Presenter: Howard S. Hochster, MD. Presenter's Affiliation: New York University Cancer Institute, New York, New York Type of Session: Scientific
5-Fluorouracil (5FU) is a very old chemotherapy drug for colorectal cancer, and recent research has demonstrated that the use of 5FU in combination with other drugs like oxaliplatin and irinotecan can improve outcomes.
Before targeted agents, a large randomized study (N9741) demonstrated that the combination of oxaliplatin with 5FU and leucovorin (FOLFOX) was the most active regimen for metastatic colorectal cancer.
Growing tumors need access to nutrients and a blood supply, and the process of new blood vessel formation is called angiogenesis.
Considerable research has demonstrated the importance of angiogenesis for tumor growth and development.
Growing tumors secrete molecules that signal for the initiation and maintenance of angiogenesis.
One of the main molecules that signals for angiogenesis is called vascular endothelial growth factor (VEGF)
Hypoxia, inflammatory molecules, and growth factors can all cause tumor cells to begin expressing VEGF.
VEGF has 3 known receptors by which it can transmit the signal for angiogenesis to occur.
A novel strategy to control tumors involves disrupting tumor angiogenesis by either decreasing VEGF levels or blocking VEGF receptors.
Bevacizumab, a humanized anti-VEGF antibody which binds to the major ligand of the VEGFR1 receptor, was shown to be effective in preclinical, phase II, and phase III studies of colorectal cancer.
A large, randomized phase III study (AVF2107) demonstrated that the addition of bevacizumab to irinotecan, 5FU, leucovorin (bIFL) resulted in improvements in response rates, time-to-progression, and overall survival when compared to irinotecan, 5FU, leucovorin (IFL) alone.
The addition of bevacizumab increased the rates of hypertension, arterial thrombotic events, and bowel perforations.
This study lead to the approval of bevacizumab with 5FU-based chemotherapy without much data on its use with an oxaliplatin-containing regimen.
Following this, ECOG E3200 examined the efficacy of bevacizumab with FOLFOX as second line therapy for metastatic colorectal cancer, and the results of this trial were presented at ASCO 2005.
This trial showed improvements in response rates (22% vs 9%), median survival (12.9 months vs 10.8 months) and disease free survival (7.2 months vs 4.8 months) when adding bevacizumab to FOLFOX.
Materials and Methods
The TREE-1 study was designed to test the various toxicities of three different infusional strategies for delivering 5FU and oxaliplatin.
The three arms included: modified FOLFOX6 (oxali 85mg/m2 + leucovorin 350mg + 5FU 400mg/m2 bolus + 2400mg/m2 x46h day 1 q14d), bolus FOL (weekly bolus 5FU 500 mg/m2 and leucovorin 20mg/m2 x 3 every four weeks with q2 week bolus oxaliplatin 130mg/m2) and CapeOX (capecitabine 1000mg/m2 bid x 14 days q 21 days with oxaliplatin 130mg/m2).
The TREE-2 study took the TREE-1 study and added bevacizumab to each arm (either 5mg/kg q 2 weeks or 7.5mg/kg q 3 weeks).
The TREE-2 study enrolled 221 patients from November 2003 to April 2004.
Response rates for FOLFOX, FOL, and CapeOX from TREE-1 were 47%, 32%, and 38% respectively.
Response rates for bFOLFOX, bFOL, and bCapeOX from TREE-2 were 63%, 43% and 57% respectively.
Survival in TREE-1 was equal in each arm with a median survival of about 17.5 months.
Survival data from TREE-2 will be available for presentation during ASCO 2006.
In the TREE-1 study, the FOLFOX regimen had the highest rates of grade 3-4 neutropenia, the FOL regimen had the lowest rates of grade 3-4 toxicity, and the CapeOX had to be dose-reduced to 850mg/m2 bid secondary to severe diarrhea, mucositis, and increased hospitalizations.
The addition of bevacizumab in the TREE-2 study was well tolerated with no significant additive toxicities.
Bevacizumab significantly improved overall response rates in each regimen.
Bolus 5FU (bFOL) may have lower response rates with similar survival.
CapeOX tolerability improved using lowered dose capecitabine (850mg/m2 bid), with no appreciable decrease in efficacy.
Bevacizumab prevents angiogenesis and improves overall survival, progression free survival, and response rates in metastatic colorectal cancer.
Bevacizumab with IFL improves survival by 33%.
Addition of bevacizumab to FOLFOX is equally safe and improves response and survival proportionally.
Bevacizumab should be a first line agent and considered standard of care in combination regimens for patients without contraindications to its use.
Median survivals using bevacizumab with cytotoxic chemotherapy are reaching the 24 month mark.
Studies of bevacizumab with FOLFOX in the adjuvant setting are currently underway.
The author presented an exhaustive review of the literature on the efficacy of bevacizumab for the treatment of metastatic colorectal cancer. There is little doubt that this compound is effective in this disease, and the data presented support the author's conclusions that bevacizumab should be considered first line therapy. Future studies will add this compound earlier in the process as adjuvant therapy following resection of stage II and III colon cancer. This drug is also being studied with preoperative chemoradiotherapy in locally advanced rectal cancer.
Another compound, cetuximab, which is a monoclonal antibody which blocks EGFR and disrupts cell cycle progression and tumor growth, has shown efficacy as therapy for colorectal cancer. A proposed intergroup trial seeks to randomize patients to FOLFOX or FOLFIRI with either bevacizumab, cetuximab, or both bevacizumab and cetuximab. The results of this study will be very interesting to GI oncologists. For a very long period of time, the only drug for colorectal cancer was 5FU, and now patients and physicians have access to a myriad of chemotherapeutics and targeted therapies in seemingly endless combinations. The physicians, scientists, and drug developers responsible for these new agents should be commended for their continued efforts which have already made a significant difference in the lives of many of these patients.
Jun 6, 2012 - Continuing use of bevacizumab (Avastin) in combination with second-line chemotherapy improves overall survival and progression-free survival in patients with metastatic colorectal cancer who have progressed after discontinuation of first-line bevacizumab and chemotherapy, according to the results of a phase III study presented at the annual meeting of the American Society of Clinical Oncology, held from June 1 to 5 in Chicago.