scholarly journals 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

2017 ◽  
Vol 35 (17) ◽  
pp. 1929-1937 ◽  
Author(s):  
Lindsay A. Renfro ◽  
Richard M. Goldberg ◽  
Axel Grothey ◽  
Alberto Sobrero ◽  
Richard Adams ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Performance Status ◽  
External Validation ◽  
Cox Proportional Hazards ◽  
Early Mortality ◽  
Phase Iii ◽  
Cancérologie Digestive ◽  
The Impact

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.

Nomograms for overall survival (OS) and progression-free survival (PFS) in metastatic colorectal cancer (mCRC): Construction from 19,678 ARCAD patients.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 659-659
Author(s):  
Katrin Marie Sjoquist ◽  
Lindsay A. Renfro ◽  
John Simes ◽  
Niall C. Tebbutt ◽  
Stephen John Clarke ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Lung Metastases ◽  
Performance Status ◽  
Phase Iii ◽  
Survival Prediction ◽  
Continuous Variables ◽  
Cox Models ◽  
Pairwise Interactions

659 Background: Prospective survival prediction of patients with metastatic colorectal cancer is difficult. Prognosis estimation based on readily available clinicopathologic factors has the potential to inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for OS and PFS in mCRC using the multi-trial ARCAD database. Methods: Data from 19,678 mCRC pts accrued to 24 first line randomized phase III clinical trials since 1997 were used to construct and validate Cox models for PFS and OS, stratified by treatment arm within each study. Candidate variables included age, gender, BMI, performance status, colon vs. rectal cancer, prior chemotherapy, number of metastatic sites, sites of metastases (liver, lung, lymph nodes), and baseline bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil:lymphocyte ratio (dNLR). Missing data (<11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions considered if p<0.001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated using a 10% holdout sample from each trial. Results: Nomograms for OS and PFS including remaining variables were well calibrated with C-indices of 0.66 and 0.60, respectively. Evaluation of external validity revealed good concordance; 71% and 67% respectively between predicted (> vs. <50% probability) and actual (yes/no) 1-year OS and 6-month PFS, and median 1-year OS and 6-month PFS predictions fell within the actual 95% Kaplan-Meier intervals. Gender, liver and lung metastases, and dNLR were not prognostic for OS; prior chemo, colon vs. rectum, dNLR, liver and lymph node metastases, and gender did not predict for PFS. No clinically relevant pairwise interactions were identified. Conclusions: The proposed nomograms are well calibrated and internally and externally valid. These tools have the potential to aid prognostication and patient/physician communication, and balance risk in randomized trials in mCRC.

scholarly journals Association of Age With Survival in Patients With Metastatic Colorectal Cancer: Analysis From the ARCAD Clinical Trials Program

2014 ◽  
Vol 32 (27) ◽  
pp. 2975-2982 ◽  
Author(s):  
Christopher H. Lieu ◽  
Lindsay A. Renfro ◽  
Aimery de Gramont ◽  
Jeffrey P. Meyers ◽  
Timothy S. Maughan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Proportional Hazards ◽  
Performance Status ◽  
Cox Proportional Hazards ◽  
Risk Of Death ◽  
Mutational Status ◽  
Increased Risk ◽  
Risk Of Progression

Purpose This study addressed whether age is prognostic for overall survival (OS) or progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC). Patients and Methods A total of 20,023 patients from 24 first-line clinical trials in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were analyzed. Primary age effects and interactions with age, sex, performance status (PS), and metastatic site were modeled using Cox proportional hazards stratified by treatment arm within study. Results Of total patients, 3,051 (15%) were age ≤ 50 years. Age was prognostic for both OS (P < .001) and PFS (P < .001), with U-shaped risk (ie, highest risk was evident in youngest and oldest patients). Relative to patients of middle age, the youngest patients experienced 19% (95% CI, 7% to 33%) increased risk of death and 22% (95% CI, 10% to 35%) increased risk of progression. The oldest patients experienced 42% (95% CI, 31% to 54%) increased risk of death and 15% (95% CI, 7% to 24%) increased risk of progression or death. This relationship was more pronounced in the first year of follow-up. Age remained marginally significant for OS (P = .08) when adjusted for PS, sex, and presence of liver, lung, or peritoneal metastases, and age was significant in an adjusted model for PFS (P = .005). The age effect did not differ by site of metastatic disease, year of enrollment, type of therapy received, or biomarker mutational status. Conclusion Younger and older age are associated with poorer OS and PFS among treated patients with mCRC. Younger and older patients may represent higher-risk populations, and additional studies are warranted.

