Time to deterioration in cancer randomized clinical trials for patient-reported outcomes data: a systematic review.

PURPOSE: The time to deterioration (TTD) approach has been proposed as a modality of longitudinal analysis of patient-reported outcomes (PROs) in cancer randomized clinical trials (RCTs). The objective of this study was to perform a systematic review of how the TTD approach has been used in phase III RCTs to analyze longitudinal PRO data. METHODS: A systematic literature search was conducted in PubMed/MEDLINE, the Cochrane Library and through manual search to identify studies published between January 2014 and June 2018. All phase III cancer RCTs including a PRO endpoint using the TTD approach were considered. We collected general information about the study, PRO assessment and the TTD approach, such as the event definition, the choice of reference score and whether the deterioration was definitive or not. RESULTS: A total of 1549 articles were screened, and 39 studies were finally identified as relevant according to predefined criteria. Among these 39 studies, 36 (92.3%) were in advanced and/or metastatic cancer. Several different deterioration definitions were used in RCTs, 10 studies (25.6%) defined the deterioration as "definitive", corresponding to a deterioration maintained over time until the last PRO assessment available for each patient. The baseline score was explicitly stated as the reference score to qualify the deterioration for most studies (n = 31, 79.5%). CONCLUSION: This review highlights the lack of standardization of the TTD approach for the analysis of PRO data in RCTs. Special attention should be paid to the definition of "deterioration", and this should be based on the specific cancer setting.

PRODIG (Prevention of new onset diabetes after transplantation by a short term treatment of Vildagliptin in the early renal post-transplant period) study: study protocol for a randomized controlled study.

BACKGROUND: Post-transplant diabetes is a frequent and serious complication of kidney transplantation. There is currently no treatment to prevent or delay the disease. Nevertheless, identification of risk factors make it possible to target a population at risk of developing de novo diabetes. We hypothesized that a short-term treatment with vildagliptin may prevent new onset diabetes after transplantation (NODAT) in high-risk patients. METHODS/DESIGN: This is a multicenter, double-blind, placebo-controlled randomized clinical trial. Patients undergoing first kidney transplantation will be included from ten French transplant centers. Included patients will be randomized (1:1) to receive either vildagliptin 100 or 50 mg/day (depending on glomerular filtration rate) during 2 months (the first dose being administered before entering the operating theatres) or placebo. Additional antidiabetic therapy could be administered according to glycemic control. The primary outcome is the proportion of diabetic patients 1 year after transplantation, defined as patients receiving a diabetic treatment, or having a fasting glucose above 7 mmol/l, and/or with an abnormal oral glucose tolerance test. Secondary outcomes include glycated hemoglobin, the occurrence of acute rejection, infection, graft loss and patient death at 3 months, 6 months, and 12 months after transplantation. Outcomes will be correlated to clinical and general characteristics of the patient, cardiovascular history, nephropathy, dialysis history, transplantation data, biological data, health-related quality of life, and the cost-effectiveness of prevention of diabetes with vildagliptin. DISCUSSION: We have scarce data on the pharmacological prevention of post-transplant diabetes. If our hypothesis is verified, our results will have a direct application in clinical practice and could limit diabetes-associated morbidity, reduce cardiovascular complications, increase quality of life of renal transplant patients, and consequently promote graft and patient survival. Our results may possibly serve for non-transplant patients carrying a high-risk of diabetes associated with other co-morbidities. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02849899 . Registered on 8 February 2016.

RILA blood biomarker as a predictor of radiation-induced sarcoma in a matched cohort study.

PURPOSE: Radiation-induced sarcoma (RIS) is a rare but serious event. Its occurrence has been discussed during the implementation of new radiation techniques and justified appropriate radioprotection requirements. New approaches targeting intrinsic radio-sensitivity have been described, such as radiation-induced CD8 T-lymphocyte apoptosis (RILA) able to predict late radio-induced toxicities. We studied the role of RILA as a predisposing factor for RIS as a late adverse event following radiation therapy (RT). PATIENTS AND METHODS: In this prospective biological study, a total of 120 patients diagnosed with RIS were matched with 240 control patients with cancer other than sarcoma, for age, sex, primary tumor location and delay after radiation. RILA was prospectively assessed from blood samples using flow cytometry. RESULTS: Three hundred and forty-seven patients were analyzed (118 RIS patients and 229 matched control patients). A majority (74%) were initially treated by RT for breast cancer. The mean RT dose was comparable with a similar mean (± standard deviation) for RIS (53.7 ±â€¯16.0 Gy) and control patients (57.1 ±â€¯15.1 Gy) (p = .053). Median RILA values were significantly lower in RIS than in control patients with respectively 18.5% [5.5-55.7] and 22.3% [3.8-52.2] (p = .0008). Thus, patients with a RILA >21.3% are less likely to develop RIS (p < .0001, OR: 0.358, 95%CI [0.221-0.599]. CONCLUSION: RILA is a promising indicator to predict an individual risk of developing RIS. Our results should be followed up and compared with molecular and genomic testing in order to better identify patients at risk. A dedicated strategy could be developed to define and inform high-risk patients who require a specific approach for primary tumor treatment and long term follow-up.

RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study.

Background: RAS mutations are currently sought for in tumor samples, which takes a median of almost 3 weeks in western European countries. This creates problems in clinical situations that require urgent treatment and for inclusion in therapeutic trials that need RAS status for randomization. Analysis of circulating tumor DNA might help to shorten the time required to determine RAS mutational status before anti-epidermal growth factor receptor antibody therapy for metastatic colorectal cancer. Here we compared plasma with tissue RAS analysis in a large prospective multicenter cohort. Patients and methods: Plasma samples were collected prospectively from chemotherapy-naive patients and analyzed centrally by next-generation sequencing (NGS) with the colon lung cancer V2 Ampliseq panel and by methylation digital PCR (WIF1 and NPY genes). Tumoral RAS status was determined locally, in parallel, according to routine practice. For a minimal κ coefficient of 0.7, reflecting acceptable concordance (precision ± 0.07), with an estimated 5% of non-exploitable data, 425 subjects were necessary. Results: From July 2015 to December 2016, 425 patients were enrolled. For the 412 patients with available paired plasma and tumor samples, the κ coefficient was 0.71 [95% confidence interval (CI), 0.64-0.77] and accuracy was 85.2% (95% CI, 81.4% to 88.5%). In the 329 patients with detectable ctDNA (at least one mutation or one methylated biomarker), the κ coefficient was 0.89 (95% CI, 0.84-0.94) and accuracy was 94.8% (95% CI, 91.9% to 97.0%). The absence of liver metastases was the main clinical factor associated with inconclusive circulating tumor DNA results [odds ratio = 0.11 (95% CI, 0.06-0.21)]. In patients with liver metastases, accuracy was 93.5% with NGS alone and 97% with NGS plus the methylated biomarkers. Conclusion: This prospective trial demonstrates excellent concordance between RAS status in plasma and tumor tissue from patients with colorectal cancer and liver metastases, thus validating plasma testing for routine RAS mutation analysis in these patients. Clinical Trial registration: Clinicaltrials.gov, NCT02502656.

Phase III study of the European Organisation for Research and Treatment of Cancer satisfaction with cancer care core questionnaire (EORTC PATSAT-C33) and specific complementary outpatient module (EORTC OUT-PATSAT7).

Advances in cancer care delivery require revision and further development of questionnaires assessing patients' perceived quality of care. This study pre-tested the revised EORTC satisfaction with cancer care core questionnaire applicable in both the cancer inpatient and outpatient settings, and its new, outpatient-specific complementary module. The process of revision, development of the extended application, and pre-testing of these questionnaires was based on phases I to III of the "EORTC Quality of Life Group Module Development Guidelines." In phase III, patients in 11 countries in four European regions, South America and Asia completed provisional versions of the questionnaires. Fifty-seven relevant issues selected from literature reviews and input from experts were operationalized into provisional items, and subsequently translated into ten languages. Assessment of understanding, acceptability, redundancy and relevance by patients (n = 151) from oncology inpatient wards, and outpatient chemotherapy, radiotherapy and consultation settings, led to retention of, deletion of and merging of 40, 14 and 6 items respectively. Cronbach's alpha coefficients for hypothesized questionnaire scales were above 0.80. Our results provide preliminary support for the 33-item EORTC Satisfaction with cancer care core questionnaire and the 7-item complementary module specific for the outpatient care setting. A large scale phase IV cross-cultural psychometric study is now underway.

How health-related quality of life assessment should be used in advanced colorectal cancer clinical trials.

