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Neoadjuvant FOLFIRI+bevacizumab in patients with resectable liver metastases from colorectal cancer: a phase 2 trial.

ABSTRACT: BACKGROUND: Preoperative treatment of resectable liver metastases from colorectal cancer (CRC) is a matter of debate. The aim of this study was to assess the feasibility and activity of bevacizumab plus FOLFIRI in this setting. METHODS: Patients aged 18-75 years, PS 0-1, with resectable liver-confined metastases from CRC were eligible. They received bevacizumab 5 mg kg(-1) followed by irinotecan 180 mg m(-)(2), leucovorin 200 mg m(-)(2), 5-fluorouracil 400 mg m(-)(2) bolus and 5-fluorouracil 2400 mg m(-)(2) 46-h infusion, biweekly, for 7 cycles. Bevacizumab was stopped at cycle 6. A single-stage, single-arm phase 2 study design was applied with 1-year progression-free rate as the primary end point, and 39 patients required. RESULTS: From October 2007 to December 2009, 39 patients were enrolled in a single institution. Objective response rate was 66.7% (95% exact CI: 49.8-80.9). Of these, 37 patients (94.9%) underwent surgery, with a R0 rate of 84.6%. Five patients had a pathological complete remission (14%). Out of 37 patients, 16 (43.2%) had at least one surgical complication (most frequently biloma). At 1 year of follow-up, 24 patients were alive and free from disease progression (61.6%, 95% CI: 44.6-76.6). Median PFS and OS were 14 (95% CI: 11-24) and 38 (95% CI: 28-NA) months, respectively. CONCLUSION: Preoperative treatment of patients with resectable liver metastases from CRC with bevacizumab plus FOLFIRI is feasible, but further studies are needed to define its clinical relevance.

SUBMITTER: Nasti G

PROVIDER: S-EPMC3668480 | biostudies-other | 2013 Apr

REPOSITORIES: biostudies-other

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Project description:BackgroundFollowing resection of liver metastases from colorectal cancer, 5-year survivals are reportedly 30 - 39%. It can be assumed that this clinical situation represents systemic disease. Therefore, it is postulated that systemic chemotherapy would improve outcomes, particularly in those whose disease is sensitive to the agents administered. One potential advantage of neoadjuvant chemotherapy is that it provides in vivo chemosensitivity data. Response to neoadjuvant chemotherapy could therefore guide adjuvant chemotherapy following resection of liver metastases from colorectal cancer.Methods and designThis is a prospective Phase II evaluation of outcomes in patients with potentially resectable liver metastases. Patients will receive neoadjuvant chemotherapy and will undergo resection. Postoperative chemotherapy will be directed by the degree of response to preoperative chemotherapy. All patients with Stage IV colorectal adenocarcinoma isolated to the liver that have disease that is amenable to complete ablation by resection, radiofrequency ablation, and/or cryoablation will be candidates for the trial. Patients will receive CPT-11 180 mg/m2 IV (over 90 minutes) on day 1 with 5-FU 400 mg/m2 bolus and 600 mg/m2 by 22 hour infusion and calcium folinate 200 mg/m2 on days 1 and 2, every 2 weeks. Altogether, six cycles of chemotherapy will be administered. Patients will then undergo resection and/or radiofrequency ablation. Patients who had stable disease or a clinical response with preoperative chemotherapy will receive an additional 12 cycles of CPT-11 180 mg/m2 IV (over 90 minutes) on day 1 with 5-FU 400 mg/m2 bolus and 600 mg/m2 by 22 hour infusion and calcium folinate 200 mg/m2 on days 1 and 2 (given every 2 weeks). Patients with resectable disease who had progressive disease during neoadjuvant chemotherapy will receive best supportive care or an alternative agent, at the discretion of the treating physician. Those patients who are not rendered free of disease following the neoadjuvant chemotherapy and surgery will receive best supportive care or an alternative agent, at the discretion of the treating physician. The primary endpoint of the study is disease-free survival. Secondary endpoints include overall survival, safety and feasibility, response to chemotherapy, and quality of life.

Project description:PurposeNumerous preclinical studies have demonstrated that angiogenesis inhibitors can increase the efficacy of radiotherapy (RT). We sought to examine the safety and efficacy of bevacizumab (BV) and RT in soft tissue sarcomas and explore biomarkers to help determine the treatment response.Methods and materialsPatients with ≥5 cm, intermediate- or high-grade soft tissue sarcomas at significant risk of local recurrence received neoadjuvant BV alone followed by BV plus RT before surgical resection. Correlative science studies included analysis of the serial blood and tumor samples and serial perfusion computed tomography scans.ResultsThe 20 patients had a median tumor size of 8.25 cm, with 13 extremity, 1 trunk, and 6 retroperitoneal/pelvis tumors. The neoadjuvant treatment was well tolerated, with only 4 patients having Grade 3 toxicities (hypertension, liver function test elevation). BV plus RT resulted in ≥80% pathologic necrosis in 9 (45%) of 20 tumors, more than double the historical rate seen with RT alone. Three patients had a complete pathologic response. The median microvessel density decreased 53% after BV alone (p <.05). After combination therapy, the median tumor cell proliferation decreased by 73%, apoptosis increased 10.4-fold, and the blood flow, blood volume, and permeability surface area decreased by 62-72% (p <.05). Analysis of gene expression microarrays of untreated tumors identified a 24-gene signature for treatment response. The microvessel density and circulating progenitor cells at baseline and the reduction in microvessel density and plasma soluble c-KIT with BV therapy also correlated with a good pathologic response (p <.05). After a median follow-up of 20 months, only 1 patient had developed local recurrence.ConclusionsThe results from the present exploratory study indicated that BV increases the efficacy of RT against soft tissue sarcomas and might reduce the incidence of local recurrence. Thus, this regimen warrants additional investigation. Gene expression profiles and other tissue and circulating biomarkers showed promising correlations with treatment response.

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Neoadjuvant FOLFIRI+bevacizumab in patients with resectable liver metastases from colorectal cancer: a phase 2 trial.

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