Using intervention mapping to facilitate and sustain return-to work after breast cancer: protocol for the FASTRACS multicentre randomized controlled trial.

BACKGROUND: Women with breast cancer face many barriers to return to work (RTW) after their cancer. The main objective of the FASTRACS-RCT is to evaluate the impact of the FASTRACS (Facilitate and Sustain Return to Work after Breast Cancer) intervention on the sustainable RTW of breast cancer patients, 12 months after the end of active treatment. METHODS: FASTRACS-RCT is a prospective, national, multicentre, randomized, controlled and open-label study. A total of 420 patients with early breast cancer scheduled for surgery and (neo)adjuvant chemotherapy, will be randomly assigned (1:1 ratio) to: (i) the intervention arm comprising four steps over 6 months : Handing over the intervention tools; transitional medical consultation with the general practitioner (GP); pre-RTW visit with the company's occupational physician (OP); catch-up visit with a hospital-based RTW expert (if sick leave > 10 months) (ii) the control arm to receive usual care. The design of the FASTRACS intervention was informed by intervention mapping for complex interventions in health promotion planning, and involved patients and representatives of relevant stakeholders. Specific tools were developed to bridge the gap between the hospital, the GP, the OP and the workplace: a toolkit for breast cancer patients comprising a theory-based guide; specific checklists for the GP and the OP, respectively; and a theory-based guide for workplace actors (employer, manager, colleagues). The primary endpoint will associate sustainable RTW (full-time or part-time work at 50% or more of working time, for at least 28 consecutive days) and days off work. It will be assessed at 4, 8 and 12 months after the end of active oncological treatment. Secondary endpoints will include quality of life, anxiety, depression, RTW self-efficacy, physical activity, social support, job accommodations, work productivity, job status, and the usefulness and acceptability of the intervention's tools. DISCUSSION: FASTRACS-RCT will be supplemented by a realist evaluation approach aimed at understanding the influence of context in activating the intervention's mechanisms and effects. If the expected impact of the intervention is confirmed, the intervention will be adapted and scaled-up for other cancers and chronic diseases to better integrate healthcare and work disability prevention. TRIAL REGISTRATION: NCT04846972 ; April 15, 2021.

Comparison of Neoadjuvant Systemic Chemotherapy Protocols for the Curative-Intent Management of Peritoneal Metastases from Colorectal Cancer, Regarding Morphological Response, Pathological Response, and Long-Term Outcomes: A Retrospective Study.

BACKGROUND: Selected patients with colorectal cancer peritoneal metastases (CRPM) could be offered a curative-intent strategy based on complete cytoreductive surgery (CRS), potentially combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and perioperative systemic chemotherapy. The impact of different neoadjuvant systemic chemotherapy (NACT) regimens remains unclear due to a lack of comparative data. METHODS: Consecutive CRPM patients from a monocentric database who were treated with complete CRS after single-line NACT were included in this study. Chemotherapy regimens were tailored as a doublet drug (FOLFOX/FOLFIRI) with/without targeted therapy (anti-epidermal growth factor receptor/bevacizumab) and triplet-drug combination (FOLFIRINOX). Morphological response (MR) was assessed using the Response Evaluation Criteria in Solid Tumors criteria, and pathological response (PR) was assessed using the Peritoneal Regression Grading Score (PRGS). Long-term oncologic outcomes were compared. RESULTS: The cohort comprised 388 patients, including 127, 202, and 59 patients in the doublet, doublet + targeted, and triplet groups, respectively. MR rates were higher in the triplet (68.0%) and doublet + targeted groups (64.2%) when compared with the doublet group (42.4%, p = 0.003). Complete and major PRs were observed in 13.6% and 32.0% of patients, respectively. Higher MR rates were observed after doublet + targeted or triplet regimens, while no difference was observed for PR rates. In multivariate analysis, FOLFIRINOX was independently associated with better overall survival (hazard ratio 0.49, 95% confidence interval 0.25-0.96; p = 0.037). FOLFIRINOX also resulted in a higher rate of severe postoperative complications. CONCLUSIONS: In this retrospective study, a FOLFIRINOX regimen as NACT seemed to result in better long-term outcomes for CRPM patients after complete CRS/HIPEC, although with higher morbidity. Prospective studies are needed, including groups without NACT and those with FOLFIRINOX + bevacizumab.

Influence of Extraperitoneal Metastases on the Curative-Intent Management of Colorectal Peritoneal Metastases.