Traditionally, the efficacy of cancer treatment in patients with advance or metastatic disease in clinical studies has been studied using overall survival and more recently tumor-based end points such as progression-free survival, measurements of response to treatment. However, these seem not to be the relevant clinical end points in current situation if such end points were no validated as surrogate of overall survival to demonstrate the clinical efficacy. Appropriate, meaningful, primary patient-oriented and patient-reported end points that adequately measure the effects of new therapeutic interventions are then crucial for the advancement of clinical research in metastatic colorectal cancer to complement the results of tumor-based end points. Health-related quality of life (HRQoL) is effectively an evaluation of quality of life and its relationship with health over time. HRQoL includes the patient report at least of the way a disease or its treatment affects its physical, emotional and social well-being. Over the past few years, several phase III trials in a variety of solid cancers have assessed the incremental value of HRQoL in addition to the traditional end points of tumor response and survival results. HRQoL could provide not only complementary clinical data to the primary outcomes, but also more precise predictive and prognostic value. This end point is useful for both clinicians and patients in order to achieve the dogma of precision medicine. The present article examines the use of HRQoL in phase III metastatic colorectal cancer clinical trials, outlines the importance of HRQoL assessment methods, analysis, and results presentation. Moreover, it discusses the relevance of including HRQoL as a primary/co-primary end point to support the progression-free survival results and to assess efficacy of treatment in the advanced disease setting.

Subgroups and prognostication in stage III colon cancer: future perspectives for adjuvant therapy.

Since the MOSAIC study, oxaliplatin-based adjuvant chemotherapy has been the standard treatment of stage III colon cancer. Combination therapy with fluoropyrimidines and oxaliplatin has improved overall survival (OS) and reduced the risk of recurrence in patients with resected stage III colon cancer. However, only 20% of patients really benefit from adjuvant chemotherapy, exposing 80% of patients to unnecessary toxicity. Recent analyses of large multicenter adjuvant studies have focused on the prognostication of OS and disease-free survival in stage III colon cancer in order to reduce over-treatment and to find more accurate prognostic tools than those used for adjuvant treatment decision-making in stage II disease. Indeed, clinical and pathological prognostic factors, although important, are not sufficient to decide which stage III patients will benefit from adjuvant therapy, and biomarkers will help select patient that need adjuvant treatment. Molecular markers such as microsatellite status and BRAF and KRAS mutations have recently been explored, and molecular signatures have been identified as promising prognostic factor for OS. Furthermore, recent studies have highlighted the prognostic value of immune infiltration. This review focuses on pathologic, immunologic and molecular prognostic markers for stage III colon cancer that could help clinicians tailor adjuvant treatment in a comprehensive transversal approach.

Cancer-related fatigue management: evaluation of a patient education program with a large-scale randomised controlled trial, the PEPs fatigue study.

BACKGROUND: To assess the efficacy of a patient educational program built according to guidelines that aims at reducing cancer-related fatigue (CRF). METHODS: Randomised controlled trial, multicentre, comparing a patient education program, vs the standard of care. Patients were adult cancer outpatients with any tumour site. The primary outcome was fatigue severity assessed with a visual analogical scale (VAS), between the day of randomisation and week 7. Secondary outcomes were fatigue assessed with other scales, health-related quality of life, anxiety and depression. The time to fatigue severity deterioration was assessed. Analyses were performed in a modified intent-to-treat way, that is, including all patients with at least one baseline and 1 week 7 score. RESULTS: A total of 212 patients were included. Fatigue severity assessment was made on 79 patients in the experimental group and 65 in the control group. Between randomisation and week 7, the fatigue (VAS) improved by 0.96 (2.85) points in the experimental group vs 1.63 (2.63) points in the control group (P=0.15). No differences with the secondary outcomes were highlighted between two groups. No other factors were found to be associated with fatigue severity deterioration. CONCLUSIONS: Despite rigorous methodology, this study failed to highlight the program efficacy in fatigue reduction for cancer patients. Other assessment tools should be developed to measure the effect of the program on CRF and behaviour. The implementation of the program should also be explored in order to identify its mechanisms and longer-term impact.

Patients' perceived tolerance of side effects in phase I cancer clinical trials: A qualitative study.