Ziv-aflibercept: A novel angiogenesis inhibitor for the treatment of metastatic colorectal cancer

2013 ◽  
Vol 70 (21) ◽  
pp. 1887-1896 ◽  
Author(s):  
Clement Chung ◽  
Nisha Pherwani
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Performance Status ◽  
Angiogenesis Inhibitor ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Second Line ◽  
Patient Response ◽  
Line Setting

Abstract Purpose The pharmacology, pharmacokinetics, clinical efficacy, safety, and administration of ziv-aflibercept in combination therapy for metastatic colorectal cancer (mCRC) are reviewed. Summary Ziv-aflibercept (Zaltrap, Regeneron Pharmaceuticals and sanofi-aventis) is a novel recombinant fusion protein that targets the angiogenesis signaling pathway of tumor cells by blocking vascular endothelial growth factor (VEGF) receptors that play a key role in tumor growth and metastasis; it is a more potent VEGF blocker than bevacizumab. Ziv-aflibercept is approved by the Food and Drug Administration for use in combination with fluorouracil, irinotecan, and leucovorin (the FOLFIRI regimen) for second-line treatment of patients with mCRC who have disease progression during first-line oxaliplatin-based chemotherapy. A Phase III trial demonstrated that relative to FOLFIRI therapy alone, the use of ziv-aflibercept was associated with significantly improved patient response, overall survival, and progression-free survival in patients with good performance status at baseline, including some who had received prior bevacizumab therapy. The most common grade 3 or 4 adverse effects associated with ziv-aflibercept use in clinical studies were neutropenia, hypertension, and diarrhea; the U.S. product labeling warns of potential hemorrhage and other treatment-related risks. Conclusion Current clinical data are insufficient to directly compare ziv-aflibercept and bevacizumab when used with standard combination chemotherapy as first- or second-line regimens for mCRC. The role of ziv-aflibercept is currently limited to the second-line setting in combination with irinotecan-based regimens in mCRC patients who have not received irinotecan previously. The role of ziv-aflibercept in chemotherapy for other tumor types is yet to be determined.

The impact of data errors on the outcome of randomized clinical trials

2017 ◽  
Vol 14 (5) ◽  
pp. 499-506 ◽  
Author(s):  
Marc Buyse ◽  
Pierre Squifflet ◽  
Elisabeth Coart ◽  
Emmanuel Quinaux ◽  
Cornelis JA Punt ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Randomized Clinical Trials ◽  
Systematic Errors ◽  
Age Related Macular Degeneration ◽  
Random Errors ◽  
Significant Treatment ◽  
Age Related ◽  
The Impact

Background/aims Considerable human and financial resources are typically spent to ensure that data collected for clinical trials are free from errors. We investigated the impact of random and systematic errors on the outcome of randomized clinical trials. Methods We used individual patient data relating to response endpoints of interest in two published randomized clinical trials, one in ophthalmology and one in oncology. These randomized clinical trials enrolled 1186 patients with age-related macular degeneration and 736 patients with metastatic colorectal cancer. The ophthalmology trial tested the benefit of pegaptanib for the treatment of age-related macular degeneration and identified a statistically significant treatment benefit, whereas the oncology trial assessed the benefit of adding cetuximab to a regimen of capecitabine, oxaliplatin, and bevacizumab for the treatment of metastatic colorectal cancer and failed to identify a statistically significant treatment difference. We simulated trial results by adding errors that were independent of the treatment group (random errors) and errors that favored one of the treatment groups (systematic errors). We added such errors to the data for the response endpoint of interest for increasing proportions of randomly selected patients. Results Random errors added to up to 50% of the cases produced only slightly inflated variance in the estimated treatment effect of both trials, with no qualitative change in the p-value. In contrast, systematic errors produced bias even for very small proportions of patients with added errors. Conclusion A substantial amount of random errors is required before appreciable effects on the outcome of randomized clinical trials are noted. In contrast, even a small amount of systematic errors can severely bias the estimated treatment effects. Therefore, resources devoted to randomized clinical trials should be spent primarily on minimizing sources of systematic errors which can bias the analyses, rather than on random errors which result only in a small loss in power.

scholarly journals Bevacizumab Maintenance Versus No Maintenance During Chemotherapy-Free Intervals in Metastatic Colorectal Cancer: A Randomized Phase III Trial (PRODIGE 9)

