Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study

Abstract

Purpose: To assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response.

Patients and methods: In a phase I/II study, 32 patients received four cycles of therapy consisting of: bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; fluorouracil infusion (225 mg/m(2)/24 hours) during cycles 2 to 4; external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks); and surgery 7 to 10 weeks after completion of all therapies. We measured molecular, cellular, and physiologic biomarkers before treatment, during bevacizumab monotherapy, and during and after combination therapy.

Results: Tumors regressed from a mass with mean size of 5 cm (range, 3 to 12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7 to 6.0 cm) in all 32 patients. Histologic examination revealed either no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site. This treatment resulted in an actuarial 5-year local control and overall survival of 100%. Actuarial 5-year disease-free survival was 75% and five patients developed metastases postsurgery. Bevacizumab with chemoradiotherapy showed acceptable toxicity. Bevacizumab decreased tumor interstitial fluid pressure and blood flow. Baseline plasma soluble vascular endothelial growth factor receptor 1 (sVEGFR1), plasma vascular endothelial growth factor (VEGF), placental-derived growth factor (PlGF), and interleukin 6 (IL-6) during treatment, and circulating endothelial cells (CECs) after treatment showed significant correlations with outcome.

Conclusion: Bevacizumab with chemoradiotherapy appears safe and active and yields promising survival results in locally advanced rectal cancer. Plasma VEGF, PlGF, sVEGFR1, and IL-6 and CECs should be further evaluated as candidate biomarkers of response for this regimen.

Fig 1.

Study design and macroscopic tumor response. (A) Red dots indicate time points of data collection. (B, C) Representative sigmoidoscopy images of a (B) locally advanced rectal tumor before therapy and presurgery, (see arrow in C) after completion of all neoadjuvant therapies. Pre-Tx, pretreatment; BV, bevacizumab; FU, fluorouracil; CT, computed tomography; PET, positron emission tomography; IFP, interstitial fluid pressure.

Fig 2.

Phase II trial treatment outcome: Kaplan-Meier local control and survival distributions. (A) Overall survival, (B) local control, and (C) disease-free survival in 32 advanced rectal cancer patients receiving bevacizumab with chemoradiotherapy.

Fig A1.

Measurements of vascular endothelial growth factor (VEGF) concentration in plasma of a cancer patient after 1 hour of preincubation with increasing concentrations of bevacizumab (2.3 pM to 3,000 nmol/L) using Meso-Scale Discovery Growth Factor 1 ELISA plates. The initial measurement (ie, for a 0 pM concentration of bevacizumab) showed a level of 555pg/mL of VEGF. Bevacizumab decreased the measured concentration in a dose-dependent manner. Arrow points to the estimated concentration of bevacizumab in plasma of cancer patients (approximately 390 nmol/L) at the time when blood is drawn for analysis after infusion.