BACKGROUND: Selected patients with colorectal cancer peritoneal metastasis (CRPM) and extraperitoneal disease could be treated radically with a multimodal approach combining complete cytoreductive surgery, thermoablation, radiotherapy, and systemic and intraperitoneal chemotherapy. The impact of extraperitoneal metastatic sites (EPMS) in this setting remains unclear. PATIENTS AND METHODS: Patients with CRPM undergoing complete cytoreduction in 2005-2018 were grouped in: peritoneal disease only (PDO), one EPMS (1 + EPMS), two or more EPMS (2 + EPMS). A retrospective analysis compared overall survival (OS) and postoperative outcomes. RESULTS: Of 433 patients, 109 had 1 + EPMS and 31 had 2 + EPMS. Overall, 101 patients had liver metastasis, 19 lung metastasis, and 30 retroperitoneal lymph node (RLN) invasion. The median OS was 56.9 months. There was no significant OS difference between PDO and 1 + EPMS groups (64.6 and 57.9 months, respectively), whereas OS was lower in the 2 + EPMS group (29.4 months, p = 0.005). In multivariate analysis, 2 + EPMS [hazard ratio (HR) 2.86, 95% confidence interval (CI) 1.33-6.12, p = 0.007], Sugarbaker's Peritoneal Carcinomatosis Index (PCI) > 15 (HR 3.86, 95% CI 2.04-7.32, p < 0.001), poorly differentiated tumors (HR 2.62, 95% CI 1.21-5.66, p = 0.015), and BRAF mutation (HR 2.10, 95% CI 1.11-3.99, p = 0.024) were independent poor prognostic factors, while adjuvant chemotherapy was beneficial (HR 0.33, 95% CI 0.20-0.56, p < 0.001). Patients with liver resection did not show higher severe complication rates. CONCLUSION: In patients with CRPM selected for a radical surgical approach, limited extraperitoneal disease involving one site, notably the liver, does not seem to significantly impair postoperative results. RLN invasion appeared as a poor prognostic factor in this population.

Evaluation of Scores to Reflect Toxicity Impact on Quality of Life of Patients With Platinum-Resistant Ovarian Cancer: AURELIA Substudy.

BACKGROUND: Current standards for toxicity reporting do not fully capture the impact of adverse events (AEs) on patients' quality of life (QoL). This study aimed to evaluate the association between toxicity and QoL by using toxicity scores that take into account CTCAE grade grouping and AE duration and cumulation. METHODS: Analyses were performed on the AURELIA trial dataset, including 361 patients with platinum-resistant ovarian cancer treated with chemotherapy alone or with bevacizumab. Global and physical functioning QoL were issued from the EORTC QoL Questionnaire-Core 30 (QLQ-C30), collected at baseline and 8/9 and 16/18 weeks after treatment initiation. Four toxicity scores were computed: the total number of AEs, multiplied by their grade and not, and the cumulative duration of AEs, weighted by their grade and not. Each score included all AEs or only grade 3/4 nonlaboratory or treatment-related AEs. The relationship between toxicity scores and QoL was assessed through linear mixed regression. RESULTS: We found that 171 (47.5%) and 43 (11.9%) patients experienced at least one grade 3 or 4 AE, respectively, whereas 113 (31.4%) experienced grade 2 AEs only. Physical QoL was negatively associated with all toxicity scores when computed with all grades of AEs (all P<.01), with a weaker association when treatment-related AEs were considered. Global QoL was negatively associated with toxicity scores computed with nonlaboratory all-grade AEs only (ß, -3.42 to -3.13; all P<.01). Degrees of association were lower when considering the AE duration. CONCLUSIONS: In this analysis of patients with platinum-resistant ovarian cancer, toxicity scores based on the cumulative number of AEs, modulated or not by grade, were more effective at predicting QoL changes than those based on AE duration. Toxicity impact on QoL was better reflected when grade 2 AEs were taken into account together with grade 3/4 AEs, whatever their treatment imputability, and when laboratory AEs were excluded.

Individualized Net Benefit estimation and meta-analysis using generalized pairwise comparisons in N-of-1 trials.

