A randomized phase II study of weekly nab-paclitaxel plus gemcitabine or simplified LV5FU2 as first-line therapy in patients with metastatic pancreatic cancer: the AFUGEM GERCOR trial

International audienceBackground : Metastatic pancreatic adenocarcinoma (PAC) prognosis remains dismal and gemcitabine monotherapy has been the standard treatment over the last decade. Currently, two first-line regimens are used in this setting: FOLFIRINOX and nab-paclitaxel plus gemcitabine. Increasing translational data on the predictive value of hENT1 for determining gemcitabine efficacy suggest that a non-gemcitabine-based regimen is favored in about 60 % of patients with PAC due to high resistance of PAC to this cytotoxic drug. This study aims to evaluate the efficacy of weekly nab-paclitaxel combined with gemcitabine or a simplified (s) LV5FU2 regimen in patients with previously untreated metastatic PAC.Methods/design : AFUGEM is a two-stage, open-label, randomized, multicenter, phase II trial. Patients with PAC who meet the inclusion criteria and provide written informed consent will be randomized in a 1:2 ratio to either nab-paclitaxel (125 mg/m 2 ) plus gemcitabine (1000 mg/m 2 ) given on days 1, 8, and 15 every 28 days or nab-paclitaxel (125 mg/m 2 ) plus sLV5FU2 (leucovorin 400 mg/m 2 followed by bolus 400 mg/m 2 5-fluorouracil and by 5-fluorouracil 2400 mg/m 2 as an 46-h intravenous infusion) given on days 1 and 15 every 28 days. A total of 114 patients will be randomized to one of the treatment arms. The primary endpoint is progression-free survival at 4 months. Secondary outcomes are rate and duration of response, disease control, overall survival, safety, and quality of life. Potential biomarkers of gemcitabine (hENT1, dCK) and 5-fluorouracil (TS) efficacy will be assessed.Discussion : The AFUGEM trial is designed to provide valuable information regarding efficacy and tolerability of nab-paclitaxel plus gemcitabine and nab-paclitaxel plus sLV5FU2 regimens. Identification of potential predictive biomarkers of gemcitabine and 5-fluorouracil is likely to drive therapeutic decisions in patients with metastatic PAC

STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer

International audienceBackground: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. Methods/Design: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies.Discussion: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. Trial registration: STRATEGIC-1 is registered a

Association of Bevacizumab Plus Oxaliplatin-Based Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II Colon Cancer A Secondary Analysis of the AVANT Trial

IMPORTANCE: In the pivotal Bevacizumab-Avastin Adjuvant (AVANT) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin-based chemotherapy; however, the trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial. OBJECTIVE: To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC. DESIGN, SETTING, AND PARTICIPANTS: This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019. INTERVENTION: Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab. MAIN OUTCOMES AND MEASURES The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC. RESULTS The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4. CONCLUSIONS AND RELEVANCE: In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited

Trajectories of body weight change and survival among patients with mCRC treated with systemic therapy: Pooled analysis from the ARCAD database

Background Higher body mass index is associated with a higher incidence of colorectal cancer (CRC) but also with improved survival in metastatic CRC (mCRC). Whether weight change after mCRC diagnosis is associated with survival remains largely unknown. Methods We analysed individual patient data for previously untreated patients enrolled in five phase 3 randomised trials conducted between 1998 and 2006. Weight measurements were prospectively collected at baseline and up to 59.4 months after diagnosis. We used stratified multivariable Cox models to assess the prognostic associations of weight loss with overall and progression-free survival, adjusting for other factors. The primary end-point was a difference in overall survival (OS) between populations with weight loss and stable or increasing weight. Findings Data were available for 3504 patients. The median weight change at 3 months was −0.54% (IQR −3.9 … +1.5%). We identified a linear trend of increasing risk of death associated with progressive weight loss. Unstratified median OS was 20.5, 18.0, and 11.9 months (p < 0.001) for stable weight or gain, <5% weight loss, and ≥5% weight loss at 3 months, respectively. Weight loss was associated with a higher risk of death (<5% loss: aHR 1.18 [1.06–1.30], p < 0.002; ≥5% loss: aHR 1.87 [1.67–2.1], p < 0.001) as compared to stable or increasing weight at 3 months post-baseline (reference), while adjusting for age, sex, performance, and a number of metastatic sites. Interpretation Patients losing weight during systemic therapy for metastatic colorectal cancer have significantly shorter OS. The degree of weight loss is proportional to the observed increased risk of death and remains evident among underweight, normal weight, and obese individuals. On-treatment weight change could be used as an intermediate end-point