This qualitative study aimed to explore cancer patients' perceived tolerance of side effects in phase I drug trials. Patients with solid tumours receiving molecularly targeted agents with/without chemotherapy were eligible for inclusion. In-depth semi-structured interviews were carried out with 17 patients with a median [range] age of 63 [41-72] years. Treatment was discontinued in seven patients. Verbatim transcripts of the audio-taped interviews were analysed using a constructivist grounded theory approach. Four conceptual categories emerged from data analysis, labelled "suffering from side effects" comprising a range of symptoms, psychosocial or role disturbances; "striving to cope with side effects" reflecting psychological strategies for managing side effects; "hoping" reflecting expectations about treatment efficacy and relief from side effects; and "appraisal of care." Among patients remaining in the trial, treatment was currently perceived as fairly tolerable. For most respondents, whether still in a trial or not, treatment discontinuation could not be justified by the non-tolerance of treatment side effects. These results question the adequacy of patient-perceived tolerance reports to determine an optimal drug dose for phase II trials. Confronted with patients' hopes and inappropriate beliefs, communication is challenging in phase I trials and could benefit from facilitating psychosocial interventions.

[Bevacizumab in combination with first-line treatment for metastatic non-small cell lung cancer in clinical practice. Results of the EOLE study]. / Bevacizumab en association à une première ligne de chimiothérapie chez des patients atteints d'un cancer bronchique non à petites cellules, non épidermoïde, à un stade avancé ou en rechute : résultats de l'étude non interventionnelle EOLE.

INTRODUCTION: The EOLE cohort aimed to describe, in routine clinical practice, the characteristics and management of patients receiving bevacizumab in combination with first-line metastatic chemotherapy for advanced metastatic or recurrent non squamous non-small cell lung cancer (nsNSCLC), as well as its efficacy and safety. METHODS: A total of 423 patients were enrolled in this prospective, national, multicenter study. Data were collected every 3 months over an 18-month period. RESULTS: Amongst the 407 patients analyzed (mean age 60±10 years, male 68%, ECOG-PS≤1 88%, smokers or former smokers 87%, cardiovascular comorbidities 40%), all except for 2 patients received bevacizumab (7.5 or 15mg/kg/3 weeks in 99% of patients) in combination with doublet chemotherapy. A total of 160 (60%) patients who completed induction received bevacizumab maintenance therapy. Median progression-free survival was 6.9 months (95% CI=[6.0-7.5]). Median overall survival (12.8 months [10.4-14.7]) was longer in patients with ECOG-PS≤1 (14.4 months [12.3-15.9] versus 4.9 months [3.4-8.3] if ECOG-PS=2). A total of 131 (32%) patients experienced at least one serious adverse event (SAE), and 51 (12%) at least one bevacizumab-related SAE. CONCLUSION: EOLE confirms the efficacy and safety of bevacizumab in aNSCLC patients, in current medical practice.

Perioperative docetaxel, cisplatin, and 5-fluorouracil compared to standard chemotherapy for resectable gastroesophageal adenocarcinoma.

BACKGROUND: Even though the perioperative chemotherapy improves the overall survival (OS) compared to surgery alone in patients with a resectable gastroesophageal adenocarcinoma (GEA), prognosis of these patients remains poor. Docetaxel (D), cisplatin (C), and 5-fluorouracil (F) regimen improves OS compared to CF among patients with advanced GEA. We evaluated the potential interest of a perioperative DCF regimen, compared to standard (S) regimens, in resectable GEA patients. METHODS: We identified 459 patients treated with preoperative DCF or S regimens. The primary endpoint was OS. Propensity scores were estimated with a logistic regression model in which all baseline covariates were included. We then used two methods to take PS into account and thus make DCF and S patients comparable. OS analyses were performed with Kaplan-Meier and Cox models in propensity score matched samples, and inverse probability of treatment weighted (IPTW) samples. RESULTS: In the propensity score matched sample, the p-value from the log rank test for OS was 0.0961, and the 3-year OS rate was 73% and 55% in DCF and S groups, respectively. The multivariate Cox regression underlined a Hazard Ratio of 0.55 (95% CI 0.27-1.13) for DCF patients compared to S patients. The results from IPTW analyses showed that DCF was significantly and independently associated with OS (HR = 0.52; 95% CI 0.40-0.69). CONCLUSIONS: In this retrospective multicenter, hypothesis-generating study, the propensity score analyses underlined encouraging results in favor of DCF compared to S regimens regarding OS. This promising result should be validated in a phase-3 trial.

Impact of pharmaceutical intervention on quality of life and coping strategies in patients with haematological malignancies.

