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
Por:
Fernández-Martos C, Pericay C, Losa F, García-Carbonero R, Layos L, Rodríguez-Salas N, Martin-Richard M, Alonso-Orduña V, Vera R, Gallego J, Capdevila J, Salud A, Nogué M, Maurel J, Guash I, Montagut C, Lopez C, Macias I, Jain RK and Garcia-Albeniz X
Publicada:
1 nov 2019
Ahead of Print:
29 ago 2019
Resumen:
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 Espanol 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 2:1treatment to control arm ratio. The primary end point was evaluated at 2 interim and l final analyses. The study was designed to perform hypothesis testing at alpha = .2 and beta = .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) (ypTONO). Secondary end points included toxic effects, surgical morbidity, RO 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.
Filiaciones:
Fernández-Martos C:
Fundación Instituto Valenciano de Oncología, Valencia, Spain
Pericay C:
Hospital de Sabadell Corporació Sanitària Parc Taulí, Barcelona, Spain
Losa F:
Hospital Sant Joan Despí Moisès Broggi, Barcelona, Spain
García-Carbonero R:
Hospital Universitario 12 de Octubre, Madrid, Spain
Layos L:
B-ARGO Group Catalan, Institute of Oncology (ICO), Badalona, Spain
Rodríguez-Salas N:
Hospital Universitario La Paz, Madrid, Spain
Martin-Richard M:
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Alonso-Orduña V:
Hospital Universitario Miguel Servet, Zaragoza, Spain
Vera R:
Hospital de Navarra, Pamplona, Spain
:
Hospital General Universitario de Elche, Alicante, Spain
Capdevila J:
Hospital Universitario Vall d'Hebron, Barcelona, Spain
Salud A:
Hospital Universitario Arnau de Vilanova, Lleida, Spain
Nogué M:
Hospital General de Granollers, Barcelona, Spain
Maurel J:
Hospital Clinic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, University of Barcelona, Spain
Guash I:
Fundació Althaia de Manresa, Barcelona, Spain
Montagut C:
Hospital del Mar, Barcelona, Spain
Lopez C:
Hospital Universitario Marqués de Valdecilla, Santander, Spain
Macias I:
Hospital de Sabadell Corporació Sanitària Parc Taulí, Barcelona, Spain
Jain RK:
Edwin Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Harvard Medical School, Boston
Garcia-Albeniz X:
RTI Health Solutions, Barcelona, Spain
Green Published, Bronze
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