According to the results of a clinical trial presented at the Gastrointestinal Cancers Symposium in San Francisco, treatment of patients with metastatic colorectal cancer with a four-drug chemotherapy regimen plus Avastin® (bevacizumab) doubles survival when compared to a standard three drug regimen and Avastin.There is good news about colorectal cancer in the United States: death rates associated with the disease have dropped during the past 15 years, and advances continue to be made in screening, prevention, and treatment. Unfortunately many individuals will fail initial therapy and develop metastatic disease. Continued development of drugs to treat metastatic colon cancer is necessary to further improve outcomes.The standard treatment of advanced colon cancer is with chemotherapy and the addition of Avastin has been reported to improve treatment. Avastin targets the vascular endothelial growth factor (VEGF). VEGF is implicated in cell spread and survival. Avastin binds to components of VEGF and reduces or prevents the spread of cancer cells. It can be used in combination with fluorouracil-based chemotherapy for metastatic colorectal cancer.(1)In the current study doctors from Italy treated patients with metastatic colon cancer under the age of 75 with either leucovorin, fluorouracil (5-FU), Camptosar® (irinotecan), Eloxatin® (oxaliplatin) (FOLFOXIRI), and Avastin or with leucovorin-fluorouracil- Camptosar® (FOLFIRI)-Avastin and directly compared the outcomes.The time to cancer progression was modestly improved from 9.7 months with FOLFIRI to 12.3 months with FOLFOXIRI. However, the number of patients surviving 5 years was significantly increased; doubling from 24.9% for FOLFOXIRI-Avastin compared to only12.4% for FOLFIRI-Avastin.“FOLFOXIRI-Avastin doubles the estimated 5-year overall survival rate as compared to FOLFIRI-Avastin,” the lead investigator, Cremolini said during a press briefing that preceded the symposium. “FOLFOXIRI-Avastin represents a valuable option for the upfront treatment of metastatic colorectal cancer.” She added that the more intense regimen was also associated with increased toxicity, which was manageable. However, the regimen would not be suitable for patients older than 75 or those who are 70 to 75 and not in good health.The two most widely used first-line chemotherapy regimens for metastatic colorectal cancer are FOLFIRI and FOLFOX (leucovorin-fluorouracil- Eloxatin®). Giving Avastin in addition to the chemotherapy has been shown to improve survival compared with chemotherapy alone.This study clearly demonstrates that FOLFOXIRI-Avastin is a safe and effective option for patients with advanced colorectal cancer who can tolerate the regimen.References:
- Emmanouilides C, Sfakiotaki G, Androulakis N, et al. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter Phase II study. 2007;7:91. Available at : http://www.biomedcentral.com/1471-2407/7/91. Accessed August 2007.
- Cremolini C, Loupakis F, Masi G, et al. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (mCRC): Updated survival results of the phase III TRIBE trial by the GONO group. J Clin Oncol. 33, 2015 (suppl 3; abstr 657).
The U.S. Food and Drug Administration (FDA) has approved the use of Avastin® (bevacizumab), in combination with 5-fluorouracil (5-FU)-based chemotherapy, for the treatment of advanced colorectal cancer in patients who have received a prior therapeutic regimen. Avastin is already approved for use as initial treatment in combination with 5-FU-based chemotherapy in patients with advanced colorectal cancer.
Avastin belongs to a group of drugs called monoclonal antibodies. Avastin produces its anticancer effects by targeting and binding to vascular endothelial growth factor (VEGF) and preventing the interaction of VEGF with its receptors.
VEGF, a type of protein, is important in a process leading to cellular growth, replication and spread, and new blood vessel formation. Avastin binds to VEGF and inhibits its normal effects. It reduces the growth and spread of cancer cells by inhibiting the growth of new blood vessels, making it harder for the tumor to grow.
Previously, Avastin was approved for the initial treatment of advanced colorectal cancer in combination with 5-fluorouracil-based chemotherapy. Avastin continues to be evaluated with different chemotherapy combinations and targeted agents for the treatment of several different types of cancers.
The trial that prompted the new FDA indication for Avastin was called the E3200 trial. Avastin plus chemotherapy was directly compared to chemotherapy alone in patients with metastatic colorectal cancer who had received prior therapy. This trial included 829 patients who were treated with either Avastin plus the regimen referred to as FOLFOX4 (5-FU, Eloxatin® [xaliplatin], leucovorin), or FOLFOX4 only and were directly compared.
• Patients treated with Avastin/FOLFOX4 had a 33% improvement in overall survival compared to those treated with FOLFOX4 only.
• The median survival for patients treated with Avastin/FOLFOX4 was 13 months, compared to 10.8 months for those treated with FOLFOX4 only.
• The addition of Avastin was generally well tolerated.
Patients with metastatic colorectal cancer that has progressed or returned following previous treatment may wish to speak with their physicians regarding their individual risks and benefits of treatment with Avastin.
FOLFOXIRI + Bevacizumab Improves Outcomes for Metastatic Colorectal Cancer
According to a recent report in The New England Journal of Medicine, initial treatment with FOLFOXIRI plus Avastin® (bevacizumab), rather than FOLFIRI plus Avastin, improved progression-free survival in adults with inoperable metastatic colorectal cancer.
According to estimates from the American Cancer Society, more than 102,000 new cases of colon cancer and about 40,000 new cases of rectal cancer were diagnosed in the United States in 2013. Together, the diseases were responsible for over 50,000 deaths. There is, however, good news about colorectal cancer in the United States: death rates associated with the disease have dropped during the past 15 years, and advances continue to be made in screening, prevention, and treatment. Unfortunately many individuals will fail initial therapy and develop metastatic disease. Continued development of drugs to treat metastatic colon cancer is necessary to further improve outcomes.
