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Rectal Cancer: Aflibercept Increases Treatment Efficacy

A phase 2 trial reports that in patients with high-risk, locally advanced rectal adenocarcinoma, adding aflibercept (Zaltrap®, Regeneron Pharmaceuticals, Inc.) enhances the efficacy of neoadjuvant chemotherapy that is followed by standard chemoradiotherapy and surgery.

By inhibiting vascular endothelial growth factor (VEGF), aflibercept blocks angiogenesis—the formation of new blood vessels—in cancer cells, thereby inhibiting their growth.

"Preclinical studies suggest that a VEGF blockade may play a role in the preoperative treatment of rectal adenocarcinoma," write the authors of the study now published in JAMA Oncology, led by first author Carlos Fernández-Martos, MD, Head of Gastrointestinal Oncology at the Valencian Oncology Institute Foundation in Valencia, Spain. "However, how to combine anti-VEGF drugs with neoadjuvant chemotherapy and/or chemoradiotherapy remains controversial."

In the Grupo Español Multidisciplinar En Cancer Digestivo (GEMCAD) 1402 trial, the researchers evaluated the efficacy of induction chemotherapy with aflibercept plus a modified schedule of fluorouracil/leucovorin/oxaliplatin (mFOLFOX6) followed by standard chemoradiotherapy and total mesorectal excision surgery. One hundred and eighty patients with high-risk, locally advanced rectal adenocarcinoma were randomized in a 2:1 ratio to receive neoadjuvant mFOLFOX6 with or without aflibercept, followed in both treatment arms by standard chemoradiotherapy and surgical excision. The study's principal end point was pathologic complete response, with secondary end points of toxic effects, surgical morbidity, R0 (microscopically negative-margin) resections, compliance, and three-year disease-free survival.

In the intention-to-treat population, patients receiving aflibercept/mFOLFOX6 had a pathologic complete response rate of 22.6%, compared with 13.8% of patients receiving mFOLFOX6 without aflibercept. Patients in the aflibercept arm had higher rates of grade 3/4 hypertension during the induction phase; postoperative complications occurred at similar rates in both treatment groups (15.5% vs 12.9%).

"The findings suggest that adding aflibercept to an induction regimen using mFOLFOX6 plays a role in increasing the [pathologic complete response] rate in patients with high-risk rectal adenocarcinoma, without substantially increasing surgical complications," conclude Dr. Fernández-Martos and colleagues. "The GEMCAD 1402 trial provides a rationale for phase 3 trials."

For More Information

Fernández-Martos C, Pericay C, Losa F, et al (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. JAMA Oncol. [Epub ahead of print] DOI:10.1001/jamaoncol.2019.2294

Image credit: DBCLS. Licensed under CC BY 4.0

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