2018 ◽  
Vol 36 (7) ◽  
pp. 674-681 ◽  
Author(s):  
Thomas Aparicio ◽  
Francois Ghiringhelli ◽  
Valérie Boige ◽  
Karine Le Malicot ◽  
Julien Taieb ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Induction Chemotherapy ◽  
Controlled Trial ◽  
Performance Status ◽  
Multivariable Analysis ◽  
Phase Iii ◽  
Tumor Control ◽  
Primary Tumors

Purpose Conflicting results are reported for maintenance treatment with bevacizumab during chemotherapy-free intervals (CFI) in metastatic colorectal cancer after induction chemotherapy. Patients and Methods In this open-label, phase III, randomized controlled trial, we compared the tumor control duration (TCD) observed with bevacizumab maintenance and with no treatment (observation) during CFI subsequent to induction chemotherapy with 12 cycles of fluorouracil, leucovorin, and irinotecan plus bevacizumab. After disease progression, the induction regimen was repeated for eight cycles, followed by a new CFI. Results From March 2010 to July 2013, 491 patients were randomly assigned. Disease progression or death occurred during induction chemotherapy in 85 patients (17%); 261 patients (53%) had at least one reinduction, 107 (22%) had two reinductions, and 56 (11%) had three or more reinductions. The median TCD was 15 months in both groups; the median progression-free survival (PFS) from randomization was 9.2 and 8.9 months in the maintenance group and observation groups, respectively. The TCD observed in both groups was higher compared with the TCD hypotheses of the trial. The median overall survival (OS) was 21.7 and 22.0 months in the maintenance and observation groups, respectively. In the per-protocol population, defined as patients with at least one reinduction after the first progression, the median duration of the first CFI was 4.3 months in both arms; the median TCD was 17.8 and 23.3 months ( P = .339), the median PFS was 9.9 and 9.5 months, and the median OS was 27.6 and 28.5 months in the maintenance and observation groups, respectively. Multivariable analysis revealed that female gender, WHO performance status ≥ 2, and unresected primary tumors were associated with a shorter TCD. Conclusion Bevacizumab maintenance monotherapy did not improve TCD, CFI duration, PFS, or OS.

Evaluation of treatment benefit to an unselected population of patients with metastatic colorectal cancer, referred to oncological treatment.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14677-e14677
Author(s):  
Svend Erik Nielsen
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Primary Tumor ◽  
Performance Status ◽  
Treatment Modalities ◽  
Treatment Benefit ◽  
Primary Tumor Site ◽  
Oncological Treatment ◽  
Line Chemotherapy

e14677 Background: Patients, with metastatic colorectal cancer (mCRC), participating in clinical trials are a selected group with a better performance status compared to all patients, who are referred to oncological treatment. The aim of the study was to evaluate the benefit of standard treatment modalities, offered to an unselected group of patients, referred to our Dept. of Oncology. Methods: Consecutive patients treated with more than one cycle of chemotherapy, registrated in our database from May 2003 to July 2012, were included. Clinical information was obtained from patient files. The outcome was overall survival for various groups. Following parameters were collected: Gender, age, primary tumor site, resection status of primary tumor, number of metastic sites, liver-only mets, number of chemotherapy regimens, +/- Bevazicumab and rate of palliative radiation. Results: 266 consequtive patients, treated with more than one cycle of chemotherapy, were included. Median age 67 (31-86) years, 150 male (59%). Distribution of the primary tumor was 35/37/28% for rectum/left colon/right colon. 192/59/15 (72/22/6%) had the primary tumor resected/not resected/stent. 54/37/9% had one metastic site/ two sites/three or more sites. 24% had liver only. As first line chemotherapy 29% received Capecitabine (CAP), 55% CAP + Oxaliplatin, and 8% CAP + Irinotecan. 44% received Bevacizumab. 69%/27% received either second and third line chemotherapy. 19% received palliative radiotherapy. Median OS for the whole population was 17 months CI ( 15-19). Patients with one, two or three, or more mets sites had a OS of 21(CI: 16-26)/17 (14-20)/9 (4-149) months, respectively. For patients receiving one, two, or three lines of chemotherapy OS was respectively 8/16/28 months. Addition of Bevacizumab to chemotherapy regimens had an OS of 27 months CI (24-30), compared to 20 months (16-24) for chemotherapy alone. Conclusions: Unselected mCRC patients, treated with standard chemotherapy regimens, seem to obtain the same OS benefit as seen in clinical trials. Survival benefit was dependent on the number of metastatic sites, the number of cht. regimens received and addition of Bevacizumab to the treatment.

