Which patients with metastatic hormone-sensitive prostate cancer benefit from docetaxel: a systematic review and meta-analysis of individual participant data from randomised trials.

BACKGROUND: Adding docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer, but uncertainty remains about who benefits most. We therefore aimed to obtain up-to-date estimates of the overall effects of docetaxel and to assess whether these effects varied according to prespecified characteristics of the patients or their tumours. METHODS: The STOPCAP M1 collaboration conducted a systematic review and meta-analysis of individual participant data. We searched MEDLINE (from database inception to March 31, 2022), Embase (from database inception to March 31, 2022), the Cochrane Central Register of Controlled Trials (from database inception to March 31, 2022), proceedings of relevant conferences (from Jan 1, 1990, to Dec 31, 2022), and ClinicalTrials.gov (from database inception to March 28, 2023) to identify eligible randomised trials that assessed docetaxel plus ADT compared with ADT alone in patients with metastatic, hormone-sensitive prostate cancer. Detailed and updated individual participant data were requested directly from study investigators or through relevant repositories. The primary outcome was overall survival. Secondary outcomes were progression-free survival and failure-free survival. Overall pooled effects were estimated using an adjusted, intention-to-treat, two-stage, fixed-effect meta-analysis, with one-stage and random-effects sensitivity analyses. Missing covariate values were imputed. Differences in effect by participant characteristics were estimated using adjusted two-stage, fixed-effect meta-analysis of within-trial interactions on the basis of progression-free survival to maximise power. Identified effect modifiers were also assessed on the basis of overall survival. To explore multiple subgroup interactions and derive subgroup-specific absolute treatment effects we used one-stage flexible parametric modelling and regression standardisation. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool. This study is registered with PROSPERO, CRD42019140591. FINDINGS: We obtained individual participant data from 2261 patients (98% of those randomised) from three eligible trials (GETUG-AFU15, CHAARTED, and STAMPEDE trials), with a median follow-up of 72 months (IQR 55-85). Individual participant data were not obtained from two additional small trials. Based on all included trials and patients, there were clear benefits of docetaxel on overall survival (hazard ratio [HR] 0·79, 95% CI 0·70 to 0·88; p<0·0001), progression-free survival (0·70, 0·63 to 0·77; p<0·0001), and failure-free survival (0·64, 0·58 to 0·71; p<0·0001), representing 5-year absolute improvements of around 9-11%. The overall risk of bias was assessed to be low, and there was no strong evidence of differences in effect between trials for all three main outcomes. The relative effect of docetaxel on progression-free survival appeared to be greater with increasing clinical T stage (pinteraction=0·0019), higher volume of metastases (pinteraction=0·020), and, to a lesser extent, synchronous diagnosis of metastatic disease (pinteraction=0·077). Taking into account the other interactions, the effect of docetaxel was independently modified by volume and clinical T stage, but not timing. There was no strong evidence that docetaxel improved absolute effects at 5 years for patients with low-volume, metachronous disease (-1%, 95% CI -15 to 12, for progression-free survival; 0%, -10 to 12, for overall survival). The largest absolute improvement at 5 years was observed for those with high-volume, clinical T stage 4 disease (27%, 95% CI 17 to 37, for progression-free survival; 35%, 24 to 47, for overall survival). INTERPRETATION: The addition of docetaxel to hormone therapy is best suited to patients with poorer prognosis for metastatic, hormone-sensitive prostate cancer based on a high volume of disease and potentially the bulkiness of the primary tumour. There is no evidence of meaningful benefit for patients with metachronous, low-volume disease who should therefore be managed differently. These results will better characterise patients most and, importantly, least likely to gain benefit from docetaxel, potentially changing international practice, guiding clinical decision making, better informing treatment policy, and improving patient outcomes. FUNDING: UK Medical Research Council and Prostate Cancer UK.

A non-inferiority randomized phase III trial of standard immunotherapy by checkpoint inhibitors vs. reduced dose intensity in responding patients with metastatic cancer: the MOIO protocol study.