BACKGROUND: The Net Benefit (Δ) is a measure of the benefit-risk balance in clinical trials, based on generalized pairwise comparisons (GPC) using several prioritized outcomes and thresholds of clinical relevance. We extended Δ to N-of-1 trials, with a focus on patient-level and population-level Δ. METHODS: We developed a Δ estimator at the individual level as an extension of the stratum-specific Δ, and at the population-level as an extension of the stratified Δ. We performed a simulation study mimicking PROFIL, a series of 38 N-of-1 trials testing sildenafil in Raynaud's phenomenon, to assess the power for such an analysis with realistic data. We then reanalyzed PROFIL using GPC. This reanalysis was finally interpreted in the context of the main analysis of PROFIL which used Bayesian individual probabilities of efficacy. RESULTS: Simulations under the null showed good size of the test for both individual and population levels. The test lacked power when being simulated from the true PROFIL data, even when increasing the number of repetitions up to 140 days per patient. PROFIL individual-level estimated Δ were well correlated with the probabilities of efficacy from the Bayesian analysis while showing similarly wide confidence intervals. Population-level estimated Δ was not significantly different from zero, consistently with the previous Bayesian analysis. CONCLUSION: GPC can be used to estimate individual Δ which can then be aggregated in a meta-analytic way in N-of-1 trials. GPC ability to easily incorporate patient preferences allow for more personalized treatment evaluation, while needing much less computing time than Bayesian modeling.

On the use of extreme value tail modeling for generalized pairwise comparisons with censored outcomes.

In randomized clinical trials, methods of pairwise comparisons such as the 'Net Benefit' or the 'win ratio' have recently gained much attention when interests lies in assessing the effect of a treatment as compared to a standard of care. Among other advantages, these methods are usually praised for delivering a treatment measure that can easily handle multiple outcomes of different nature, while keeping a meaningful interpretation for patients and clinicians. For time-to-event outcomes, a recent suggestion emerged in the literature for estimating these treatment measures by providing a natural handling of censored outcomes. However, this estimation procedure may lead to biased estimates when tails of survival functions cannot be reliably estimated using Kaplan-Meier estimators. The problem then extrapolates to the other outcomes incorporated in the pairwise comparison construction. In this work, we suggest to extend the procedure by the consideration of a hybrid survival function estimator that relies on an extreme value tail model through the Generalized Pareto distribution. We provide an estimator of treatment effect measures that notably improves on bias and remains easily apprehended for practical implementation. This is illustrated in an extensive simulation study as well as in an actual trial of a new cancer immunotherapy.

Non-resectable Malignant Peritoneal Mesothelioma Treated with Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Plus Systemic Chemotherapy Could Lead to Secondary Complete Cytoreductive Surgery: A Cohort Study.

BACKGROUND: Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive primary peritoneal neoplasia. At diagnosis, few patients are eligible for a recommended cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Among neoadjuvant strategies, pressurized intraperitoneal aerosol chemotherapy (PIPAC) combined with systemic chemotherapy has been recently proposed. This study evaluated this strategy in a cohort of DMPM patients. METHODS: Patients with DMPM and primary or recurrent non-resectable diseases who received at least one PIPAC procedure in alternation with systemic chemotherapy were included in this retrospective study to analyze oncologic outcomes. RESULTS: Overall, 26 DMPM patients were treated with at least one PIPAC, including 20 patients with no previous CRS. Of 22 patients (85%) who had symptoms, 9 had perceptible ascites. Overall, 79 PIPAC procedures were performed, with half of the patients receiving three PIPAC procedures or more. Among eight patients (31%), 10 adverse events (13% of procedures) were reported, including two severe complications, both corresponding to digestive perforations. Improvement of symptoms was reported for 32% of the patients, whereas control of ascites was noted in 46%. All but one procedure among 14 patients (54%) secondarily treated by CRS-HIPEC were considered complete resections. After a median follow-up period of 29.6 months (95% confidence interval [CI], 17.6-not reached [NR]), the median overall survival period was 12 months (95% CI 11.1-NR). The median progression-free survival (PFS) was significantly better among the patients who underwent resection than among those who did not (33.5 vs 7.4 months; hazard ratio [HR], 0.18; 95% CI 0.06-0.755; p < 0.001). CONCLUSIONS: For patients with initially non-resectable DMPM, PIPAC is feasible for treatment with neoadjuvant intent and could facilitate complete secondary resection.

Health-related quality of life analysis in ovarian cancer clinical trials involving PARP inhibitors: a critical methodological perspective.

