Characteristics of Patients and Prognostic Factors Across Treatment Lines in Metastatic Colorectal Cancer: An Analysis From the Aide et Recherche en Canérologie Digestive Database

Jean-Baptiste Bachet (1), Aimery de Gramont (2,3), Morteza Raeisi (4), Manel Rakez (4), Richard M. Goldberg (5), Niall C. Tebbutt (6), Eric Van Cutsem (7), Daniel G. Haller (8), J. Randolph Hecht (9) Robert J. Mayer (10), Stuart M. Lichtman (11), Al B. Benson (12), Alberto F. Sobrero (13), Josep Tabernero (14), Richard Adams (15), John R. Zalcberg (16), Axel Grothey (17), Takayuki Yoshino (18), Thierry André (3,19), Qian Shi (20), Benoist Chibaudel (2)
(1) Hepato-gastroenterology and Digestive Oncology Department, Pitiè Salpêtrière Hospital, APHP, Sorbonne Universitê, Paris, France
(2) Department of Medical Oncology, Franco-British Hospital, Fondation Cognacq-Jay, Cancèrologie Paris Ouest, Levallois-Perret, France
(3) ARCAD Foundation, Paris, France
(4) Statistical Unit, ARCAD Foundation, Paris, France
(5) Department of Medicine, West Virginia University Cancer Institute, Morgantown, WV
(6) Department of Medical Oncology, Olivia Newton-John Cancer, Wellness and Research Centre, Austin Health, Heidelberg, VIC, Australia
(7) Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium
(8) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
(9) UCLA Jonsson Comprehensive Cancer Center, Santa Monica, CA
(10) Dana-Farber Cancer Institute, Boston, MA
(11) Wilmot Cancer Institute Geriatric Oncology Research Group, University of Rochester, Rochester, NY
(12) Division of Hematology/Oncology, Northwestern University’s Feinberg School of Medicine, Chicago, IL
(13) Department of Medical Oncology, Ospedale San Martino, Genoa, Italy
(14) Vall d’Hebron Hospital Campus and Vall d’Hebron Institute of Oncology (VHIO), IOB-Quiron, Barcelona, Spain
(15) Cardiff University and Velindre Cancer Centre, Cardiff, United Kingdom
(16) Department of Medical Oncology, Monash University School of Public Health and Preventive Medicine, Alfred Health, Melbourne, VIC, Australia
(17) West Cancer Center, Germantown, TN
(18) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
(19) Department of Medical Oncology, Saint Antoine Hospital, APHP, Sorbonne Universitè, Paris, France
(20) Department of Quantitative Health Sciences, Mayo CLinic, ROchester, MN

Purpose: Several lines of treatment can be used sequentially in patients with metastatic colorectal cancer. We investigated the evolution of patient/tumor characteristics and their prognostic impact across treatment lines to
develop an overall prognostic score (OPS).

Patients and methods: Individual patient data from 48 randomized trials were analyzed. The end point was overall survival (from random assignment to death). Missing data were imputed. The complete data set was then separated into construction (80%) and validation sets (20%). The Cox’s model was used to define risk groups for survival using the OPS. The discrimination capability was assessed in each treatment-line via bootstrapping to obtain optimism corrected calibration and discrimination C-indices. Internal validation was done in the validation set.

Results: A total of 37,560 patients (26,974 in first-line [1L], 7,693 in second-line [2L], and 2,893 in third-line [3L]) were analyzed. Some clinical, biological, and molecular characteristics of patients/tumors included in therapeutic trials evolve over the lines. Seven independent prognostic variables were retained in the final multivariate model common to all lines: Eastern Cooperative Oncology Group performance status, hemoglobin, platelet count, WBC/absolute neutrophil count ratio, lactate dehydrogenase, alkaline phosphatase, and the number of metastatic sites. The OPS was used to define four patient subgroups with significantly different prognoses in 1L, 2L, and 3L, separately, with adequate C-indices: 0.65, 0.66, and 0.69 in the construction set and 0.65, 0.66, and 0.68 in the validation set, respectively. The OPS was not predictive, with 3L drugs (v placebo) or subsequent line (2L/1L or 3L/2L) extending survival in all prognostic groups.

Conclusion: The same prognostic model using practical variables can be used before all treatment lines. The OPS
could better stratify patients in future clinical trials and help to therapeutic decision in routine practice.