A phase II study of neoadjuvant bevacizumab plus capecitabine and concomitant radiotherapy in patients with locally advanced rectal cancer.
OBJECTIVE
To assess safety and activity of neoadjuvant bevacizumab, capecitabine and standard radiotherapy in locally advanced rectal cancer as well as potential predictive biomarkers.


METHODS
The multicentric phase II study enrolled 43 patients who received bevacizumab infusion (5 mg/kg) every 2 weeks for 4 cycles; oral capecitabine at 825 mg/m(2) twice a day for 5.5 weeks with external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks). We determined certain biomarkers before and after therapy for correlation with response.


RESULTS
Post-operative histologic examination revealed no residual cancer cells in 6 of the 43 patients (14%; 95% confidence limits 3.60-24.31%). In another 22 patients (51.2%) a varying percentage of cancer cells in residual areas of fibrosis/ necrosis was found, corresponding to Mandard TRG 2 or 3 classification. Tumor resection with negative circumferential margin was achieved in 38/40 (95%) operated patients. Sphincter-sparing surgery was obtained in 31 (72.1%) patients. Primary tumor and lymph nodes downstaging was observed in 15 (34.9%) and 16 (37.2%) cases, respectively. Neoadjuvant therapy was safe and well tolerated. The most frequent side effects were G1-2 diarrhea, proctitis, rectal bleeding and hypertension. No biomarker tested was significantly predictive of both pathological complete response and disease-free survival. Pre-treatment CD-34 vessel density, post-treatment Ki-67 labeling index and VEGFR-2 cancer cells expression significantly correlated with residual tumor area.


CONCLUSIONS
The schedule of neoadjuvant therapy tested was safe and active. Pre-treatment vessel density by the panendothelial marker anti CD-34 antibody, post-treatment Ki-67 labeling index and VEGFR-2 expression were significantly associated to residual tumor area. The biomarkers correlations warrant further evaluation in prospective clinical trials.
Unità Operativa Complessa di Oncologia Medica, Azienda Complesso Ospedaliero di Rilevanza Nazionale S. Filippo Neri, Via G. Martinotti, 20, 00135 Rome, Italy. gasparini.oncology@hotmail.it
Giampietro
G
Gasparini
Francesco
F
Torino
Takayuki
T
Ueno
Stefano
S
Cascinu
Teresa
T
Troiani
Alberto
A
Ballestrero
Rossana
R
Berardi
Junichi
J
Shishido
Akihiko
A
Yoshizawa
Yukiko
Y
Mori
Satoshi
S
Nagayama
Paola
P
Morosini
Masakazu
M
Toi
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000378:metabolism; D000069287:Capecitabine; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011379:Prognosis; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D016896:Treatment Outcome
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D005472:Fluorouracil