OBJECTIVES: We conducted a prospective study approved by the local ethics committee to determine the impact of a pharmaceutical intervention (PI) on pain, fatigue, quality of life (QoL) and coping strategies in patients with HMs starting chemotherapy sessions. MATERIAL AND METHODS: Patients received either usual care (UC)+PI (PI group) or UC alone (UC group). They had to complete 2 questionnaires, QLQ-C30 and MAC 21, at 3 different time points: before starting the 1st chemotherapy session (T1), during the intercure (T2) and the day before starting the 2nd chemotherapy session (T3). To determine predictive factors of pain, fatigue, QoL and coping scores at T3, a multivariate ANOVA was used. QoL and coping scores were analysed longitudinally using a linear mixed model. RESULTS: Sixty-eight patients were included in the PI (n=34) or UC groups (n=34). Ninety-two percent of the patients returned all the questionnaires. At inclusion, QoL was significantly better in the PI group (P=0.047). At T3, the group had no influence on pain, fatigue, nor coping scores but a trend towards a better QoL was observed in the PI group (P=0.090). Longitudinally, the PI group did not present significantly better scores on pain, fatigue but both a trend toward better Qol scores and lower anxious preoccupations scores. CONCLUSION: A PI at the beginning of chemotherapy sessions did not have any significant impact on pain and fatigue but a trend towards better Qol scores and lower anxious preoccupations scores.

A phase I dose escalation study using simultaneous integrated-boost IMRT with temozolomide in patients with unifocal glioblastoma.

PURPOSE: To evaluate the maximum tolerated dose of simultaneous integrated-boost intensity-modulated radiotherapy (SIB-IMRT) associated with temozolomide in patients with glioblastoma. PATIENTS AND METHODS: Between November 2009 and January 2012, nine patients with malignant glioma were enrolled in this phase I clinical trial. Radiotherapy was delivered using fractions of 2.5Gy on the planning target volume b and of 1.9Gy on the planning target volume a. Volumes were defined as follow: gross tumour volume b: tumour taking up contrast on T1 weighted MRI images; clinical target volume b: gross tumour volume b+0.5cm (adapted to the anatomical structures) and lastly planning target volume b: clinical target volume b+0.5cm; gross tumour volume a: tumour (gross tumour volume b)+2cm and including oedema outlined on T2Flair MRI sequences; clinical target volume a gross tumour volume a+0.5cm (adapted to the anatomical structures); planning target volume a: clinical target volume a+0.5cm. Three patients were enrolled at each of the three levels of dose (70, 75 and 80Gy prescribed on the planning target volume b and 56, 60 and 60.8Gy on the planning target volume a). Radiotherapy was delivered with temozolomide according to the standard protocol. Dose-limiting toxicities were defined as any haematological toxicities at least grade 4 or as any radiotherapy-related non-haematological acute toxicities at least grade 3, according to the Common Terminology Criteria for Adverse Events, version 3.0. RESULTS: Until the last dose level of 80Gy, no patient showed dose-limiting toxicity. CONCLUSIONS: SIB-IMRT, at least until a dose of 80Gy in 32 daily fractions, associated with temozolomide is feasible and well tolerated.

[Practices and attitudes regarding HPV vaccination among general practitioners from Besançon]. / Pratiques et attitudes des médecins généralistes de Besançon vis-à-vis de la vaccination anti-HPV.

OBJECTIVES: To assess opinions, practices and difficulties of general practitioners (GP) of Besançon concerning human papillomavirus (HPV) vaccination. MATERIALS AND METHODS: A survey among the 140 GP of Besançon, France, was conducted in 2015. RESULTS: A percentage of 77.1 reported being favourable to HPV vaccination and 72.9% practices HPV vaccination. The 2 main concerns about HPV vaccination for GP are the fear of side effects (for 40.6% of GP) and the doubt on efficacy. According to GP, the hepatitis B vaccination controversy, the fear of side effects, the limited clinical efficacy experience and the lack of confidence in health authorities are concerns about HPV vaccination for 77.1%, 76%, 74% and 49% of patients, respectively. CONCLUSION: Courses for GP on HPV vaccination must be pursued and reinforced. A school-based program could be developed to facilitate communication between GP and patients to improve HPV vaccination coverage.

[Fat grafting in breast reconstruction. Retrospective study of satisfaction and quality of life about 68 patients]. / Lipofilling en reconstruction mammaire. Étude rétrospective de la satisfaction et de la qualité de vie à propos de 68 patientes.

