70 research outputs found
Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies
Background: Bevacizumab is frequently combined with 5-fluorouracil-based chemotherapy for patients with metastatic colorectal cancer (mCRC). The relative benefit of bevacizumab in older patients has not been widely studied and is of interest.
Patients and methods: This retrospective analysis used data from three first-line randomized controlled studies and one second-line randomized controlled study of bevacizumab plus chemotherapy in medically fit (Eastern Cooperative Oncology Group performance status 0 or 1) patients with mCRC. Overall survival (OS) and on-treatment progression-free survival (PFS) were assessed in patients aged greater than 65, greater than or equal to 65, and greater than or equal to 70 years. Results were compared using unstratified hazard ratios (HRs). Grade 3-5 adverse events were also assessed.
Results: Bevacizumab statistically significantly improved PFS [HR 0.58; 95% confidence interval (CI) 0.49-0.68] and OS (HR 0.85; 95% CI 0.74-0.97) in patients aged greater than or equal to 65 years; patients aged greater than or equal to 70 years had similar improvements. Benefits were consistent across the studies, irrespective of setting, bevacizumab dose, or chemotherapy regimen. Increases in thromboembolic events were observed in patients aged greater than or equal to 65 and greater than or equal to 70 years in the bevacizumab group compared with the control group, mainly as a result of increases in arterial thromboembolic events. No other substantial age-related increases in grade 3-5 adverse events were observed.
Conclusions: In medically fit older patients, bevacizumab provides similar PFS and OS benefits as in younger patients
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
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 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
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
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
Combined Analysis of Efficacy: The Addition of Bevacizumab to Fluorouracil/Leucovorin Improves Survival for Patients With Metastatic Colorectal Cancer
Dacomitinib, an irreversible Pan-ErbB inhibitor significantly abrogates growth in head and neck cancer models that exhibit low response to cetuximab.
Aberrant epidermal growth factor (EGF) signaling is associated with tumor growth in squamous cell carcinoma of the head and neck in humans (HNSCC), and is a major focus of targeted therapy. Cetuximab, a monoclonal antibody against EGFR, has been successful at prolonging survival but has only a 10% tumor shrinkage response rate in a clinical setting. The goal of this study was to compare dacomitinib (PF-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple HER family receptors (HER-1 (EGFR), HER-2 and HER-4 tyrosine kinases), to cetuximab, the current FDA approved anti-EGFR medication for HNSCC and erlotinib, an EGFR specific small molecule tyrosine kinase inhibitor. Dacomitinib, erlotinib and cetuximab were tested in a panel of 27 HNSCC cell lines. Treatment with 100 ug/ml of cetuximab or 1 uM of erlotinib inhibited growth by at least 50% in 7/27 cell lines, while treatment with 1 uM of dacomitinib had similar growth inhibition in 17/27 lines. Cell lines representing three levels of sensitivity to dacomitinib were further examined using Western blots, cell cycle and apoptosis analysis. Treatment with 100 nM of dacomitinib reduced EGFR activity and downstream AKT and ERK pathways more effectively than treatment with 100 ug/ml of cetuximab in all ten tested lines. Although both compounds induced apoptosis at similar levels, dacomitinib caused greater G0/G1 arrest. Sensitivity to EGFR blockade was associated with levels of EGFR and ERK and was not associated with common oncogenic mutations and copy number variations. Phosphorylated and total EGFR and ERK levels correlate with sensitivity to both cetuximab and dacomitinib. Three of the four lines in the exquisitely sensitive group had the highest levels of phosphorylated and total EGFR and ERK among the ten lines selected, while the three resistant lines collectively had the lowest levels. Neither pAKT nor tAKT was associated with sensitivity
Phase II, Randomized Trial Comparing Bevacizumab Plus Fluorouracil (FU)/Leucovorin (LV) With FU/LV Alone in Patients With Metastatic Colorectal Cancer
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