BACKGROUND: Immunotherapy (IO) has become a standard of care for treating various types of metastatic cancers and has significantly improved clinical outcome. With the exception of metastatic melanoma in complete response for which treatment can be stopped at 6 months, these treatments are currently administered until either disease progression for some IO, 2 years for others, or unacceptable toxicity. However, a growing number of studies are reporting maintenance of response despite discontinuation of therapy. There is currently no evidence of a dose effect of IO in pharmacokinetic studies. Maintaining efficacy despite a reduction in treatment intensity by decreasing the frequency of administration in patients with highly selected metastatic cancer, is the hypothesis evaluated in the MOIO study. METHOD/DESIGN: This non-inferiority, randomized phase III study aims to compare the standard regimen to a 3 monthly regimen of variousIO drugs in adult patients with metastatic cancer in partial (PR) or complete response (CR) after 6 months of standard IO dosing (except melanoma in CR). This is a French national study conducted in 36 centers. The main objective is to demonstrate that the efficacy of a three-monthly administration is not unacceptably less efficacious than a standard administration. Secondary objectives are cost-effectiveness, quality of life (QOL), anxiety, fear of relapse, response rate, overall survival and toxicity. After 6 months of standard IO, patients with partial or complete response will be randomized 1:1 between standard IO or a reduced intensity dose of IO, administered every 3 months. The randomization will be stratified on therapy line,, tumor type, IO type and response status. The primary endpoint is the hazard ratio of progression-free survival. With a planned study duration of 6 years, including 36 months enrolment time, 646 patients are planned to demonstrate with a statistical level of evidence of 5% that the reduced IO regimen is non-inferior to the standard IO regimen, with a relative non-inferiority margin set at 1.3. DISCUSSION: Should the hypothesis of non-inferiority with an IO reduced dose intensity be validated, alternate scheduling could preserve efficacy while being cost-effective and allowing a reduction of the toxicity, with an increase in patient's QOL. TRIAL REGISTRATION: NCT05078047.

New late-emphasis and combination tests based on infimum and supremum logrank statistics with application in oncology trials.

Immunotherapy cancer clinical trials routinely feature an initial period during which the treatment is given without evident therapeutic benefit, which may be followed by a period during which an effective therapy reduces the hazard for event occurrence. The nature of this treatment effect is incompatible with the proportional hazards assumption, which has prompted much work on the development of alternative effect measures of frameworks for testing. We consider tests based on individual and combination of early- and late-emphasis infimum and supremum logrank statistics, describe how they can be implemented, and evaluate their performance in simulation studies. Through this work and illustrative applications we conclude that this class of test statistics offers a new and powerful framework for assessing treatment effects in cancer clinical trials involving immunotherapies.

A stratified adaptive two-stage design with co-primary endpoints for phase II clinical oncology trials.

BACKGROUND: Given the inherent challenges of conducting randomized phase III trials in older cancer patients, single-arm phase II trials which assess the feasibility of a treatment that has already been shown to be effective in a younger population may provide a compelling alternative. Such an approach would need to evaluate treatment feasibility based on a composite endpoint that combines multiple clinical dimensions and to stratify older patients as fit or frail to account for the heterogeneity of the study population to recommend an appropriate treatment approach. In this context, stratified adaptive two-stage designs for binary or composite endpoints, initially developed for biomarker studies, allow to include two subgroups whilst maintaining competitive statistical performances. In practice, heterogeneity may indeed affect more than one dimension and incorporating co-primary endpoints, which independently assess each individual clinical dimension, would therefore appear quite pertinent. The current paper presents a novel phase II design for co-primary endpoints which takes into account the heterogeneity of a population.  METHODS: We developed a stratified adaptive Bryant & Day design based on the Jones et al. and Parashar et al. algorithm. This two-stage design allows to jointly assess two dimensions (e.g. activity and toxicity) in two different subgroups. The operating characteristics of this new design were evaluated using examples and simulation comparisons with the Bryant & Day design in the context where the study population is stratified according to a pre-defined criterion. RESULTS: Simulation results demonstrated that the new design minimized the expected and maximum sample sizes as compared to parallel Bryant & Day designs (one in each subgroup), whilst controlling type I error rates and maintaining a competitive statistical power as well as a high probability of detecting heterogeneity. CONCLUSIONS: In a heterogeneous population, this two-stage stratified adaptive phase II design provides a useful alternative to classical one and allows to identify a subgroup of interest without dramatically increasing sample size. As heterogeneity is not limited to older populations, this new design may also be relevant to other study populations such as children or adolescents and young adults or the development of targeted therapies based on a biomarker.

TRAINING-Ovary 01 (connecTed pRehabiliAtIoN pelvIc caNcer surGery): multicenter randomized study comparing neoadjuvant chemotherapy for patients managed for ovarian cancer with or without a connected pre-habilitation program.

