Carlos Fernández-Martos, MD, and colleagues recently reported that in patients with high-risk, locally advanced rectal adenocarcinoma, adding aflibercept (Zaltrap®, Regeneron Pharmaceuticals, Inc.) to a modified schedule of fluorouracil/leucovorin/oxaliplatin (FOLFOX6) followed by standard chemoradiotherapy and total mesorectal excision surgery increased treatment efficacy, producing a higher complete pathologic response rate. In this interview with i3 Health, Dr. Fernández-Martos discusses the findings of his study—the phase 2 GEMCAD 1402 trial—and shares his perspective on challenges and therapeutic advances in the treatment of high-risk rectal adenocarcinoma.
In your opinion, what are the biggest challenges in treating high-risk rectal adenocarcinoma?
Carlos Fernández-Martos, MD: There is no consensus to define locally advanced high-risk rectal cancer, but we know certain tumor characteristics that are associated with an increased risk of local and/or distant relapse. These include T3 tumors with deep infiltration of the perirectal fat, distal T3 tumors, T4 tumors, N2 tumors, tumors that affect or threaten the mesorectal fascia, and tumors with extramural venous invasion. A major challenge for the treatment of these tumors is a correct pretreatment staging to accurately detect risk factors and avoid overtreatment.
Can you comment on the significance of your study's findings?
Dr. Fernández-Martos: We have observed a higher rate of complete pathologic responses when a drug that blocks vascular endothelial growth factor (VEGF) is given in combination with chemotherapy and before standard chemoradiotherapy and surgery. There was preclinical evidence of the possible beneficial effect of VEGF blockade on the efficacy of chemoradiotherapy (CRT) due to the effect of vascular normalization. This study supports this theory.
Is further research underway for aflibercept in this setting? What additional research advances are on the horizon for high-risk rectal adenocarcinoma?
Dr. Fernández-Martos: We are currently waiting for the more mature data from this study, which we will report with a median follow-up of three years. Additional research on the horizon includes data from the RAPIDO phase 3 study (NCT01558921) comparing two preoperative treatment strategies in high-risk patients. In addition, other studies are examining the potential efficacy of novel systemic agents during CRT.
What advice can you give to community oncologists and gastroenterologists treating patients with high-risk rectal adenocarcinoma?
Dr. Fernández-Martos: It is essential to ascertain correct staging with magnetic resonance imaging (MRI), followed by discussion of the case in a multidisciplinary committee and discussion with the patient of current strategies.
About Dr. Fernández-Martos
Carlos Fernández-Martos, MD, a medical oncologist, is Head of Gastrointestinal Oncology at the Valencian Oncology Institute Foundation in Valencia, Spain. He is both a founding member and current Chair of the Multidisciplinary Spanish Group on Digestive Cancer (GEMCAD). In addition, he is a member of the US National Cancer Institute (NCI)'s rectal and anal cancer work group, the Spanish Society of Medical Oncology (SEOM), the European Society of Medical Oncology (ESMO), and the American Society of Clinical Oncology (ASCO). His research is focused on gastrointestinal cancers, with a particular interest in innovative therapeutic strategies for colorectal and pancreatic cancer.
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