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

Abstract

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.

FIG 1.

Flow diagram of the population study. ARCAD, Aide et Recherche en Cancérologie Digestive; OS, overall survival; PFS, progression-free survival.

FIG 2.

OS curves according to four risk classes of the prognostic model in 2L treatment of patients with mCRC from (A) construction set and (B) validation set. 2L, second-line; HR, hazard ratio; mCRC, metastatic colorectal cancer; OS, overall survival.

FIG 3.

OS curves according to four risk classes of the prognostic model in 3L treatment of patients with mCRC from (A) construction set and (B) validation set. 3L, third-line; HR, hazard ratio; mCRC, metastatic colorectal cancer; OS, overall survival.

FIG 4.

OS curves according to four risk classes of the prognostic model in 1L treatment of patients with mCRC from (A) construction set and (B) validation set. 1L, first-line; HR, hazard ratio; mCRC, metastatic colorectal cancer; OS, overall survival.

FIG 5.

Assessment of the predictive value of the OPS: (A) Assessment of the association between the OPS and the treatment effect of the oral drugs (regorafenib or TAS-102) versus placebo in highly pretreated patients (≥3L) included in CORRECT (N = 760) and RECOURSE (N = 800) studies with HR (95% CI). Assessment of the association between the OPS and the presence of a subsequent line (B) on the subset of 1L (impact 2L) and (C) on the subset of 2L (impact 3L) reported by median OS (95% CI) with comparison of HR (95% CI) of presence versus absence of a subsequent line. 1L, first-line; 2L, second-line; 3L, third-line; HR, hazard ratio; OPS, overall prognostic score; OS, overall survival; PBO, placebo.