BACKGROUND: Patients undergoing neoadjuvant chemotherapy before surgery for advanced ovarian cancer may have impaired functional capacity, nutritional status, and emotional well-being. PRIMARY OBJECTIVES: TRAINING-01 aims to determine if a connected pre-habilitation program during neoadjuvant chemotherapy for patients treated for an advanced ovarian cancer will improve physical capacity before major abdomino-pelvic surgery. STUDY HYPOTHESIS: A pre-habilitation program during neoadjuvant chemotherapy will bring a fitter patient to surgery and will decrease treatment morbidity and improve oncological outcomes. TRIAL DESIGN: This study is a prospective, multi-center, phase III study. The pre-habilitation program consists of providing multi-dimensional support during neoadjuvant chemotherapy using connected devices. The control group will receive usual care. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients will be women with International Federation of Gynecology and Obstetrics stage III-IV advanced ovarian cancer undergoing neoadjuvant chemotherapy. Patients must be able to perform a cardiopulmonary exercise test. PRIMARY ENDPOINTS: The primary endpoint will be the comparison of the variation in maximum oxygen uptake (VO2 max) between baseline and surgery in the pre-habilitation group and control groups. SAMPLE SIZE: 136 patients (68 per arm) will be recruited to demonstrate a medium standardized effect d=0.5 in the variations of VO2 max between baseline and surgery. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The duration of the study includes 24 months of recruitment and 5 years of follow up. We anticipate reporting primary endpoint results in 2024. TRIAL REGISTRATION: TRAINING-01-IPC 2018-039 (NCT04451369).

The actual benefit of intraoperative radiation therapy using 50 kV x-rays in early breast cancer: A retrospective study of 676 patients.

This French study reports the 5-year results of partial-breast irradiation using intraoperative radiation therapy (IORT) with 50 kV x-rays, in select early breast cancer patients. We report a retrospective analysis of 676 consecutive early breast cancer patients treated between November 2011 and December 2015 by partial-breast irradiation using the INTRABEAM® system. Patients were highly selected based on the ASTRO and GEC-ESTRO criteria and underwent breast-conservative surgery and IORT, completed with additional whole-breast irradiation (WBI) when unexpected unfavorable prognostic factors were found at the final pathology report. Patients' outcomes relative to local and distant control, overall and breast cancer-specific survival, and toxicity are presented, as well as rates of additional WBI. Additional WBI was mandatory in one third of patients (31%), mainly due to lymph node involvement and extensive intraductal component. With a median follow-up time of 54 months, the 5-year local recurrence rate was 1.7% [95%CI: 0.9-3.3]; the median time to local recurrence was 23 months; ipsilateral breast recurrences mainly occurred in the same quadrant (7/11); in the restricted population, meeting all predefined criteria and treated with IORT alone (406 patients), the local recurrence rate was 1.5% [95%CI: 0.6-3.6]. Five-year distant tumor control was 98.6% [95%CI: 97.2-99.3], and the median time to distant recurrence was 22 months. Five-year overall survival was 96.5% [95%CI: 94.2-97.8], and 5-year breast cancer-specific survival was 98.9% [95%CI: 97.6-99.7]. In patients treated with IORT alone, there was no grade 3 toxicity, only four grade 3 (mainly fibrosis) affected patients treated with IORT and WBI. Grade 1-2 toxicity rates were 14% and 34.4% in patients treated with IORT alone and IORT plus WBI, respectively. Partial-breast irradiation using IORT by a 50 kV photon device is safe and well-tolerated in select patients with early breast cancer and is a valuable option in patients reluctant for adjuvant WBI.

Lymph node positivity in different early breast carcinoma phenotypes: a predictive model.

BACKGROUND: A strong correlation between breast cancer (BC) molecular subtypes and axillary status has been shown. It would be useful to predict the probability of lymph node (LN) positivity. OBJECTIVE: To develop the performance of multivariable models to predict LN metastases, including nomograms derived from logistic regression with clinical, pathologic variables provided by tumor surgical results or only by biopsy. METHODS: A retrospective cohort was randomly divided into two separate patient sets: a training set and a validation set. In the training set, we used multivariable logistic regression techniques to build different predictive nomograms for the risk of developing LN metastases. The discrimination ability and calibration accuracy of the resulting nomograms were evaluated on the training and validation set. RESULTS: Consecutive sample of 12,572 early BC patients with sentinel node biopsies and no neoadjuvant therapy. In our predictive macro metastases LN model, the areas under curve (AUC) values were 0.780 and 0.717 respectively for pathologic and pre-operative model, with a good calibration, and results with validation data set were similar: AUC respectively of 0.796 and 0.725. Among the list of candidate's regression variables, on the training set we identified age, tumor size, LVI, and molecular subtype as statistically significant factors for predicting the risk of LN metastases. CONCLUSIONS: Several nomograms were reported to predict risk of SLN involvement and NSN involvement. We propose a new calculation model to assess this risk of positive LN with similar performance which could be useful to choose management strategies, to avoid axillary LN staging or to propose ALND for patients with high level probability of major axillary LN involvement but also to propose immediate breast reconstruction when post mastectomy radiotherapy is not required for patients without LN macro metastasis.