Treatment breaks in first line treatment of advanced colorectal cancer: an individual patient data meta-analysis

Background Intermittent systemic anti-cancer therapy in patients with advanced colorectal cancer (aCRC) may improve quality of life without compromising overall survival (OS). We aimed to use individual patient data meta-analysis (IPDMA) from multiple randomised controlled trials evaluating intermittent strategies to inform clinical practice. We also aimed to validate whether thrombocytosis as a predictive biomarker identified patients with significantly reduced OS receiving a complete treatment break. Patients and Methods An IPDMA of intermittent strategy impact on survival was undertaken, including all relevant trials in which data were available. Intermittent strategies were classified into two groups: a planned stopping of all therapy (“treatment break strategy”; 6 trials; 2,907 patients) or to the same treatment omitting oxaliplatin (“maintenance strategy”; 3 trials; 1,271 patients). The primary analysis sample was of patients successfully completing induction therapy. Additionally, a pre-planned analysis of the predictive value of thrombocytosis on survival under a continuous versus an intermittent strategy was undertaken. Results All trials had comparable inclusion criteria. The overall IPDMA of intermittent therapy versus continuous therapy demonstrated no detriment in OS (HR=1.03 [95% CI 0.93-1.14]), whether from complete break (HR 1.04 [95% CI 0.87-1.26]) or maintenance strategies (HR 0.99 [95% CI 0.87-1.13]). Thrombocytosis was confirmed as a marker of poor prognosis in aCRC, but did not predict for OS detriment from treatment break strategies (interaction HR=0.97 [95% CI 0.66-1.40] compared to continuous therapy). Conclusion The highest levels of evidence from this IPMDA indicate no detriment in survival for patients receiving an intermittent therapy strategy, either for maintenance or complete break strategies. Although, thrombocytosis is confirmed as a marker of poor prognosis, it is not predictive of poor outcome for patients treated with intermittent therapy. An intermittent chemotherapy strategy can therefore be applied irrespective of baseline platelet count and does not result in inferior OS compared to continuous chemotherapy

Clinical Calculator for Early Mortality in Metastatic Colorectal Cancer: An Analysis of Patients From 28 Clinical Trials in the Aide et Recherche en Cancérologie Digestive Database

Purpose: Factors contributing to early mortality after initiation of treatment of metastatic colorectal cancer are poorly understood. Materials and Methods: Data from 22,654 patients enrolled in 28 randomized phase III trials contained in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were pooled. Multivariable logistic regression models for 30-, 60-, and 90-day mortality were constructed, including clinically and statistically significant patient and disease factors and interaction terms. A calculator (nomogram) for 90-day mortality was developed and validated internally using bootstrapping methods and externally using a 10% random holdout sample from each trial. The impact of early progression on the likelihood of survival to 90 days was examined with time-dependent Cox proportional hazards models. Results: Mortality rates were 1.4% at 30 days, 3.4% at 60 days, and 5.5% at 90 days. Among baseline factors, advanced age, lower body mass index, poorer performance status, increased number of metastatic sites, BRAF mutant status, and several laboratory parameters were associated with increased likelihood of early mortality. A multivariable model for 90-day mortality showed strong internal discrimination (C-index, 0.77) and good calibration across risk groups as well as accurate predictions in the external validation set, both overall and within patient subgroups. Conclusion: A validated clinical nomogram has been developed to quantify the risk of early death for individual patients during initial treatment of metastatic colorectal cancer. This tool may be used for patient eligibility assessment or risk stratification in future clinical trials and to identify patients requiring more or less aggressive therapy and additional supportive measures during and after treatment

