Phase 2 study of preoperative radiation with concurrent capecitabine, oxaliplatin, and bevacizumab followed by surgery and postoperative 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX), and bevacizumab in patients with locally advanced rectal cancer: ECO

Recent studies have demonstrated the feasibility of combining oxaliplatin with 5-fluorouracil (5-FU) or capecitibine and radiation therapy. The addition of bevacizumab to chemotherapy improves overall survival for metastatic disease. We initiated a phase 2 trial to evaluate preoperative capecitabine, oxaliplatin, and bevacizumab with radiation therapy followed by surgery and postoperative 5-FU, leucovorin, oxaliplatin (FOLFOX) and bevacizumab for locally advanced rectal cancer. Fifty-seven patients with resectable T3/T4 rectal adenocarcinoma were enrolled. Preoperative treatment was capecitabine (825 mg/m(2) twice daily from Monday to Friday), oxaliplatin (50 mg/m(2) weekly), bevacizumab (5 mg/kg on days 1, 15, 29), and radiation therapy (50.4 Gy). Surgery was performed by 6 weeks after neoadjuvant therapy. Beginning 8 to 12 weeks after surgery, patients received FOLFOX plus bevacizumab (5 mg/kg) every 2 weeks for 12 cycles. Fifty-four of 57 enrolled patients were eligible. Forty-nine (91%) patients completed preoperative therapy and underwent surgery. Nine patients (17%; 90% confidence interval, 9%-27%) achieved pathologic complete response. Thirty-two patients (59%) experienced pathologic tumor downstaging, and 53% and 15% of patients experienced worst grade 3 and grade 4 acute toxicity, respectively. Forty-seven percent of patients who underwent surgery experienced a surgical complication. The primary endpoint of a 30% pathologic complete response rate was not reached; however, the majority of patients experienced pathologic downstaging with this regimen. Increased wound-healing delays and complications may have been related to the addition of bevacizumab, oxaliplatin, or both. Continued observation of these patients will establish the long-term morbidity and efficacy of this combined modality approach.

Landry JC ，Feng Y ，Cohen SJ ，Staley CA 3rd ，Whittington R ，Sigurdson ER ，Nimeiri H ，Verma U ，Prabhu RS ，Benson AB ... -  《-》

Phase II Trial of Preoperative Radiation With Concurrent Capecitabine, Oxaliplatin, and Bevacizumab Followed by Surgery and Postoperative 5-Fluorouracil, Leucovorin, Oxaliplatin (FOLFOX), and Bevacizumab in Patients With Locally Advanced Rectal Cancer: 5-

The 5-year oncologic outcomes from the trial regimen were excellent. However, the neoadjuvant and surgical toxicity of this regimen was significant and was the primary reason for the low compliance with adjuvant systemic therapy.Due to the lack of an improvement in the pathologic complete response rate, the substantial associated toxicity, and the negative phase III trials of adjuvant bevacizumab in colon cancer, this regimen will not be pursued for further study. The addition of bevacizumab to chemotherapy improves overall survival for metastatic colorectal cancer. We initiated a phase II trial to evaluate preoperative capecitabine, oxaliplatin, and bevacizumab with radiation therapy (RT) followed by surgery and postoperative 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX), and bevacizumab for locally advanced rectal cancer. The purpose of this report is to describe the 5-year oncologic outcomes of this regimen. In a phase II Simon two-stage design study, we evaluated preoperative treatment with capecitabine (825 mg/m(2) b.i.d. Monday-Friday), oxaliplatin (50 mg/m(2) weekly), bevacizumab (5 mg/kg on days 1, 15, and 29), and RT (50.4 Gy). Surgery was performed by 8 weeks after RT. Beginning 8-12 weeks after surgery, patients received FOLFOX plus bevacizumab (5 mg/kg) every 2 weeks for 12 cycles (oxaliplatin stopped after 9 cycles). The primary endpoint was a pathologic complete response (path-CR) rate of 30%. Fifty-seven patients with resectable T3/T4 rectal adenocarcinoma were enrolled between 2006 and 2010. Of 57 enrolled patients, 53 were eligible and included in the analysis. Forty-eight (91%) patients completed preoperative therapy, all of whom underwent curative surgical resection. Nine patients (17%) achieved path-CR. There were 29 worst grade 3 events, 8 worst grade 4 events, and 2 patient deaths, 1 of which was attributed to study therapy. Twenty-six patients (54%) began adjuvant chemotherapy. After a median follow-up period of 41 months, the 5-year overall survival (OS) rate for all patients was 80%. Only 2 patients experienced cancer recurrence: 1 distant (liver) and 1 loco-regional (pelvic lymph nodes), respectively. Both of these patients are still alive. The 5-year relapse-free survival rate was 81%. Despite the path-CR primary endpoint of this trial not being reached, the 5-year OS and recurrence-free survival rates were excellent. However, the neoadjuvant and surgical toxicity of this regimen was significant and was the primary reason for the low compliance with adjuvant systemic therapy. Because of the lack of an improvement in the path-CR rate, the substantial associated toxicity, and the negative phase III trials of adjuvant bevacizumab in colon cancer, this regimen will not be pursued for further study.