Survival among metastatic colorectal patients in clinical trials compared to the real world.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 673-673
Author(s):  
Ziwei Wang ◽  
Lindsay Hwang ◽  
James Don Murphy
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Median Survival ◽  
Real World ◽  
Randomized Clinical Trials ◽  
Phase Iii ◽  
The Real ◽  
Clinical Trial Results

673 Background: Randomized clinical trials play a central role in clinical research though only a small fraction of patients partake in clinical studies. Questions thus arise regarding the generalizability of clinical trial results to the remainder of the population. This study evaluated whether patient survival from randomized clinical trials in metastatic colorectal cancer reflects real world outcomes. Methods: A Pubmed search was used to identify randomized phase III clinical trials of first-line treatment for metastatic colorectal cancer published between 2005 and 2010. We excluded secondary or pooled analyses, second-line treatments, non-metastatic patients, non-English language, and non-randomized studies. Thirty-one clinical trials met these criteria, comprised of 79 distinct clinical trial arms. Overall survival among clinical trial patients was compared to metastatic colorectal cancer patients within the Surveillance, Epidemiology, and End Results (SEER) program. Within SEER, we restricted the analysis time-period and age of patients to match the enrollment period and age of patients within each individual clinical trial. Results: The clinical trials enrolled a total of 16,614 patients. Among all clinical trial arms the median survival ranged from 6.7-62 months, 1-year survival ranged from 30-97%, and 2-year survival ranged from 6-88%. Compared to SEER, the median survival was higher in 95% of the individual clinical trial arms by an average of 5.4 months (p<0.0001). The 1-year survival was higher in 94% of the clinical trial arms by an average of 16.7% (p<0.0001). The 2-year survival was higher in 71% of the clinical trial arms by an average of 7.2% (p<0.0001). Conclusions: This study found substantially improved survival among clinical trial participants compared to patients in the SEER database suggesting that survival estimates from clinical trials may not generalize to the “real world.” Potential patient factors such as differences in underlying comorbidity, performance status, disease burden, as well as variation in treatment could not be addressed in this study, though these factors likely explain some of the observed survival differences.

PARADIGM study: A multicenter, randomized, phase III study of 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus panitumumab or bevacizumab as first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS776-TPS776 ◽  
Author(s):  
Takayuki Yoshino ◽  
Hiroyuki Uetake ◽  
Katsuya Tsuchihara ◽  
Kohei Shitara ◽  
Kentaro Yamazaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Performance Status ◽  
Phase Iii ◽  
Type I ◽  
Line Treatment ◽  
Wild Type ◽  
First Line ◽  
Exon 2 ◽  
First Line Treatment

TPS776 Background: Optimal combination of monoclonal antibody (anti-VEGF vs. anti-EGFR antibody) with standard chemotherapy as first-line treatment in patients (pts) with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC) remains controversial. FIRE-3 study demonstrated a significant improvement in overall survival (OS) with anti-EGFR over bevacizumab in pts with KRAS exon 2 wild type mCRC, while CALGB 80405 study did not. PARADIGM study is designed to compare panitumumab vs. bevacizumab combined with mFOLFOX6 in pts with RAS wild-type chemotherapy-naive mCRC. Methods: Eligible pts are aged 20-79 years with ECOG performance status (PS) 0-1 and histologically/cytologically confirmed RAS wild-type mCRC. 800 pts will be randomly assigned in a 1:1 ratio to mFOLFOX6 plus panitumumab or bevacizumab, and stratified according to institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). Each treatment regimen includes oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, 5-fluorouracil (5-FU) iv 400 mg/m2 at day 1, 5-FU civ 2400 mg/m2 at day 1-3, and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg at day 1 every two weeks. The primary endpoint is the OS; the study was designed to detect the OS hazard ratio of 0.76, with a one-sided type I error of 0.025 and 80% power. Secondary efficacy endpoints include progression-free survival, response rate, duration of response, and curative resection rate. One interim analysis is planned for the OS when approximately 70% of the targeted 570 events has been observed. Exploratory endpoint is to investigate possible biomarkers including oncogenic mutations using tumor tissue and circulating tumor DNA (Study ID: NCT02394834). As of August 2015, 21 pts have been randomized and recruitment is ongoing. Clinical trial information: NCT02394795.