Overview of the pathological results and treatment characteristics in the first 1000 patients randomized in the SERC trial: axillary dissection versus no axillary dissection in patients with involved sentinel node.

BACKGROUND: Three randomized trials have concluded at non inferiority of omission of complementary axillary lymph node dissection (cALND) for patients with involved sentinel node (SN). However, we can outline strong limitations of these trials to validate this attitude with a high scientific level. We designed the SERC randomized trial ( ClinicalTrials.gov , number NCT01717131) to compare outcomes in patients with SN involvement treated with ALND or no further axillary treatment. The aim of this study was to analyze results of the first 1000 patients included. METHODS: SERC trial is a multicenter non-inferiority phase 3 trial. Multivariate logistic regression analysis was used to identify independent factors associated with adjuvant chemotherapy administration and non-sentinel node (NSN) involvement. RESULTS: Of the 963 patients included in the analysis set, 478 were randomized to receive cALND and 485 SLNB alone. All patient demographics and tumor characteristics were balanced between the two arms. SN ITC was present in 6.3% patients (57/903), micro metastases in 33.0% (298), macro metastases in 60.7% (548) and 289 (34.2%) were non eligible to Z0011 trial criteria. Whole breast or chest wall irradiation was delivered in 95.9% (896/934) of patients, adjuvant chemotherapy in 69.5% (644/926), endocrine therapy in 89.6% (673/751) and the proportions were similar in the two arms. The overall rate of positive NSN was 19% (84/442) for patients with cALND. Crude rates of positive NSN according to SN status were 4.5% for ITC (1/22), 9.5% for micro metastases (13/137), 23.9% for macro metastases (61/255) and were respectively 29.36% (64/218), 9.33% (7/75) and 7.94% (10/126) when chemotherapy was administered after cALND, before cALND and for patients without chemotherapy. CONCLUSION: The main objective of SERC trial is to demonstrate non inferiority of cALND omission. A strong interaction between timing of cALND and chemotherapy with positive NSN rate was observed. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov , number NCT01717131 October 19, 2012.

Impact of Patient- and Clinician-Reported Cumulative Toxicity on Quality of Life in Patients With Metastatic Castration-Naïve Prostate Cancer.

Background: Current toxicity evaluation is primarily focused on high-grade adverse events (AEs) reported by clinicians. However, the cumulative effect of multiple lower-grade AEs may also impact patients' quality of life (QoL). Further, patient-reported toxicity may be more representative of patients' treatment experiences. This study aimed to determine whether cumulative toxicity comprising all-grade AEs is more associated with QoL than cumulative toxicity comprising high-grade AEs only, and whether patient-reported cumulative toxicity is more associated with QoL than clinician-reported cumulative toxicity. Methods: Patients with metastatic castration-naïve prostate cancer participating in the phase III GETUG-AFU 15 trial completed questionnaires on AEs (at 3 and 6 months) and QoL (at baseline and 3 and 6 months). Clinicians reported AEs during clinical visits. Cumulative toxicity scores were calculated for clinicians and patients in 3 ways: total number of high-grade AEs, total number of all-grade AEs, and total number of all AEs multiplied by their grade (severity score). Relationships between cumulative toxicity scores and QoL were studied using longitudinal regression analyses; unstandardized (B) and standardized regression coefficients (ß) are reported. Results: Of 385 patients, 184 with complete QoL and toxicity data were included. Clinician-reported all-grade AEs (B, -2.2; 95% CI, -3.3 to -1.1; P<.01) and severity score (B, -1.4; 95% CI, -2.2 to -0.7; P<.01) were associated with deteriorated physical QoL, whereas the total number of high-grade AEs was not. All patient-reported scores were significantly (P<.01 for all) associated with deteriorated physical and global QoL. Standardized regression coefficients indicated that patient-reported toxicity scores were more associated with QoL outcomes than clinician-reported scores, with the strongest association found for the all-grade AEs and severity cumulative toxicity scores. Conclusions: Patient- and clinician-based cumulative toxicity scores comprising all-grade AEs better reflect impact on patient QoL than toxicity scores comprising high-grade AEs only. To assess the effect of toxicity on QoL, patient-reported cumulative toxicity scores are preferred.

Prognostic Value of Resection Margin Involvement After Pancreaticoduodenectomy for Ductal Adenocarcinoma: Updates From a French Prospective Multicenter Study.

