Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study.
OBJECTIVE
To assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response.


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.


CONCLUSIONS
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.
Willett
Christopher G
CG
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA. christopher.willett@duke.edu
Duda
Dan G
DG
di Tomaso
Emmanuelle
E
Boucher
Yves
Y
Ancukiewicz
Marek
M
Sahani
Dushyant V
DV
Lahdenranta
Johanna
J
Chung
Daniel C
DC
Fischman
Alan J
AJ
Lauwers
Gregory Y
GY
Shellito
Paul
P
Czito
Brian G
BG
Wong
Terence Z
TZ
Paulson
Erik
E
Poleski
Martin
M
Vujaskovic
Zeljko
Z
Bentley
Rex
R
Chen
Helen X
HX
Clark
Jeffrey W
JW
Jain
Rakesh K
RK
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D000068258:Bevacizumab; D015415:Biomarkers / Q000097:blood*; D003131:Combined Modality Therapy; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D012004:Rectal Neoplasms / Q000401:mortality / Q000532:radiotherapy / Q000601:surgery / Q000628:therapy*; D042461:Vascular Endothelial Growth Factor A
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D015850:Interleukin-6; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D005472:Fluorouracil