The poly (ADP-ribose) polymerase inhibitors (PARPi) have yielded significant clinical benefits as maintenance therapy in women with newly diagnosed and relapsed platinum-sensitive advanced ovarian cancer. These drugs were approved based on progression-free survival, the primary endpoint of their respective pivotal trials. Health-related quality of life (HRQoL) and/or patient-reported outcomes were included in these trials as a secondary exploratory endpoint. Nevertheless, many weaknesses in the analysis of HRQoL across these trials can be noticed. Heterogeneity and suboptimal HRQoL analysis in oncology trials contribute to misconceptions about this endpoint among oncologists and prevent quality of life as being an endpoint used for approvals. In this article, we discuss these HRQoL results from a methodological perspective and propose some solutions for improvement that could be used by regulatory and academic institutions running ovarian cancers trials. Notably, we suggest to measure and analyze HRQoL data after disease progression, to focus dedicated papers on the statistical analyses of HRQoL recommended by the SISAQOL consortium (linear mixed model for repeated measures and time-to-event approaches) and to communicate on available guidelines to ensure compliance with best international practices regarding the measurement and analysis of HRQoL.

Basket clinical trial design for targeted therapies for cancer: a French National Authority for Health statement for health technology assessment.

During the past decade, health technology assessment bodies have faced new challenges in establishing the benefits of new drugs for individuals and health-care systems. A topic of increasing importance to the field of oncology is the so-called agnostic regulatory approval of targeted therapies for cancer (independent of tumour location and histology) granted on the basis of basket trials. Basket trials in oncology offer the advantage of simultaneously evaluating treatments for multiple tumours, even rare cancers, in a single clinical trial. To address the novel challenges introduced by these trials, an interdisciplinary panel was convened on behalf of the Transparency Committee of the French National Authority for Health to clarify an approach designed to guarantee a transparent, reproducible, and fair assessment of histology-agnostic treatments for reimbursement by the French National Health Insurance Fund. The requirements of this approach include the need for randomisation, clinically relevant endpoints, appropriate correction for multiple significance testing, characterisation of subgroup heterogeneity, and validation of underlying biomarker assays. A prospectively designated external control is encouraged when the implementation of a direct comparison is deemed infeasible. We also underline the importance of recording outcomes from basket trials in a registry for use as future external controls.

Net benefit in the presence of correlated prioritized outcomes using generalized pairwise comparisons: A simulation study.

BACKGROUND: The prioritized net benefit (Δ) is a measure of the benefit-risk balance in clinical trials, based on generalized pairwise comparisons (GPC) using several prioritized outcomes. Its estimation requires the classification as Wins or Losses of all possible pairs of patients, one from the experimental treatment (E) group and one from the control treatment (C) group. In this simulation study, we assessed the impact of the correlation between prioritized outcomes on Δ, its estimate, bias, size, and power. METHODS: The theoretical Δ value was derived for the specific case of two correlated binary outcomes when a normal copula is used. Focusing on one efficacy and one toxicity outcome, two situations frequently met in practice were simulated: binary efficacy outcome with binary toxicity outcome, or time to event efficacy outcome with categorical toxicity outcome. Several scenarios of efficacy and toxicity were generated, with various levels of correlation. RESULTS: When E was more effective than C, positive correlations were mainly associated with a decrease in the proportion of Losses, while negative correlations were associated with a decrease in the proportion of Wins on the toxicity outcome. This resulted in an increase of Δ^ with the intensity of the positive correlation without adding any bias. Results were similar whatever the type of outcomes generated but led to power alteration. CONCLUSION: Correlations between outcomes analyzed with GPC led to substantial but predictable modifications of Δ and its estimate. Correlations should be taken into consideration when performing sample size estimations in clinical trials.

Multicystic peritoneal mesothelioma treated with cytoreductive surgery followed or not by hyperthermic intraperitoneal chemotherapy: results from a large multicentric cohort.