OBJECTIVE: The aim of the study was to assess the relevance of resection margin status for survival after resection of pancreatic-head ductal adenocarcinoma. SUMMARY BACKGROUND DATA: The definition and prognostic value of incomplete microscopic resection (R1) remain controversial. METHODS: Prognostic factors were analyzed in 147 patients included in a prospective multicenter study on the impact of tumor clearance evaluated using a standardized pathology protocol. RESULTS: Thirty patients received neoadjuvant treatment (NAT = 20%); 41 had venous resection (VR = 28%), and 70% received adjuvant chemotherapy. In-hospital mortality was 3% (5/147). Follow-up was 83 months. Tumor clearance was 0, <1.0, <1.5, and <2.0 mm in 35 (25%), 92 (65%), 95 (67%), and 109 (77%) patients, respectively. R0-resection rates decreased from 75% to 35% when changing the definition of R1 status from R1-direct invasion (0 mm) to R1 <1.0 mm. On univariate analysis, clearance <1.0 or <1.5 mm, pT stage, pN stage, LNR ≥0.2, tumor grade 3, and lymphovascular invasion were significantly associated with 5-year survival. On multivariate analysis, pN was the most powerful independent predictor (P = 0.004). Clearance <1.0 or <1.5 mm had borderline significance for the entire cohort, but was relevant in certain subgroups (upfront pancreatectomy (n = 117; P = 0.049); without VR or NAT (n = 87; P = 0.003); N+ without VR or NAT (n = 50; P = 0.004). No N0-patient had R1-0 mm. Additional independent risk predictors were (1) R1 <1.0 mm for the SMA-margin in specific subgroups (upfront pancreatectomy, N0 patients without NAT, N+ patients without NAT or VR; (2) R1-0 mm posterior-margin for the NAT group (P = 0.004). CONCLUSION: Tumor clearance <1.0 or <1.5 mm was an independent determinants of postresection survival in certain subgroups. To avoid misinterpretation, future trials should specify the clearance margin in millimeter. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00918853.

A multicentre randomised controlled trial to evaluate the efficacy, morbidity and functional outcome of endoscopic transanal proctectomy versus laparoscopic proctectomy for low-lying rectal cancer (ETAP-GRECCAR 11 TRIAL): rationale and design.

BACKGROUND: Total mesorectal excision is the standard surgical treatment for mid- and low-rectal cancer. Laparoscopy represents a clear leap forward in the management of rectal cancer patients, offering significant improvements in post-operative measures such as pain, first bowel movement, and hospital length of stay. However, there are still some limits to its applications, especially in difficult cases. Such cases may entail either conversion to an open procedure or positive resection margins. Transanal endoscopic proctectomy (ETAP) was recently described and could address the difficulties of approaching the lower third of the rectum. Early series and case-control studies have shown favourable short-term results, such as a low conversion rate, reduced hospital length of stay and oncological outcomes comparable to laparoscopic surgery. The aim of the proposed study is to compare the rate of positive resection margins (R1 resection) with ETAP versus laparoscopic proctectomy (LAP), with patients randomly assigned to each arm. METHODS/DESIGN: The proposed study is a multicentre randomised trial using two parallel groups to compare ETAP and LAP. Patients with T3 lower-third rectal adenocarcinomas for whom conservative surgery with manual coloanal anastomosis is planned will be recruited. Randomisation will be performed immediately prior to surgery after ensuring that the patient meets the inclusion criteria and completing the baseline functional and quality of life tests. The study is designed as a non-inferiority trial with a main criterion of R0/R1 resection. Secondary endpoints will include the conversion rate, the minimal invasiveness of the abdominal approach, postoperative morbidity, the length of hospital stay, mesorectal macroscopic assessment, functional urologic and sexual results, faecal continence, global quality of life, stoma-free survival, and disease-free survival at 3 years. The inclusion period will be 3 years, and every patient will be followed for 3 years. The number of patients needed is 226. DISCUSSION: There is a strong need for optimal evaluation of the ETAP because of substancial changes in the operative technique. Assessment of oncological safety and septic risk, as well as digestive and urological functional results, is particularily mandatory. Moreover, benefits of the ETAP technique could be demonstrated  in post-operative outcome. TRIAL REGISTRATION: ClinicalTrial.gov: NCT02584985 . Date and version identifier: Version n°2 - 2015 July 6.

Goodness-of-fit test for monotone proportional subdistribution hazards assumptions based on weighted residuals.

Recently goodness-of-fit tests have been proposed for checking the proportional subdistribution hazards assumptions in the Fine and Gray regression model. Zhou, Fine, and Laird proposed weighted Schoenfeld-type residuals tests derived under an assumed model with specific form of time-varying regression coefficients. Li, Sheike, and Zhang proposed an omnibus test based on cumulative sums of Schoenfeld-type residuals. In this article, we extend the class of weighted residuals tests by allowing random weights of Schoenfeld-type residuals at ordered event times. In particular, it is demonstrated that weighted residuals tests using monotone weight functions of time are consistent against monotone proportional subdistribution hazards assumptions. Extensive Monte Carlo studies were conducted to evaluate the finite-sample performance of recent goodness-of-fit tests. Results from simulation studies show that weighted residuals tests using monotone random weight functions commonly used in non-proportional hazards regression settings tend to be more powerful for detecting monotone departures than other goodness-of-fit tests assuming no specific time-varying effect or misspecified time-varying effects. Two examples using real data are provided for illustrations. Copyright © 2016 John Wiley & Sons, Ltd.