Impact of geography on prognostic outcomes of 21,509 patients with metastatic colorectal cancer enrolled in clinical trials: an ARCAD database analysis

Impact of geography on prognostic outcomes of 21,509 patients with metastatic colorectal cancer enrolled in clinical trials: an ARCAD database analysis Show less Jun Yin*, Shaheenah Dawood*, Romain Cohen, Jeff Meyers, John Zalcberg, Takayuki Yoshino, Matthew Seymour, Tim Maughan, Leonard Saltz, Eric Van Cutsem, Alan Venook, Hans-Joachim Schmoll, Richard Goldberg, Paulo Hoff, J. Randolph Hecht, Herbert Hurwitz, Cornelis Punt, Eduard Diaz Rubio, Miriam Koopman, Chiara Cremolini, Volker Heinemann, Christophe Tournigard, Carsten Bokemeyer, Charles Fuchs, Niall Tebbutt, John Souglakos, Jean-Yves Doulliard, Fairooz Kabbinavar, Benoist Chibaudel, Aimery de Gramont, Qian Shi, Axel Grothey, Richard AdamsFirst Published June 30, 2021 Research Article https://doi.org/10.1177/17588359211020547 Article information Article has an altmetric score of 7 Open AccessCreative Commons Attribution, Non Commercial 4.0 License Article Information Volume: 13 Article first published online: June 30, 2021; Issue published: January 1, 2021 Received: December 29, 2020; Accepted: May 05, 2021 Jun Yin* Department of Health Sciences Research, Mayo Clinic, 200 First Street, SW Rochester, MN 55905, USA Shaheenah Dawood* Mediclinic City Hospital: North Wing, Dubai Health Care City, Dubai UAE Romain Cohen Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA Jeff Meyers Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA John Zalcberg School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia Takayuki Yoshino Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan Matthew Seymour NIHR Clinical Research Network, Leeds, UK Tim Maughan CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, UK Leonard Saltz Memory Sloan Kettering Cancer Center, New York, NY, USA Eric Van Cutsem Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium Alan Venook Department of Medicine, The University of California San Francisco, San Francisco, CA, USA Hans-Joachim Schmoll Klinik fur Innere Med IV, University Clinic Halle, Saale, Germany Richard Goldberg Department of Oncology, West Virginia University, Morgantown, WV, USA Paulo Hoff Centro de Oncologia de Brasilia do Sirio Libanes: Unidade Lago Sul, Siro Libanes, Brazil J. Randolph Hecht Ronald Reagan UCLA Medical Center, UCLS Medical Center, Santa Monica, CA, USA Herbert Hurwitz Duke Cancer Institute, Duke University, Durham, NC, USA Cornelis Punt Department of Medical Oncology, University of Amsterdam, Amsterdam, The Netherlands Eduard Diaz Rubio Department Oncology, Hospital Clínico San Carlos, Madrid, Spain Miriam Koopman Department of Medical Oncology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands Chiara Cremolini Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy Volker Heinemann Department of Medical Oncology and Comprehensive Cancer Center, University of Munich, Munich, Germany Christophe Tournigard Hopital Henri Mondor, Creteil, France Carsten Bokemeyer Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Charles Fuchs Director of Yale Cancer Center, Boston, MA, USA Niall Tebbutt Sydney Medical School, University of Sydney, Sydney, Australia John Souglakos University of Crete, Heraklion, Greece Jean-Yves Doulliard University of Nantes Medical School, Nantes, France Fairooz Kabbinavar UCLA Medical Center, Santa Monica, CA, USA Benoist Chibaudel Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France Aimery de Gramont Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France Qian Shi Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA Axel Grothey West Cancer Center, Germantown, TN, USA Richard Adams Cardiff University and Velindre Cancer Center, Cardiff, UK Corresponding Author: [email protected] *Co-first authors. https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage). Abstract Background: Benchmarking international cancer survival differences is necessary to evaluate and improve healthcare systems. Our aim was to assess the potential regional differences in outcomes among patients with metastatic colorectal cancer (mCRC) participating in international randomized clinical trials (RCTs). Design: Countries were grouped into 11 regions according to the World Health Organization and the EUROCARE model. Meta-analyses based on individual patient data were used to synthesize data across studies and regions and to conduct comparisons for outcomes in a two-stage random-effects model after adjusting for age, sex, performance status, and time period. We used mCRC patients enrolled in the first-line RCTs from the ARCAD database, which provided enrolling country information. There were 21,509 patients in 27 RCTs included across the 11 regions. Results: Main outcomes were overall survival (OS) and progression-free survival (PFS). Compared with other regions, patients from the United Kingdom (UK) and Ireland were proportionaly over-represented, older, with higher performance status, more frequently male, and more commonly not treated with biological therapies. Cohorts from central Europe and the United States (USA) had significantly longer OS compared with those from UK and Ireland (p = 0.0034 and p < 0.001, respectively), with median difference of 3–4 months. The survival deficits in the UK and Ireland cohorts were, at most, 15% at 1 year. No evidence of a regional disparity was observed for PFS. Among those treated without biological therapies, patients from the UK and Ireland had shorter OS than central Europe patients (p < 0.001). Conclusions: Significant international disparities in the OS of cohorts of mCRC patients enrolled in RCTs were found. Survival of mCRC patients included in RCTs was consistently lower in the UK and Ireland regions than in central Europe, southern Europe, and the USA, potentially attributed to greater overall population representation, delayed diagnosis, and reduced availability of therapies