BACKGROUND: Multicystic peritoneal mesothelioma (MCPM) is a rare, slowly growing, condition prone to recur after surgery. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) added to complete cytoreductive surgery (CRS) remains controversial and difficult to assess. As patients are mostly reproductive age women, surgical approach, and fertility considerations are important aspects of the management. This observational retrospective review aimed to accurate treatment strategy reflections. METHODS: The RENAPE database (French expert centers network) was analyzed over a 1999-2019 period. MCPM patients treated with CRS were included. A special focus on HIPEC, mini-invasive approach, and fertility considerations was performed. RESULTS: Overall 60 patients (50 women) were included with a median PCI of 10 (4-14) allowing 97% of complete surgery, followed by HIPEC in 82% of patients. A quarter of patients had a laparoscopic approach. Twelve patients (20%) recurred with a 3-year recurrence free survival of 84.2% (95% confidence interval 74.7-95.0). The hazard of recurrence was numerically reduced among patients receiving HIPEC, however, not statistically significant (hazard ratio 0.41, 0.12-1.42, p = 0.200). A severe post-operative adverse event occurred in 22% of patients with five patients submitted to a subsequent reoperation. Among four patients with a childbearing desire, three were successful (two had a laparoscopic-CRS-HIPEC and one a conventional CRS without HIPEC). CONCLUSION: MCPM patients treatment should aim at a complete CRS. The intraoperative treatment options as laparoscopic approach, fertility function sparing and HIPEC should be discussed in expert centers to propose the most appropriate strategy.

Correcting the bias of the net benefit estimator due to right-censored observations.

Generalized pairwise comparisons (GPCs) are a statistical method used in randomized clinical trials to simultaneously analyze several prioritized outcomes. This procedure estimates the net benefit (Δ). Δ may be interpreted as the probability for a random patient in the treatment group to have a better overall outcome than a random patient in the control group, minus the probability of the opposite situation. However, the presence of right censoring introduces uninformative pairs that will typically bias the estimate of Δ toward 0. We propose a correction to GPCs that estimates the contribution of each uninformative pair based on the average contribution of the informative pairs. The correction can be applied to the analysis of several prioritized outcomes. We perform a simulation study to evaluate the bias associated with this correction. When only one time-to-event outcome was generated, the corrected estimates were unbiased except in the presence of very heavy censoring. The correction had no effect on the power or type-1 error of the tests based on the Δ. Finally, we illustrate the impact of the correction using data from two randomized trials. The illustrative datasets showed that the correction had limited impact when the proportion of censored observations was around 20% and was most useful when this proportion was close to 70%. Overall, we propose an estimator for the net benefit that is minimally affected by censoring under the assumption that uninformative pairs are exchangeable with informative pairs.

A new measure of treatment effect in clinical trials involving competing risks based on generalized pairwise comparisons.

In survival analysis with competing risks, the treatment effect is typically expressed using cause-specific or subdistribution hazard ratios, both relying on proportional hazards assumptions. This paper proposes a nonparametric approach to analyze competing risks data based on generalized pairwise comparisons (GPC). GPC estimate the net benefit, defined as the probability that a patient from the treatment group has a better outcome than a patient from the control group minus the probability of the opposite situation, by comparing all pairs of patients taking one patient from each group. GPC allow using clinically relevant thresholds and simultaneously analyzing multiple prioritized endpoints. We show that under proportional subdistribution hazards, the net benefit for competing risks settings can be expressed as a decreasing function of the subdistribution hazard ratio, taking a value 0 when the latter equals 1. We propose four net benefit estimators dealing differently with censoring. Among them, the Péron estimator uses the Aalen-Johansen estimator of the cumulative incidence functions to classify the pairs for which the patient with the best outcome could not be determined due to censoring. We use simulations to study the bias of these estimators and the size and power of the tests based on the net benefit. The Péron estimator was approximately unbiased when the sample size was large and the censoring distribution's support sufficiently wide. With one endpoint, our approach showed a comparable power to a proportional subdistribution hazards model even under proportional subdistribution hazards. An application of the methodology in oncology is provided.

Impact of acute kidney injury on anticancer treatment dosage and long-term outcomes: a pooled analysis of European Organisation for Research and Treatment of Cancer trials.

BACKGROUND: The impact of kidney dysfunction on long-term outcomes of patients with advanced cancer remains unclear. METHODS: Patients with advanced cancer included in trials conducted by the European Organisation for Research and Treatment of Cancer were eligible for this retrospective analysis. Acute kidney injury (AKI) was identified using serum creatinine levels and using adverse events reported by investigators. The impact of baseline estimated glomerular filtration rates (eGFRs) on progression-free survival (PFS) and overall survival (OS) was investigated. Pooled estimates of the impact of AKI on dose intensity, treatment duration, PFS and OS were obtained following a meta-analytic process. RESULTS: Nine trials were included in this study, totalling 2872 metastatic patients with various tumour types and various systemic treatment types. Baseline eGFR had homogeneously no impact on PFS or OS. Most Risk, Injury, Failure, Loss of kidney function and End-stage kidney disease (RIFLE) events occurred early during the course of the treatment. AKI was not associated with an increased rate of treatment discontinuation, while it decreased the study treatment dose intensity. Occurrence of a first RIFLE event significantly and homogeneously reduced PFS (pooled hazard ratio = 1.18, 95% confidence interval 1.07-1.30; P = 0.0012), while its impact on OS was more heterogeneous across trials. CONCLUSION: AKI is associated with reduced treatment dose intensity and reduced PFS. Therefore, close monitoring of the kidney function during the first months of treatment should be included in clinical trial protocols and probably also in daily practice to enable early AKI diagnosis and management. Collaboration between oncologists and nephrologists is needed to reduce the risk of undertreatment of patients experiencing AKI.