Enhanced recovery after surgery program in Gynaecologic Oncological surgery in a minimally invasive techniques expert center.

BACKGROUND: Enhanced Recovery After Surgery Programs (ERP) includes multimodal approaches of perioperative patient's clinical pathways designed to achieve early recovery after surgery and a decreased length of hospital stay (LOS). METHODS: This observational study evaluated the implementation of ERP in gynaecologic oncological surgery in a minimally invasive techniques (MIT) expert center with more than 85% of procedures done with MIT. We compared a prospective cohort of 100 patients involved in ERP between December 2015 and June 2016 to a 100 patients control group, without ERP, previously managed in the same center between April 2015 and November 2015. All the included patients were referred for hysterectomy and/or pelvic or para-aortic lymphadenectomy for gynaecological cancer. The primary objective was to achieve a significant decrease of median LOS in the ERP group. Secondary objectives were decreases in proportion of patients achieving target LOS (2 days), morbidity and readmissions. RESULTS: Except a disparity in oncological indications with a higher proportion of endometrial cancer in the group with ERP vs. the group without ERP (42% vs. 22%; p = 0.003), there were no differences in patient's characteristics and surgical procedures. ERP were associated with decreases of median LOS (2.5 [0 to 11] days vs. 3 [1 to 14] days; p = 0.002) and proportion of discharged patient at target LOS (45% vs. 24%; p = 0.002). Morbidities occurred in 25% and 26% in the groups with and without ERP and readmission rates were respectively of 6% and 8%, without any significant difference. CONCLUSION: ERP in gynaecologic oncological surgery is associated with a decrease of LOS without increases of morbidity or readmission rates, even in a center with a high proportion of MIT. Although it is already widely accepted that MIT improves early recovery, our study shows that the addition of ERP's clinical pathways improve surgical outcomes and patient care management.

Pancreatic adenocarcinoma with venous involvement: is up-front synchronous portal-superior mesenteric vein resection still justified? A survey of the Association Française de Chirurgie.

BACKGROUND: Venous resection (VR) during pancreatectomy has been reported to neither increase mortality nor morbidity and to provide similar survival outcomes in same stage tumors. However, controversy remains regarding the indications for up-front surgery according to the degree of venous involvement. METHODS: From 2004 to 2009, 1,399 patients included in a French multicenter survey underwent pancreaticoduodenectomy or total pancreatectomy for pancreatic adenocarcinoma, either without VR (997 standard resections [SR]) or with VR (402 patients; 29 %). Postoperative and long-term outcomes were compared in both groups. RESULTS: VR was associated with the following factors: larger tumors (p < 0.001), poorly differentiated tumors (p = 0.004), higher numbers of positive lymph nodes (p = 0.042), and positive resection margins (R1; p < 0.001). Overall, VR increased neither postoperative morbidity nor postoperative mortality (5 vs. 3 % in SR patients; p = 0.16). The median and 3-year survival rates in VR patients versus SR patients were 21 months and 31 % vs. 29 months and 44 %, respectively (p = 0.0002). In the entire cohort, multivariate analysis identified VR as a significant poor prognostic factor for long-term survival (hazard ratio [HR] 1.75, 95 % confidence interval [CI] 1.28-2.40; p = 0.0005). In the VR patients, lymph node ratio, whatever the cutoff (<0.3: p = 0.093; ≥ 0.3: p = 0.0098), R1 resection (p = 0.010), and segmental resection (p = 0.016) were independent risk factors; neoadjuvant treatment (HR 0.52, 95 % CI 0.29-0.94; p = 0.031) and adjuvant treatment (HR 0.55, 95 % CI 0.35-0.85; p = 0.006) were significantly associated with improved long-term survival. CONCLUSIONS: Long-term survival after pancreatectomy was significantly altered when up-front VR was performed. Neoadjuvant treatment may be a better strategy than up-front resection in patients with preoperative suspicion of venous involvement.

Low non-relapse mortality and long-term preserved quality of life in older patients undergoing matched related donor allogeneic stem cell transplantation: a prospective multicenter phase II trial.

