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Original Investigation
August 29, 2019

Effect of Aflibercept Plus Modified FOLFOX6 Induction Chemotherapy Before Standard Chemoradiotherapy and Surgery in Patients With High-Risk Rectal Adenocarcinoma: The GEMCAD 1402 Randomized Clinical Trial

Author Affiliations
  • 1Fundación Instituto Valenciano de Oncología, Valencia, Spain
  • 2Hospital de Sabadell Corporació Sanitària Parc Taulí, Barcelona, Spain
  • 3Hospital Sant Joan Despí Moisès Broggi, Barcelona, Spain
  • 4Hospital Universitario 12 de Octubre, Madrid, Spain
  • 5B-ARGO Group Catalan, Institute of Oncology (ICO), Badalona, Spain
  • 6Hospital Universitario La Paz, Madrid, Spain
  • 7Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  • 8Hospital Universitario Miguel Servet, Zaragoza, Spain
  • 9Hospital de Navarra, Pamplona, Spain
  • 10Hospital General Universitario de Elche, Alicante, Spain
  • 11Hospital Universitario Vall d’Hebron, Barcelona, Spain
  • 12Hospital Universitario Arnau de Vilanova, Lleida, Spain
  • 13Hospital General de Granollers, Barcelona, Spain
  • 14Hospital Clinic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, University of Barcelona, Spain
  • 15Fundació Althaia de Manresa, Barcelona, Spain
  • 16Hospital del Mar, Barcelona, Spain
  • 17Hospital Universitario Marqués de Valdecilla, Santander, Spain
  • 18Edwin Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 19RTI Health Solutions, Barcelona, Spain
JAMA Oncol. Published online August 29, 2019. doi:10.1001/jamaoncol.2019.2294
Key Points

Question  What is the effect of an induction chemotherapy treatment with aflibercept plus a modified schedule of fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) followed by standard chemoradiotherapy and total mesorectal excision surgery in patients with magnetic resonance imaging–defined high-risk, locally advanced rectal adenocarcinoma?

Findings  In this phase 2 randomized clinical trial of 180 patients with rectal adenocarcinoma, the proportion achieving a pathologic complete response was 22.6% with aflibercept vs 13.8% without.

Meaning  This study provides information on the design of larger trials with agents targeting the vascular endothelial growth factor for treating locally advanced rectal adenocarcinoma.

Abstract

Importance  Preclinical studies suggest that a vascular endothelial growth factor (VEGF) blockade may play a role in the preoperative treatment of rectal adenocarcinoma; however, how to combine anti-VEGF drugs with neoadjuvant chemotherapy (CT) and/or chemoradiotherapy (CRT) remains controversial.

Objective  To study the effect of aflibercept plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) induction CT prior to standard CRT and total mesorectal excision (TME) surgery in patients with high-risk rectal adenocarcinoma.

Design, Setting, and Participants  In the Grupo Español Multidisciplinar En Cancer Digestivo (GEMCAD) 1402 phase 2 randomized clinical trial, 180 patients aged 18 to 75 years, identified by centrally reviewed magnetic resonance imaging to have mrT3c-d/T4/N2 rectal adenocarcinoma, were enrolled from 20 treatment centers in Spain between January 2015 and March 2017. Patients were randomized in a 2:1 treatment to control arm ratio. The primary end point was evaluated at 2 interim and 1 final analyses. The study was designed to perform hypothesis testing at α = .2 and β = .2. A 2-sided P value of <.1984 in the final analysis of the intention-to-treat population was the threshold for considering the experimental treatment to be more effective than the control.

Interventions  Patients received neoadjuvant mFOLFOX6 with (arm A; n = 115) or without (arm B; n = 65) aflibercept, 4 mg/kg (every 2 weeks, 6 cycles, and 3 months) prior to standard CRT and TME surgery.

Main Outcomes and Measures  The primary end point was a pathologic complete response (pCR) (ypT0N0). Secondary end points included toxic effects, surgical morbidity, R0 resections, compliance, and 3-year disease-free survival.

Results  For the 115 patients who received treatment with mFOLFOX6 plus aflibercept, the median (range) age was 60 (32-75) years, 77 men (66.9%) and 38 women (33.0%). For the 65 patients who received induction CT treatment with only mFOLFOX6, the median (range) age was 65 (39-75) years, 39 men (60.0%) and 26 women (40.0%). The pCR rate in the intention-to-treat population was 22.6% (95% CI, 15.3%-31.3%) in arm A and 13.8% (95% CI, 6.5%-24.6%) in arm B (P = .15). The main differential toxic effect was grade 3/4 hypertension during the induction phase. Postoperative complications were similar in both arms (15.5% in arm A and 12.9% in arm B). A total of 106 patients (92.1%) in arm A and 63 (96.9%) in arm B received all treatment cycles.

Conclusions and Relevance  The study met its primary end point. The findings suggest that adding aflibercept to an induction regimen using mFOLFOX6 plays a role in increasing the pCR rate in patients with high-risk rectal adenocarcinoma, without substantially increasing surgical complications. The GEMCAD 1402 trial provides a rationale for phase 3 trials.

Trial Registration  ClinicalTrials.gov identifier: NCT02340949

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