BACKGROUND: Evaluate the aesthetic clinical results, satisfaction and quality of life related to health in patients who underwent breast reconstruction by exclusive lipofilling or in addition to other surgical techniques. MEANS AND METHODS: A retrospective observational study was carried between 2009 and 2014 in four groups of patients who underwent a lipofilling by the same operator either after a conservative treatment (group 1), or exclusively (group 2), or after a flap (group 3) or implants (group 4). The sociodemographic data related to lipofilling or tumor pathology were collected and reported in a software designed for this study. Satisfaction and quality of life after lipofilling was assessed using the questionnaire Q BREAST(©) postoperative reconstruction module. RESULTS: One hundred and seventy lipofilling procedures were performed in 68 patients. The average volume transferred was 1421.2cm(3) for the exclusive lipofilling group and the average number of sessions was 4.9 spread over a period of 15.6months on average. In adjuvant technique or conservative surgery, the average total volume transferred was 212.2cm(3) and the average number of sessions was 1.4. The abdomen was the site most used donor and the posterior thigh exclusively used in exclusive reconstruction. The cytosteatonecrosis rate was 8.8 % (n=6). A single case of infection was noted. The tumor recurrence at ten months after lipofilling concerned two patients. The response rate was 80.8 %. The lipofilling improves the final cosmetic result with a rate of 91.1 % of patients satisfied or very satisfied with their breast. In all, 95.4 % of patients in the exclusive lipofilling group found a secondary benefit after surgery. Quality of life after lipofilling is also improved socially and sexually in the four groups with better results in patients who underwent conservative treatment. CONCLUSION: The lipofilling is a simple, reliable technique, requiring a learning curve, improving the final aesthetic result and the quality of life it is used exclusively or to complement other techniques.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

Predictors of disease-free survival in colorectal cancer with microsatellite instability: An AGEO multicentre study.

BACKGROUND: A microsatellite instability (MSI) phenotype is found in about 12% of colorectal cancers (CRCs) and is associated with a low recurrence rate after curative surgery. Several studies have identified clinical and pathological factors predictive of recurrence in resected CRC, but not in the MSI subgroup. PATIENTS AND METHODS: This multicentre retrospective study included patients with stage I, II or III MSI CRCs. Disease-free survival (DFS) was calculated with the Kaplan-Meier method. Factors associated with DFS were identified in univariate and multivariate Cox analyses. RESULTS: We studied 521 patients with MSI CRC. Respectively 11%, 51% and 38% of patients were at stage I, II and III. Mean age was 68.7years and 36% of the patients received adjuvant chemotherapy. Median follow-up was 32.8months. The disease recurrence rates were 6% and 21% in stage II and III patients, respectively. The 3-year DFS rate was 77%. In univariate analysis, age, bowel obstruction, lymph node invasion, stage T4, vascular emboli, lymphatic invasion and perinervous invasion were associated with poorer DFS (P<0.05). Three relevant independent predictors of poor DFS were identified in multivariate analysis, namely bowel obstruction (HR=2.46; 95%CI 1.31-4.62, P=0.005), vascular emboli (HR=2.79; 95%CI 1.74-4.47, P<0.001) and stage T4 (HR=2.16; 95%CI 1.31-3.56, P=0.002). CONCLUSIONS: Bowel obstruction, vascular emboli and stage T4 are independently associated with MSI CRC recurrence, suggesting that screening for vascular emboli in routine clinical practice may assist with adjuvant chemotherapy decision-making.

Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: Using surrogate end points for overall survival, such as disease-free survival, is increasingly common in randomized controlled trials. However, the definitions of several of these time-to-event (TTE) end points are imprecisely which limits interpretation and cross-trial comparisons. The estimation of treatment effects may be directly affected by the definitions of end points. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for randomized cancer clinical trials (RCTs) in breast cancer. PATIENTS AND METHODS: A literature review was carried out to identify TTE end points (primary or secondary) reported in publications of randomized trials or guidelines. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points based on a validated consensus method that formalize the degree of agreement among experts. RESULTS: Recommended guidelines for the definitions of TTE end points commonly used in RCTs for breast cancer are provided for non-metastatic and metastatic settings. CONCLUSION: The use of standardized definitions should facilitate comparisons of trial results and improve the quality of trial design and reporting. These guidelines could be of particular interest to those involved in the design, conducting, reporting, or assessment of RCT.