73 research outputs found
A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Simtuzumab in Combination with FOLFIRI for the Second-Line Treatment of Metastatic KRAS Mutant Colorectal Adenocarcinoma.
Lessons learnedThe safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group.The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma.BackgroundSimtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase-like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro.MethodsPatients with metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant CRC were randomized to receive second-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were assessed.ResultsIn total, 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg (n = 84), FOLFIRI/simtuzumab 200 mg (n = 85), and FOLFIRI/placebo (n = 80). After a median follow-up of 5.1, 3.8, and 5.5 months, respectively, median PFS for each of the respective treatment groups was 5.5 months (adjusted HR [95% CI], p value versus placebo; 1.32 [0.92, 1.89]; p = .10), 5.4 months (1.45 [1.01, 2.06]; p = .04), and 5.8 months. Median OS was 11.4 months (1.23 [0.80, 1.91]; p = .25), 10.5 months (1.50 [0.98, 2.30]; p = .06), and 16.3 months, respectively. ORR was 11.9%, 5.9%, and 10%, respectively. Simtuzumab was tolerable in metastatic KRAS mutant CRC patients.ConclusionThe addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC. The Oncologist 2017;22:243-e8
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
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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 ClĂnico 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
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Next-Generation Approaches to Immuno-Oncology in GI Cancers.
Immunotherapy has only had a modest impact on the treatment of advanced GI malignancies. Microsatellite-stable colorectal cancer and pancreatic adenocarcinoma, the most common GI tumors, have not benefited from treatment with standard immune checkpoint inhibitors. With this huge unmet need, multiple approaches are being tried to overcome barriers to better anticancer outcomes. This article reviews a number of novel approaches to immunotherapy for these tumors. These include the use of novel checkpoint inhibitors such as a modified anti-cytotoxic T lymphocyte-associated antigen-4 antibody and antibodies to lymphocyte-activation gene 3, T cell immunoreceptor with immunoglobulin and ITIM domains, T-cell immunoglobulin-3, CD47, and combinations with signal transduction inhibitors. We will discuss other trials that aim to elicit an antitumor T-cell response using cancer vaccines and oncolytic viruses. Finally, we review attempts to replicate in GI cancers the frequent and durable responses seen in hematologic malignancies with immune cell therapies
Recommended from our members
A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Simtuzumab in Combination with FOLFIRI for the Second-Line Treatment of Metastatic KRAS Mutant Colorectal Adenocarcinoma.
Lessons learnedThe safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group.The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma.BackgroundSimtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase-like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro.MethodsPatients with metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant CRC were randomized to receive second-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were assessed.ResultsIn total, 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg (n = 84), FOLFIRI/simtuzumab 200 mg (n = 85), and FOLFIRI/placebo (n = 80). After a median follow-up of 5.1, 3.8, and 5.5 months, respectively, median PFS for each of the respective treatment groups was 5.5 months (adjusted HR [95% CI], p value versus placebo; 1.32 [0.92, 1.89]; p = .10), 5.4 months (1.45 [1.01, 2.06]; p = .04), and 5.8 months. Median OS was 11.4 months (1.23 [0.80, 1.91]; p = .25), 10.5 months (1.50 [0.98, 2.30]; p = .06), and 16.3 months, respectively. ORR was 11.9%, 5.9%, and 10%, respectively. Simtuzumab was tolerable in metastatic KRAS mutant CRC patients.ConclusionThe addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC. The Oncologist 2017;22:243-e8
Phase I and IIa studies of simtuzumab alone and in combination with FOLFIRI in patients with advanced solid tumors.
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