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.

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.

[1]  N. Hyman,et al.  Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial , 2018, Diseases of the colon and rectum.

[2]  M. Kornmann,et al.  Overstaging: A Challenge in Rectal Cancer Treatment , 2018, Visceral Medicine.

[3]  M. Gonen,et al.  Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer , 2018, JAMA oncology.

[4]  P. Gao,et al.  The efficacy of adding targeted agents to neoadjuvant therapy for locally advanced rectal cancer patients: a meta‐analysis , 2018, Cancer medicine.

[5]  N. Wolmark,et al.  NRG-GI002: A phase II clinical trial platform for total neoadjuvant therapy (TNT) in rectal cancer. , 2017 .

[6]  T. Tanimoto,et al.  Association Between Aortic Dissection and Systemic Exposure of Vascular Endothelial Growth Factor Pathway Inhibitors in the Japanese Adverse Drug Event Report Database. , 2017, Circulation.

[7]  J. Roh,et al.  Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[8]  A. Dybko,et al.  Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[9]  J. Guillem,et al.  Organ Preservation in Rectal Adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative manageme , 2015, BMC Cancer.

[10]  R. Jain,et al.  Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. , 2014, Cancer cell.

[11]  E. Van Cutsem,et al.  Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  D. Tait,et al.  Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C). , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  G. Yancopoulos,et al.  Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab , 2012, Angiogenesis.

[14]  Rakesh K. Jain,et al.  Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases , 2011, Nature Reviews Drug Discovery.

[15]  C. Pericay,et al.  Addition of bevacizumab to XELOX induction therapy plus concomitant capecitabine-based chemoradiotherapy in magnetic resonance imaging-defined poor-prognosis locally advanced rectal cancer: the AVACROSS study. , 2011, The oncologist.

[16]  S. Polo,et al.  Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer d , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  J. Monson,et al.  Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial , 2009, The Lancet.

[18]  Ravi Kumar,et al.  TIMING OF RECTAL CANCER RESPONSE TO CHEMORADIATION , 2007 .

[19]  Ricky T. Tong,et al.  Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer , 2004, Nature Medicine.

[20]  F. Greene,et al.  AJCC cancer staging handbook : from the AJCC cancer staging manual , 2002 .

[21]  Rakesh K. Jain,et al.  Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy , 2001, Nature Medicine.

[22]  H. Lynch,et al.  Psychologic Aspects of Cancer Genetic Testing: A Research Update for Clinicians , 1997 .

[23]  J. Petiot,et al.  Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations , 1994, Cancer.