sequencing approach and short‐chain fatty analysis. This short‐term change in the dietary fibre level did not have the same impact for all individuals but remained significant within each individual gut microbiota at genus level. Higher microbiota richness was associated with higher microbiota stability upon increased dietary fibre intake. Increasing fibre modulated the expression of numerous microbiota metabolic pathways such as glycan metabolism, with genes encoding carbohydrate‐active enzymes active on fibre or host glycans. High microbial richness was also associated with high proportions of Prevotella and Coprococcus species and high levels of caproate and valerate. This study provides new insights on the role of gut microbial richness in healthy adults upon dietary changes and host microbes' interaction.
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