Landry JC ，Feng Y ，Prabhu RS ，Cohen SJ ，Staley CA ，Whittington R ，Sigurdson ER ，Nimeiri H ，Verma U ，Benson AB ... -  《-》

Phase II trial of preoperative radiochemotherapy with concurrent bevacizumab, capecitabine and oxaliplatin in patients with locally advanced rectal cancer.

Dellas K ，Höhler T ，Reese T ，Würschmidt F ，Engel E ，Rödel C ，Wagner W ，Richter M ，Arnold D ，Dunst J ... -  《-》

Pre-operative bevacizumab, capecitabine, oxaliplatin and radiation among patients with locally advanced or low rectal cancer: a phase II trial.

To evaluate the safety and efficacy of pre-operative chemoradiation, using capecitabine, oxaliplatin and bevacizumab with standard doses of radiation, in patients with high-risk rectal cancer. Patients with locally advanced or low rectal cancer were treated with capecitabine 825 mg/m(2) twice daily on days 1-14 and 22-35, oxaliplatin 50mg/m(2) on days 1, 8, 22 and 29, bevacizumab 5mg/kg on days 14, 1, 15 and 29, and radiation 50.4 Gy in 28 fractions including boost. Total mesorectal excision was performed 7-9 weeks after chemoradiation. The primary end-point was complete tumour regression (ypT0NX) by central review. Forty-two evaluable patients were enrolled, and 38 proceeded to definitive surgery. Eighteen patients (43%) had clinical T4 tumours and/or N2 tumours. Mean relative dose intensity was >90% for all systemic agents, and 97% for radiation. Grade 3/4 diarrhoea occurred in 10 patients (24%) and pain in 4 patients (10%) pre-operatively, while grade 3/4 pain, fatigue and infection were each reported among 5 patients (13%) post-operatively. Re-operation due to complications occurred in 4 patients (11%). Complete tumour regression (ypT0) was seen in 9 patients (23.7%) of which two had N1 disease and the pathological complete response (pCR) rate (ypT0N0) was 18.4%. Central review changed pathologic stage in six cases (16%). In this study, pre-operative bevacizumab added to oxaliplatin, capecitabine and radiation was safe and resulted in a promising tumour regression rate. Surgical complications were closely monitored and occurred with the expected frequency. Central pathology review should be considered for trials with pathologic response as the primary end-point. British Columbia Cancer Agency, Hoffmann-La Roche Canada and Sanofi-Aventis.

Kennecke H ，Berry S ，Wong R ，Zhou C ，Tankel K ，Easaw J ，Rao S ，Post J ，Hay J ... -  《-》

Radiation Therapy Oncology Group 0247: a randomized Phase II study of neoadjuvant capecitabine and irinotecan or capecitabine and oxaliplatin with concurrent radiotherapy for patients with locally advanced rectal cancer.

To evaluate the rate of pathologic complete response (pCR) and the toxicity of two neoadjuvant chemoradiotherapy (chemoRT) regimens for Stage T3-T4 rectal cancer in a randomized Phase II study. Patients with Stage T3 or T4 rectal cancer of <12 cm from the anal verge were randomized to preoperative RT (50.4 Gy in 1.8-Gy fractions) with concurrent capecitabine (1,200 mg/m(2)/d Mondays through Friday) and irinotecan (50 mg/m(2) weekly in four doses) (Arm 1) or concurrent capecitabine (1,650 mg/m(2)/d Monday through Friday) and oxaliplatin (50 mg/m(2) weekly in five doses) (Arm 2). Surgery was performed 4-8 weeks after chemoRT, and adjuvant chemotherapy 4-6 weeks after surgery. The primary endpoint was the pCR rate, requiring 48 evaluable patients per arm. A total of 146 patients were enrolled. The protocol chemotherapy was modified because of excessive gastrointestinal toxicity after treatment of 35 patients; 96 were assessed for the primary endpoint-the final regimen described above. The patient characteristics were similar for both arms. After chemoRT, the rate of tumor downstaging was 52% and 60% and the rate of nodal downstaging (excluding N0 patients) was 46% and 40%, for Arms 1 and 2, respectively. The pCR rate for Arm 1 was 10% and for Arm 2 was 21%. For Arm 1 and 2, the preoperative chemoRT rate of Grade 3-4 hematologic toxicity was 9% and 4% and the rate of Grade 3-4 nonhematologic toxicity was 26% and 27%, respectively. Preoperative chemoRT with capecitabine plus oxaliplatin for distal rectal cancer has significant clinical activity (10 of 48 pCRs) and acceptable toxicity. This regimen is currently being evaluated in a Phase III randomized trial (National Surgical Adjuvant Breast and Bowel Project R04).

Wong SJ ，Winter K ，Meropol NJ ，Anne PR ，Kachnic L ，Rashid A ，Watson JC ，Mitchell E ，Pollock J ，Lee RJ ，Haddock M ，Erickson BA ，Willett CG ... -  《-》