Allogeneic transplantation is a challenge in patients of advanced age because of a high risk of non-relapse mortality and potential long-lasting impairment of health-related quality of life. The development of reduced-intensity conditioning regimens has allowed the use of allogeneic transplantation in this population, but the optimal regimen remains undefined. We conducted a multicenter phase II trial evaluating the safety and efficacy of a reduced-intensity conditioning regimen combining fludarabine, intravenous busulfan, and rabbit antithymocyte globulins in patients older than 55 years of age transplanted from matched-related donor. In addition, health-related quality of life was prospectively measured. Seventy-five patients with a median age of 60 years (range 55-70) were analyzed. Grade III-IV acute and extensive chronic graft-versus-host diseases were found in 3% and 27% of patients, respectively. The day 100 and 1-year non-relapse mortality incidences were 1% and 9%, respectively. The cumulative incidences of relapse, progression-free survival and overall survival at two years were 36%, 51% and 67%, respectively, with a median follow up of 49 months. Global health-related quality of life, physical functioning, emotional functioning, and social functioning were not impaired compared to baseline for more than 75% of the patients (75%, 81.4%, 82.3%, and 75%, respectively). Thirty-four of the 46 (74%) progression-free patients at one year were living without persistent extensive chronic graft-versus-host disease. We conclude that the reduced-intensity conditioning regimen combining fludarabine, intravenous busulfan, and rabbit antithymocyte globulins is well tolerated in patients older than 55 years with low non-relapse mortality and long-term preserved quality of life.

The short- and long-term outcomes of pancreaticoduodenectomy for cancer in Child A patients are acceptable: a patient-control study from the Surgical French Association report for pancreatic surgery.

BACKGROUND: On the basis of now dated studies, cirrhosis is usually considered to be a contraindication in pancreatoduodenectomy (PD) for adenocarcinoma of the pancreatic head (APH). OBJECTIVE: Examine the outcomes of PD for APH in the presence of cirrhosis. METHODS: Retrospective, multicenter study of cirrhotic patients with APH having undergone PD between January 2004 and March 2012. Cirrhotic patients were matched 1:2 for demographic, surgical and histologic criteria with non-cirrhotic patients. Primary endpoint was morbidity and mortality. Secondary endpoints were surgical parameters, morbidity related to pancreatic surgery and cirrhosis, and follow-up. RESULTS: We included 35 patients with cirrhosis. Twenty-four patients (69%) were Child A and none were Child C. The Child A cirrhotic patients and non-cirrhotic patients respectively had complication rates of 79% vs. 43% (P = 0.002), major complication rates of 33% vs. 21% (P = 0.26), pancreatic fistula rates of 13% vs. 9% (P = 0.57), post-operative mortality of 4% vs. 5% (P = 0.94), 3-year overall survival rates of 44% vs. 50% (P = 0.46). All Child B cirrhotic patients experienced post-operative complications. CONCLUSION: Pancreatoduodenectomy for APH was possible in Child A cirrhotic patients with a mortality and long-term outcomes equivalent to non-cirrhotic patients. Child B cirrhosis remains a clear contraindication to surgery.

Pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: a French multicentre prospective evaluation of resection margins in 150 evaluable specimens.

OBJECTIVES: This study aimed to determine the impact of a standardized pathological protocol on resection margin status after pancreaticoduodenectomy (PD) for ductal adenocarcinoma. METHODS: A total of 150 patients operated during 2008-2010 were included in a prospective multicentre study using a 'quality protocol'. Multicolour inking by the surgeon identified three resection margins: the portal vein-superior mesenteric vein margin (PV-SMVm) or mesenterico-portal vein groove; the superior mesenteric artery margin (SMAm), and the posterior margin. Resection margins were stratified by 0.5-mm increments (range: 0-2.0 mm). Pancreatic neck, bile duct and intestinal margins were also analysed. Correlations between histopathological factors and survival in the 0-mm resection margin group were analysed. RESULTS: Thirty-six patients (24%) had a PV-SMV resection (PV-SMVR). An analysis of resections categorized according to margin distances of 0 mm, <1.0 mm, <1.5 mm and <2.0 mm confirmed R1 resections in 35 (23%), 91 (61%), 94 (63%) and 107 (71%) patients, respectively. The most frequently invaded resection margin was the PV-SMVm (35% of all patients) and PV-SMVR was the only factor correlated with a higher risk for at least one 0-mm positive resection margin on multivariate analysis (P < 0.001). Two-year progression-free survival (PFS) and median PFS time in patients with R0 and R1 resections (at 0 mm), respectively, were 42.0% and 26.5%, and 19.5 months and 10.5 months, respectively (P = 0.02). A positive PV-SMVm and SMAm had significant impact on PFS, whereas a positive posterior margin had no impact. CONCLUSIONS: Pancreaticoduodenectomy requiring PV-SMVR was associated with a higher risk for R1 resection. The standardization of histopathological analysis has a clinically relevant impact on PFS data.