A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors.

The advent of immune checkpoint-inhibitors (CPI) has transformed treatment for several cancer types. This review was performed to assess the rate of adverse events (AEs) associated with the use of CPI, alone or in combinations. A review of AEs reporting quality was also performed. All publications of Randomized Clinical Trials (RCTs) assessing CPI published before December 2017 were included. To investigate the quality of AEs reporting, a set of items was defined based on the 2004 CONSORT harms extension statement. Rates of Grade 5, serious, and study-withdrawal related AEs were collected in each treatment category. Specific immune related AEs (irAEs) were also collected when available. Pooled estimates of adverse event rates were calculated by using generalized linear mixed model. A total of 35 RCTs including 16,485 patients were included. The overall quality of AEs reporting was satisfactory, but items pertaining to methods of data collection and analysis were infrequently reported. Grade ≥ 3 AEs were reported for 14% (95% CI 12-16) of patients treated with PD(L)-1 inhibitors, 34% (95% CI 27-42) of patients treated with CTLA-4 inhibitors, 55% (95% CI 51-59) of patients on CPI combinations and 46% (95% CI 40-53) of patients on immunotherapy-chemotherapy combination. The profile of irAEs was different among the treatment categories. The use of CPI, especially in combination, is associated with significant rates of Grade ≥ 3 AEs. Healthcare planning should anticipate the expected high number of patients presenting with irAEs in the future.

Changes in the Use of Comprehensive Geriatric Assessment in Clinical Trials for Older Patients with Cancer over Time.

BACKGROUND: The objective of this study was to describe the implementation of comprehensive geriatric assessment (CGA) in clinical trials dedicated to older patients before and after the creation of the International Society of Geriatric Oncology in the early 2000s. SUBJECTS, MATERIALS, AND METHODS: All phase I, II, and III trials dedicated to the treatment of cancer among older patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. We considered that a CGA was performed when the authors indicated an intention to do so in the Methods section of the article. We collected each geriatric domain assessed using a validated tool even in the absence of a clear CGA, including nutritional, functional, cognitive, and psychological status, comorbidity, comedication, overmedication, social status and support, and geriatric syndromes. RESULTS: A total of 260 clinical trials dedicated to older patients were identified over the two time periods: 27 phase I, 193 phase II, and 40 phase III trials. CGA was used in 9% and 8% of phase II and III trials, respectively; it was never used in phase I trials. Performance status was reported in 67%, 79%, and 75% of phase I, II, and III trials, respectively. Functional assessment was reported in 4%, 11%, and 13% of phase I, II, and III trials, respectively. Between the two time periods, use of CGA increased from 1% to 11% (p = .0051) and assessment of functional status increased from 3% to 14% (p = .0094). CONCLUSION: The use of CGA in trials dedicated to older patients increased significantly but remained insufficient. IMPLICATIONS FOR PRACTICE: This article identifies the areas in which research efforts should be focused in order to offer physicians well-addressed clinical trials with results that can be extrapolated to daily practice.

BRCA1/BRCA2 germline mutations and chemotherapy-related hematological toxicity in breast cancer patients.