Metastatic colorectal cancer outcomes by age among ARCAD first- and second-line Clinical trials

Background We evaluated the time to progression (TTP) and survival outcomes of second-line therapy for metastatic colorectal cancer among adults aged 70 years and older compared with younger adults following progression on first-line clinical trials. Methods Associations between clinical and disease characteristics, time to initial progression, and rate of receipt of second-line therapy were evaluated. TTP and overall survival (OS) were compared between older and younger adults in first- and second-line trials by Cox regression, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, number of metastatic sites and presence of metastasis in the lung, liver, or peritoneum. All statistical tests were 2-sided. Results Older adults comprised 16.4% of patients on first-line trials (870 total older adults aged >70 years; 4419 total younger adults aged ≤70 years, on first-line trials). Older adults and those with Eastern Cooperative Oncology Group Performance Status >0 were less likely to receive second-line therapy than younger adults. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariable analysis (odds ratio = 1.11, 95% confidence interval = 1.02 to 1.21, P = .01). Older and younger adults enrolled in second-line trials experienced similar median TTP and median OS (median TTP = 5.1 vs 5.2 months, respectively; median OS = 11.6 vs 12.4 months, respectively). Conclusions Older adults were less likely to receive second-line therapy for metastatic colorectal cancer, though we did not observe a statistical difference in survival outcomes vs younger adults following second-line therapy. Further study should examine factors affecting decisions to treat older adults with second-line therapy. Inclusion of geriatric assessment may provide better criteria regarding the risks and benefits of second-line therapy

Evaluation of intratumoral response heterogeneity in metastatic colorectal cancer and Its impact on patient overall survival: findings from 10,551 patients in the ARCAD database

Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS). Patients and Methods: Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic. Results: Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant. Conclusion: Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes

Prise en charge des patients atteints de cancer colorectal métastatique, Kras muté, après échec des traitements à base d'oxaliplatine et d'irinotécan selon les schémas classiques

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