Gustavsson B.,Sahlgrenska University Hospital |
Carlsson G.,Sahlgrenska University Hospital |
MacHover D.,University Paris - Sud |
Petrelli N.,Helen aham Cancer Center At Christiana Care |
And 4 more authors.
Clinical Colorectal Cancer | Year: 2015
Herein we present a historical review of the development of systemic chemotherapy for colorectal cancer (CRC) in the metastatic and adjuvant treatment settings. We describe the discovery of 5-fluorouracil (5-FU) by Heidelberger and colleagues in 1957, the potentiation of 5-FU cytotoxicity by the reduced folate leucovorin, and the advent of novel cytotoxic agents, including the topoisomerase I inhibitor irinotecan, the platinum-containing agent oxaliplatin, and the 5-FU prodrug capecitabine. The combination therapies, FOLFOX (5-FU/leucovorin and oxaliplatin) and FOLFIRI (5-FU/leucovorin and irinotecan), have become established as efficacious cytotoxic regimens for the treatment of metastatic CRC, resulting in overall survival times of approximately 2 years. When used as adjuvant therapy, FOLFOX also improves survival and is now the gold standard of care in this setting. Biological agents have been discovered that enhance the effect of cytotoxic therapy, including bevacizumab (a humanized monoclonal antibody that targets vascular endothelial growth factor, a central regulator of angiogenesis) and cetuximab/panitumumab (monoclonal antibodies directed against the epidermal growth factor receptor). Despite the ongoing development of novel antitumor agents and therapeutic principles as we enter the era of personalized cancer medicine, systemic chemotherapy involving infusional 5-FU/leucovorin continues to be the cornerstone of treatment for patients with CRC. © 2015 The Authors.
Pogue-Geile K.,National Surgical Adjuvant Breast and Bowel Project NSABP |
Yothers G.,National Surgical Adjuvant Breast and Bowel Project NSABP |
Yothers G.,Biostatistical Center |
Yothers G.,University of Pittsburgh |
And 20 more authors.
Journal of the National Cancer Institute | Year: 2013
National Surgical Adjuvant Breast and Bowel Project protocol C-08 tested the worth of adding 1 year of bevacizumab to oxaliplatin-based standard adjuvant chemotherapy regimen in the treatment of stage II/III colon cancer. Although the overall result was negative, the possibility that a molecularly defined subset could benefit from bevacizumab cannot be ruled out. We performed post hoc Cox regression analyses to test for marker-by-treatment interactions for standard pathological features and survival analyses using the Kaplan-Meier method. All statistical tests were two-sided and considered statistically significant at the. 05 level. Patients diagnosed with mismatch repair defective (dMMR) tumors derived statistically significant survival benefit from the addition of bevacizumab (hazard ratio [HR] = 0.52; 95% confidence interval [CI] = 0.29 to 0.94; P =. 02) in contrast with no benefit in patients diagnosed with mismatch repair proficient tumors (HR = 1.03; 95% CI = 0.84 to 1.27; p =. 78; Pinteraction =. 04). Although a post hoc finding, this data suggests that a molecularly defined subset of colon cancer patients may derive clinical benefit from antiangiogenesis agents and underscores the need for independent validation in other clinical trials. © 2013 © The Author 2013. Published by Oxford University Press. All rights reserved.
Allegra C.J.,Allegheny General Hospital |
Allegra C.J.,University of Florida |
Yothers G.,Allegheny General Hospital |
O'Connell M.J.,Allegheny General Hospital |
And 5 more authors.
Journal of Clinical Oncology | Year: 2013
Purpose: The National Surgical Adjuvant Breast and Bowel Project trial C-08 was designed to investigate the safety and efficacy of adding bevacizumab to fluorouracil, leucovorin, and oxaliplatin (FOLFOX6) for the adjuvant treatment of patients with stage 2-3 colon cancer. Our report summarizes the primary and secondary end points of disease-free and overall survival, respectively, with 5 years median follow-up time Patients and Methods: Patients received modified FOLFOX6 once every 2 weeks for a 6-month period (control group) or modified FOLFOX6 for 6 months plus bevacizumab (5 mg/kg) once every 2 weeks for a 12-month period (experimental group). The primary end point of the study was disease-free survival (DFS) and overall survival (OS) was a secondary end point Results: Of 2,673 analyzed patients, demographic factors were well-balanced by treatment. With a median follow-up of 5 years, the addition of bevacizumab to mFOLFOX6 did not result in an overal significant increase in DFS (hazard ratio [HR], 0.93; 95% CI, 0.81 to 1.08; P =.35). Exploratory analyses found that the effect of bevacizumab on DFS was different before and after a 1.25-year landmark (time-by-treatment interaction P value <.0001). The secondary end point of OS was no different between the two study arms for all patients (HR, 0.95; 95% CI, 0.79 to 1.13; P =.56) and for those with stage 3 disease (HR, 1.0; 95% CI, 0.83 to 1.21; P =.99) Conclusion: Bevacizumab for 1 year with modified FOLFOX6 does not significantly prolong DFS or OS in stage 2-3 colon cancer. We observed no evidence of a detrimental effect of exposure to bevacizumab. A transient effect on disease-free survival was observed during bevacizumab exposure in the study's experimental arm © 2012 by American Society of Clinical Oncology.
