Prognostic Nomogram and Patterns of Use of FOLFIRI-Aflibercept in Advanced Colorectal Cancer: A Real-World Data Analysis

Abstract

Introduction The VELOUR study evaluated the efficacy and safety of adding aflibercept to FOLFIRI (fluorouracil, leucovorin, irinotecan) in second‐line therapy for metastatic colorectal cancer (mCRC). However, a nomogram that can stratify patients according to prognosis is unavailable, and the frequency and effect of the pragmatic use of modified schedules in actual practice remains unknown. Method The sample consists of 250 patients with mCRC treated with aflibercept and irinotecan‐based chemotherapy at nine Spanish academic centers between January 2013 and September 2015. The result of a Cox proportional hazards model regression for overall survival (OS), adjusted for covariates available in daily practice, was represented as a nomogram and web‐based calculator. Harrell's c‐index was used to assess discrimination. Results The prognostic nomogram for OS includes six variables: Eastern Cooperative Oncology Group performance status, tumor location, number of metastatic sites, mutational status, better response to previous treatment(s), and carcinoembryonic antigen. The model is well calibrated and has acceptable discriminatory capacity (optimism‐corrected c‐index, 0.723; 95% confidence interval [CI], 0.666–0.778). Median OS was 6.1 months (95% CI, 5.1–8.8), 12.4 months (95% CI, 9.36–14.8), and 22.9 months (95% CI, 16.6–not reached) for high‐, intermediate‐, and low‐risk groups, respectively. Age, comorbidity, or use of modified FOLFIRI regimens did not affect prognosis in this series. Grade 3–4 adverse events were less common following modified schedules. The admission rate because of toxicity was higher in ≥65 years (9.7% vs. 19.6%; odds ratio, 2.26; p = .029). Conclusion We have developed and internally validated a prognostic model for use in individuals with colorectal cancer initiating therapy with FOLFIRI‐aflibercept to predict both OS and the effect of pragmatic modifications of the classic regime on efficacy and safety. This can aid in decision making and in designing future trials. Implications for Practice In this study, the authors developed and conducted the internal validation of a prognostic nomogram that makes it possible to stratify patients who are eligible for second‐line FOLFIRI‐aflibercept based on their probability of survival. This model was developed in a multicenter sample from nine Spanish hospitals. Furthermore, to increase the study's validity, the practical use of aflibercept in this setting was investigated, including doses or pragmatic modifications. The results suggest that the modified schedules often used in this daily clinical practice‐based patient population are associated with less severe toxicity without apparent detriment to survival endpoints. It is believed that these data complement the information provided by the VELOUR trial and are relevant for the oncologist in treating colon cancer in the second‐line setting.

Safety of Aflibercept in Metastatic Colorectal Cancer: A Literature Review and Expert Perspective on Clinical and Real-World Data

“…The most common grade 3/4 toxicities were neutropenia (13.4%), hypertension (6.8%), asthenia (6.8%), diarrhea (5.4%) and venous thrombotic disease (4.2%). Treatment-related mortality was 1.6% [34]. A real-world observational study evaluating 120 patients with RAS-WT mCRC who received second-line aflibercept plus FOLFIRI reported hypertension (7.5%), asthenia (5.9%) and perforation (2.5%) as the most frequently occurring [35].…”

Analysis of Circular RNA-Related Competing Endogenous RNA Identifies the Immune-Related Risk Signature for Colorectal Cancer

“…Therefore, it is necessary to continuously develop better methods to more accurately predict the survival of CRC. Recently, some nomograms have been widely used for predicting the prognosis of CRC (Fernández Montes et al, 2019;Qu et al, 2019). For example, Fernández Montes et al (2019) developed a nomogram to predict 3-, 6-, and 12-month OS based on six variables, including the tumor site, ECOG PS, BRAF mutations, the number of metastatic sites, the response to first-line, and CEA.…”

“…Recently, some nomograms have been widely used for predicting the prognosis of CRC (Fernández Montes et al, 2019;Qu et al, 2019). For example, Fernández Montes et al (2019) developed a nomogram to predict 3-, 6-, and 12-month OS based on six variables, including the tumor site, ECOG PS, BRAF mutations, the number of metastatic sites, the response to first-line, and CEA. Despite significant progress in these studies, few have considered the use of genetic characteristics to construct a risk stratification system of CRC.…”

Relevance of Pharmacogenomics and Multidisciplinary Management in a Young-Elderly Patient With KRAS Mutant Colorectal Cancer Treated With First-Line Aflibercept-Containing Chemotherapy

“…Reported prevalent toxicities with FOLFIRI/aflibercept were diarrhea (19.3%), mucositis (13.7%), asthenia (16.9%), HFS (2.8%), hypertension (2.9%), arterial (1.8%) and venous (7.9%) thromboembolic events, neutropenia (36.7%), and thrombocytopenia (3.3%) (8), the majority occurring within the first four cycles (26). In Spanish real-life experience, prevalent LT were neutropenia (7.9-15%), diarrhea (4.5-6.4%), asthenia (6.8-10%), and hypertension (3.4-6.8%) (30,38,39). Hypertension on-treatment was reported as a potential surrogate efficacy marker, associated with increased PFS 10.6 months and OS 17 months (30).…”

“…Hypertension on-treatment was reported as a potential surrogate efficacy marker, associated with increased PFS 10.6 months and OS 17 months (30). In real-world data, >50% of patients requiring modified FOLFIRI schedules and doses had slightly older median age (63 years, range 35-82), 44% <65 years; no significantly different outcomes were reported according to modified schedules and doses, nor in elderly patients (39); G3-4 adverse events (40) and serious toxicityrelated hospitalization were more common in elderly patients (≥65 years) (39). In Aflibercept Safety and Quality of Life Programs (41,42), including an Italian experience with 43% yE, 10% early relapsers, 13.5 and 12% receiving, respectively, 5fluorouracil and irinotecan lower dose, prevalent G3-4 toxicities were hypertension 24.1-28%, neutropenia 23.1-27.5%, and diarrhea 15.3-17%; no QoL worsening was reported; in elderly patients, G3-4 toxicities were lower than in VELOUR trial (81.3 vs. 89.3%) (41).…”