Group sequential methods based on supremum logrank statistics under proportional and nonproportional hazards.

Despite the widespread use of Cox regression for modeling treatment effects in clinical trials, in immunotherapy oncology trials and other settings therapeutic benefits are not immediately realized thereby violating the proportional hazards assumption. Weighted logrank tests and the so-called Maxcombo test involving the combination of multiple logrank test statistics have been advocated to increase power for detecting effects in these and other settings where hazards are nonproportional. We describe a testing framework based on supremum logrank statistics created by successively analyzing and excluding early events, or obtained using a moving time window. We then describe how such tests can be conducted in a group sequential trial with interim analyses conducted for potential early stopping of benefit. The crossing boundaries for the interim test statistics are determined using an easy-to-implement Monte Carlo algorithm. Numerical studies illustrate the good frequency properties of the proposed group sequential methods.

Empirical antifungal therapy for health care-associated intra-abdominal infection: a retrospective, multicentre and comparative study.

BACKGROUND: Current guidelines recommend using antifungals for selected patients with health care-associated intra-abdominal infection (HC-IAI), but this recommendation is based on a weak evidence. This study aimed to assess the association between early empirical use of antifungals and outcomes in intensive care unit (ICU) adult patients requiring re-intervention after abdominal surgery. METHODS: A retrospective, multicentre cohort study with overlap propensity score weighting was conducted in three ICUs located in three medical institutions in France. Patients treated with early empirical antifungals for HC-IAI after abdominal surgery were compared with controls who did not receive such antifungals. The primary endpoint was the death rate at 90 days, and the secondary endpoints were the death rate at 1 year and composite criteria evaluated at 30 days following the HC-IAI diagnosis, including the need for re-intervention, inappropriate antimicrobial therapy and death, whichever occurred first. RESULTS: At 90 days, the death rate was significantly decreased in the patients treated with empirical antifungals compared with the control group (11.4% and 20.7%, respectively, p = 0.02). No differences were reported for the secondary outcomes. CONCLUSION: The use of early empirical antifungal therapy was associated with a decreased death rate at 90 days, with no effect on the death rate at 1 year, the death rate at 30 days, the rate of re-intervention, the need for drainage, and empirical antibiotic and antifungal therapy failure at 30 days.

Tripartite prehabilitation of patients with acute myeloid leukaemia and high-risk myelodysplastic syndromes during intensive chemotherapy before allogeneic haematopoietic stem cell transplantation (COHABILIT): protocol for an innovating prospective multicentre study.

OBJECTIVES: Acute myeloid leukaemia (AML) and high-risk myelodysplastic syndromes (MDS) are often treated with intensive chemotherapy followed by allogeneic haematopoietic stem cell transplantation (allo-HSCT). The pretransplant treatment results in a general deterioration of the patient's health and quality of life. Furthermore, allo-HSCT can be responsible for significant toxicity with risks of graft-versus-host disease (GvHD). Developing strategies to prevent physical deconditioning, undernutrition and psychological distress could help maintain a satisfactory general state of health before transplantation and thus limit these deleterious effects. This protocol evaluates the feasibility and adherence to a personalised prehabilitation programme, which can be modulated and assisted by connected objects, provided from the diagnosis to the allo-HSCT. METHODS AND ANALYSIS: This multicentre interventional study will include 50 patients treated for AML or high-risk MDS with intensive chemotherapy and eligible for allo-HSCT. The intervention consists of a coached, supervised or self-directed physical activity programme, organised during the hospitalisation phases and periods at home. At the same time, patients will receive a weekly dietary follow-up. The whole intervention is controlled and modulated through the use of a dedicated application and connected objects allowing adaptation and individualisation. The rate of participation in the prescribed physical activity sessions will assess the feasibility of this study. In addition, the evolution of physical capacities (Short Physical Performance Battery, grip and quadriceps strengths), psychosocial parameters (Functional Assessment of Cancer Therapy - Leukaemia, Functional Assessment of Cancer Therapy - Fatigue, subjective well-being, Hospital Anxiety and Depression Scale, self-efficacy, Coach-Athlete Relationship Questionnaire, interviews) and clinical status (weight, lean body mass, survival rate, number of infections, days of hospitalisation, GvHD) will be evaluated. ETHICS AND DISSEMINATION: The study procedures have been approved by the National Ethics Committee (21.00223.000003). Consent is given in person by each participant. The information collected on the participants contains only a non-identifiable study identifier. The results of this protocol will be published in a scientific paper and communicated to the medical staff of the medical centre. TRIAL REGISTRATION NUMBER: NCT03595787.