Rubino M.S.,Helen aham Cancer Center At Christiana Care |
Abdel-Misih R.Z.,Helen aham Cancer Center At Christiana Care |
Bennett J.J.,Helen aham Cancer Center At Christiana Care |
Petrelli N.J.,Helen aham Cancer Center At Christiana Care
Surgical Oncology | Year: 2012
Recent studies have lead to a renewed interest in cytoreductive surgery and intraperitoneal chemotherapy as a regional treatment modality for patients with peritoneal surface malignancies. There have been multiple phase III randomized trials that have shown a survival advantage with intraperitoneal chemotherapy in certain patients. More well designed phase III studies are needed to further define which groups of patients may benefit from cytoreductive surgery and intraperitoneal chemotherapy. © 2010 Elsevier Ltd. All rights reserved.
Yothers G.,N-of-One |
Yothers G.,University of Pittsburgh |
O'Connell M.J.,N-of-One |
Allegra C.J.,N-of-One |
And 8 more authors.
Journal of Clinical Oncology | Year: 2011
Purpose: The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial demonstrated that the addition of oxaliplatin to fluorouracil plus leucovorin (FULV) improved disease-free survival (DFS) in patients with stage II or III colon cancer. This analysis is the first publication of overall survival (OS) for the NSABP C-07 study. We updated DFS and examined both end points in clinically relevant patient subsets. Patients and Methods: Other studies have identified patients age 70 or older and those with stage II disease as patient subsets in which oxaliplatin may not be effective. We investigated toxicity as a driver of divergent outcomes in these subsets. Results: In all, 2,409 eligible patients with follow-up were randomly assigned to either FULV (FU 500 mg/m 2 by intravenous [IV] bolus weekly for 6 weeks; leucovorin 500 mg/m 2 IV weekly for 6 weeks of each 8-week cycle for three cycles) or FLOX (FULV plus oxaliplatin 85 mg/m 2 IV on days 1, 15, and 29 of each cycle). With 8 years median follow-up, OS was similar between treatment groups (hazard ratio [HR], 0.88; 95% CI, 0.75 to 1.02; P = .08). FLOX remained superior for DFS (HR, 0.82; 95% CI, 0.72 to 0.93; P = .002). The effect of oxaliplatin on OS did not differ by stage of disease (interaction P = .38 for OS; interaction P = 0.37 for DFS) but did vary by age for OS (younger than age 70 v 70+ interaction P = .039). There was a similar trend for DFS (interaction P = .073). Oxaliplatin significantly improved OS in patients younger than age 70 (HR, 0.80; 95% CI, 0.68 to 0.95; P = .013), but no positive effect was evident in older patients. Conclusion: Overall, the addition of oxaliplatin to FULV has not been proven to extend OS in this trial, but the DFS effect remained strong. Unplanned subset analyses suggest a significant OS effect of oxaliplatin in patients younger than age 70. © 2011 by American Society of Clinical Oncology.
Primary mFOLFOX6 plus bevacizumab without resection of the primary tumor for patients presenting with surgically unresectable metastatic colon cancer and an intact asymptomatic colon cancer: Definitive analysis of NSABP Trial C-10
McCahill L.E.,National Surgical Adjuvant Breast and Bowel Project |
McCahill L.E.,Richard cks Cancer Center |
McCahill L.E.,Michigan State University |
Yothers G.,National Surgical Adjuvant Breast and Bowel Project |
And 21 more authors.
Journal of Clinical Oncology | Year: 2012
Purpose: Major concerns surround combining chemotherapy with bevacizumab in patients with colon cancer presenting with an asymptomatic intact primary tumor (IPT) and synchronous yet unresectable metastatic disease. Surgical resection of asymptomatic IPT is controversial. Patients and Methods: Eligibility for this prospective, multicenter phase II trial included Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1, asymptomatic IPT, and unresectable metastases. All received infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) combined with bevacizumab. The primary end point was major morbidity events, defined as surgical resection because of symptoms at or death related to the IPT. A 25% major morbidity rate was considered acceptable. Secondary end points included overall survival (OS) and minor morbidity related to IPT requiring hospitalization, transfusion, or nonsurgical intervention. Results: Ninety patients registered between March 2006 and June 2009: 86 were eligible with follow-up, median age was 58 years, and 52% were female. Median follow-up was 20.7 months. There were 12 patients (14%) with major morbidity related to IPT: 10 required surgery (eight, obstruction; one, perforation; and one, abdominal pain), and two patients died. The 24-month cumulative incidence of major morbidity was 16.3% (95% CI, 7.6% to 25.1%). Eleven IPTs were resected without a morbidity event: eight for attempted cure and three for other reasons. Two patients had minor morbidity events only: one hospitalization and one nonsurgical intervention. Median OS was 19.9 months (95% CI, 15.0 to 27.2 months). Conclusion: This trial met its primary end point. Combining mFOLFOX6 with bevacizumab did not result in an unacceptable rate of obstruction, perforation, bleeding, or death related to IPT. Survival was not compromised. These patients can be spared initial noncurative resection of their asymptomatic IPT. © 2012 by American Society of Clinical Oncology.
PubMed | Helen aham Cancer Center At Christiana Care
Type: Journal Article | Journal: Surgical oncology | Year: 2012
Recent studies have lead to a renewed interest in cytoreductive surgery and intraperitoneal chemotherapy as a regional treatment modality for patients with peritoneal surface malignancies. There have been multiple phase III randomized trials that have shown a survival advantage with intraperitoneal chemotherapy in certain patients. More well designed phase III studies are needed to further define which groups of patients may benefit from cytoreductive surgery and intraperitoneal chemotherapy.