A standard initial therapy for advanced colorectal cancer is FOLFIRI (fluorouracil plus leucovorin and irinotecan) plus bevacizumab (256 patients). The investigators hoped to improve the outcomes obtained with FOLFIRI by adding an additional chemotherapy agent, oxaliplatin to the regimen. This experimental regimen, FOLFOXIRI (fluorouracil plus leucovorin and irinotecan and oxaliplatin) plus bevacizumab was directly compared to FOLFIRI in the clinical study.
Overall 508 patients with unresectable metastatic colorectal cancer who had not received previous chemotherapy or biologic therapy for their metastatic disease were treated at 34 medical centers across Italy. Both groups received maintenance therapy with fluorouracil plus Avastin® until the cancer progressed or they withdrew from the study.
Study participants had been followed for an average of 32 months at the time of publication. Individuals treated with FOLFOXIRI were more likely to develop some side effects including neutropenia, diarrhea, stomatitis, and peripheral neuropathy. FOLFOXIRI treated patients survived longer and experienced a delay in cancer progression compared to those treated with FOLFIRI. Median overall survival was 5 months longer with FOLFOXIRI and survival without cancer progression was 12.1 months with FOLFOXIRI compared to 9.7 months with FOLFIRI.
Reference:(N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1403108]).
Avastin® plus Fluorouracil-based Chemotherapy Effective in Elderly with Metastatic Colorectal Cancer
The researchers concluded that the benefits of adding Avastin to fluorouracil-based chemotherapy in patients aged 65 or older “are comparable with those of the overall study population and outweigh the risks, which do not appear to be greater than those seen in younger patients with metastatic colorectal cancer.”
 Kabbinavar FF, Hurwitz HI, Yi J, et al. Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: Pooled analysis of cohorts of older patients from two randomized clinical trials. Journal of Clinical Oncology. 2008; 27:199-205.
Avastin® Fails to Provide Benefit in Early-stage Colon Cancer
According to the results of a Phase III clinical trial, the addition of the targeted therapy Avastin® (bevacizumab) to post-surgery chemotherapy does not reduce the risk of cancer recurrence among patients with early-stage colon cancer. These results were made available in a press release from Roche.
Multiple studies have shown that the addition of Avastin to standard chemotherapy improves outcomes in the treatment of patients with metastatic colorectal cancer. Given these results, researchers have also initiated studies to evaluate Avastin in the adjuvant (post-surgery) treatment of patients with earlier-stage colon cancer.
The current results are from a Phase III trial known as NSABP C-08. The study enrolled patients with Stage II or Stage III colon cancer. After surgical removal of the cancer, patients were assigned to receive adjuvant chemotherapy alone (mFOLFOX6) or adjuvant chemotherapy plus Avastin.
The results of the study indicate that the addition of Avastin to chemotherapy did not reduce the risk of cancer recurrence. Full results from this study are expected to be presented at the annual meeting of the American Society of Clinical Oncology (ASCO), which will be held May 29-June 2, 2009.
Results from another Phase III trial of Avastin in early-stage colon cancer (the AVANT study) are expected to be available in 2010.
The results of these studies do not affect the use of Avastin in advanced colon cancer.
Reference: Roche Media Release. Phase III C-08 study of Avastin in early-stage colon cancer does not meet primary endpoint. Available at: Accessed April 22, 2009.
Avastin® Linked with Increased Risk of Blood Clots
According to a combined analysis of previously published studies, cancer patients who use Avastin® (bevacizumab) may have an increased risk of venous thromboembolism (a blood clot in a vein). These results were published in the Journal of the American Medical Association.
The most common side effects related to Avastin included high blood pressure, protein in the urine, bleeding, and blood clots.
Avastin is an anticancer drug that slows or prevents the growth of new blood vessels by inhibiting a protein known as VEGF; this deprives the cancer of oxygen and nutrients. Through its effects on blood vessels, Avastin may also improve the delivery of chemotherapy to the cancer.
Avastin has been shown to improve treatment outcomes in selected patients with advanced colorectal, breast, and non–small cell lung cancer. Avastin is also being evaluated among patients with earlier-stage cancer, and among patients with other types of cancer.
Venous thromboembolism refers to a blood clot in a vein. When the clot affects a deep vein, a potential hazard is that the clot will break off and travel through the bloodstream to the lungs; this is known as a pulmonary embolus. Pulmonary emboli can damage the lung and other organs, sometimes resulting in death.
Previously, a combined analysis of five studies reported that Avastin increased the risk of arterial thromboembolism (a blood clot in an artery), but did not appear to increase the risk of venous thromboembolism. These studies, however, included a relatively small number of people.
To evaluate the risk of venous thromboembolism in a larger group of Avastin users and nonusers, researchers combined information from 15 clinical trials. These trials enrolled a total of 7,956 patients with advanced cancer
- Compared with patients who did not use Avastin, patients who did use Avastin were 33% more likely to develop venous thromboembolism.
- Overall, 11.9% of patients treated with Avastin developed venous thromboembolism. High-grade venous thromboembolism (grades 3 or 4) occurred in 6.3% of patients treated with Avastin.
These results suggest that Avastin increases the risk of venous thromboembolism. Patients taking Avastin may wish to discuss these findings with their physician.
The researchers note that future studies should explore the prevention and management of venous thrombosis among patients treated with Avastin.
 Scappaticci FA, Skillings JR, Holden SN et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. Journal of the National Cancer Institute. 2007;99:1232-1239.
Reference: Genentech. FDA Approves Avastin in Combination with Chemotherapy for Second-Line Metastatic Colorectal Cancer Patients. Available at: http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=9827. Accessed June 2006.