PURPOSE: BRCA1 and BRCA2 proteins are central to DNA repair process through homologous recombination. We hypothesize that BRCA1/BRCA2 mutation carriers may exhibit increased hematological toxicity when receiving genotoxic chemotherapy. METHODS: We included women with primary breast cancers screened for BRCA1/BRCA2 germline mutations and treated with (neo)adjuvant chemotherapy in Geneva (Swiss cohort). The primary endpoint was the incidence of febrile neutropenia following the first chemotherapy cycle (C1). Secondary endpoints were the incidence of grade 3-4 neutropenia, grade 4 neutropenia and hospitalization during C1, G-CSF use and chemotherapy dose reduction during the entire chemotherapy regimen. Long-term toxicities (hematological, cardiac and neuropathy) were assessed in the Swiss cohort and a second cohort of patients from Lyon (French cohort). RESULTS: Overall, 221 patients were assessed for acute hematological toxicity, including 23 BRCA1 and 22 BRCA2 carriers. Following the C1, febrile neutropenia had an incidence of 35% (p = 0.002), 14% (p = 0.562) and 10% among BRCA1, BRCA2 and non-carriers, respectively. Grade 4 neutropenia was found in 57% of BRCA1 (p < 0.001), 14% of BRCA2 (p = 0.861) and 18% of non-carriers. G-CSF support was necessary in 86% of BRCA1 (p = 0.005), 64% of BRCA2 (p = 0.285) and 51% of non-carriers. For long-term toxicity analysis, 898 patients were included (167 BRCA1-, 91 BRCA2- and 640 non-carriers). There was no difference between the 3 groups. CONCLUSIONS: BRCA1 germline mutations is associated with greater acute hematological toxicity in breast cancer patients. These observations could have implication for primary prophylaxis with G-CSF.

Is Nutritional Screening of Patients with Lung Cancer Optimal? An Expert Opinion Survey of French Physicians and Surgeons.

Objectives: To assess how physicians and surgeons carried out malnutrition screening and follow-up for patients with lung cancer. Materials and methods: We carried out an expert opinion survey in France using an anonymous self-administered online questionnaire. Results: In 2017, 206 practitioners responded, of which 60.7% were pulmonologists, 17.4% thoracic surgeons, 11.2% oncologists, and 10.7% radiotherapists. At initial diagnosis, 79.3% of practitioners recorded patients' percentage of weight loss. During follow-up examinations, 67.5% recorded this data for patients at risk of malnutrition and 70.4 % for malnourished patients. Food intake was evaluated by 21.7% of practitioners at initial diagnosis. Surgeons assessed percentage of weight loss and food intake significantly less often than pulmonologists did, they were less likely to request serum albumin tests and waited for a greater percentage of weight loss before referring patients to a nutrition professional. All practitioners were well aware of the prevalence of malnutrition among lung cancer patients and its consequences. The main factors preventing optimal nutritional assessment reported by practitioners were a lack of time and limited specialized knowledge. Conclusion: Nutritional assessment remained suboptimal, especially for surgical patients. The importance granted to malnutrition needs to be increased for patients with lung cancer, especially in surgical departments. Highlights Physicians and thoracic surgeons are well aware of the prevalence and consequences in lung cancer patients. Thoracic surgeons seemed to be less sensitized to malnutrition screening than pulmonologists. Lack of time and limited specialized knowledge were reported as the main factors preventing optimal nutritional assessment.

Meta-Research on Oncology Trials: A Toolkit for Researchers with Limited Resources.

"Meta-research" is a discipline that investigates research practices. Meta-research on clinical trials is an attempt to summarize descriptive and methodological features of published or ongoing clinical trials, including aspects of their implementation, design, analysis, reporting, and interpretation. In this type of investigation, the unit of analysis is a primary source of information about a clinical trial (e.g., published reports, study protocols, or abstracts), with meta-research being a second layer of information that summarizes what is known from various primary sources. After the formulation of the primary research question, the methodology of meta-research resembles that of other research projects, with predefined eligibility criteria, exposure variables, primary and secondary outcomes of interest, and an analysis plan. This type of study usually provides a high-level picture of the literature on a specific topic, always accompanied by a critical evaluation of the methodology and/or the quality of reporting of the studies included. Because relatively few resources are consumed to produce meta-research, these studies offer a great opportunity for clinical scientists working in settings with limited resources. In this article, we present the principles of designing and conducting meta-research and use our experience to suggest recommendations on how to perform and how to report this type of potentially very creative study. IMPLICATIONS FOR PRACTICE: The term meta-research pertains to a type of study in which the unit of analysis is, in most cases, the publication of a clinical trial. This type of study usually provides a high-level picture of the literature on a specific topic, always accompanied by a critical evaluation of the methodology, design, and/or the quality of reporting of the studies included. Because relatively few resources are consumed to produce meta-research, these studies offer a great opportunity for clinical scientists who work in low-income countries. This article presents the principles of designing and conducting meta-research and proposes practical recommendations on how to perform and report this type of potentially very creative study.