A multinational, randomized, phase III trial of XELIRI (+bevacizumab) versus FOLFIRI (+bevacizumab) as the second-line chemotherapy for metastatic colorectal cancer: Asian XELIRI project (AXEPT).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS780-TPS780 ◽  
Author(s):  
Kei Muro ◽  
Tae Won Kim ◽  
Young Suk Park ◽  
Hiroyuki Uetake ◽  
Tomohiro Nishina ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Metastatic Colorectal Cancer ◽  
Performance Status ◽  
Dose Intensity ◽  
Phase Iii ◽  
Second Line ◽  
Second Line Chemotherapy ◽  
Clinical Trial Information ◽  
Line Chemotherapy

TPS780 Background: Life-prolonging systemic therapy such as chemotherapy (FOLFOX, XELOX, FOLFIRI, 5-FU/LV) with / without molecular targeted agents (bevacizumab, afilibercept, cetuximab, panitumumab) are important treatment for metastatic colorectal cancer (mCRC). On the other hand, it is required to establish an evidence of convenient therapy including oral anticancer agent which is expected lower risk of safety. XELIRI was already examined by various doses in this decade, and result of AIO 0604 was regarded as one of the most appropriate regimen. The BIX phase II study showed the tolerability and promising efficacy of the AIO regimen for Japanese mCRC patients (Hamamoto Y, et al. Oncologist 2014). Methods: Asian XELIRI Project (AXEPT) is an East Asian collaborated, open label, randomized phase III clinical trial designed to demonstrate the non-inferiority of XELIRI (+bevacizumab) to the standard of care FOLFIRI (+bevacizumab) as the second-line chemotherapy in patients with mCRC. The primary endpoint is median overall survival. The secondary endpoints are progression-free survival, time to treatment failure, overall response rate, disease control rate, relative dose intensity, safety, correlation between UGT1A1 polymorphisms (*28, *6) and safety. Eligible patients were 20 years of age and older, had histologically proven CRC, ECOG performance status 0-2, adequate organ function, progression or difficult to continue after first line regimen. Patients were randomized 1:1 to standard FOLFIRI (+bevacizuamb 5mg/kg day1), repeated every 14 days (Group A) or XELIRI, Irinotecan 200mg/m2 day1, and capecitabine 1600mg/m2 day 1-14 (+bevacizumab 7.5mg/kg day1), repeated every 21 days (Group B). A Total of 464 events were needed to show non-inferiority with a two-sided α of 0·05 and a power of 80%, a target sample size of 600 patients was required. (The 95% CI upper limit of the hazard ratio was pre-specified as less than 1.3.). Enrollment has started in December 2013. As of August 2015, 98 centers in the Japan, South Korea and China are participating in this trial. Clinical trial information: NCT01996306. UMIN000012263. Clinical trial information: NCT01996306.

scholarly journals How to Deal with Second Line Dilemma in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1189 ◽  
Author(s):  
Galvano ◽  
Incorvaia ◽  
Badalamenti ◽  
Rizzo ◽  
Guarini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Objective Response ◽  
Phase Iii ◽  
Second Line ◽  
Anti Vegf ◽  
Significant Difference ◽  
Line Setting ◽  
The Impact

Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have demonstrated efficacy with chemotherapy (CT) as second line treatment for metastatic colorectal cancer (mCRC). The right sequence of the treatments in all RAS (KRAS/NRAS) wild type (wt) patients has not precisely defined. We evaluated the impact of aforementioned targeted therapies in second line setting, analyzing efficacy and safety data from phase III clinical trials. We performed both direct and indirect comparisons between anti-EGFR and anti-VEGF. Outcomes included disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and G3-G5 toxicities. Our results showed significantly improved OS (HR 0.83, 95% CI 0.72–0.94) and DCR (HR 1.27, 95% CI 1.04–1.54) favouring anti-VEGF combinations in overall population; no statistically significant differences in all RAS wt patients was observed (HR 0.87, 95% CI 0.70–1.09). Anti-EGFR combinations significantly increased ORR in all patients (RR 0.54, 95% CI 0.31–0.96), showing a trend also in all RAS wt patients (RR 0.63, 95% CI 0.48–0.83). No significant difference in PFS and DCR all RAS was registered. Our results provided for the first time a strong rationale to manage both targeted agents in second line setting.

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