Off-Label Use of Bevacizumab: Advanced Adenocarcinoma of the Pancreas
Background: In the U.S., pancreatic adenocarcinoma is the tenth most common cancer in men and the fourth leading cause of cancer deaths in men and women. Only 7% of cases are detected at an early stage, and more than 90% of patients develop metastases. The 1-year survival rate is 24%; the 5-year survival rate is 5% overall, and 20% for those diagnosed early with only local disease. For patients with advanced, unresectable disease, the standard of care is gemcitabine (Gemzar®, Eli Lilly and Co.). Gemcitabine is approved by the U.S. Food and Drug Administration (FDA) as single-agent first-line treatment for patients with locally advanced (stage II or stage III when surgery is not an option) or metastatic (stage IV) adenocarcinoma of the pancreas, including patients previously treated with 5-fluorouracil. Gemcitabine is sometimes given as part of combination therapy with another agent, such as erlotinib (Tarceva®, Genentech Bio-Oncology/OSI Oncology), which is approved by the FDA for first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine.
Objective: To determine the incremental net benefit of using bevacizumab (Avastin®, Genentech Bio-Oncology) among patients with pancreatic adenocarcinoma. This Assessment updates part of an earlier Assessment on "Off-Label Uses of Bevacizumab: Renal Cell Carcinoma and Other Miscellaneous Non-Colorectal Cancer Indications" (Vol. 21, No. 9).
Search strategy: A literature search was conducted in MEDLINE® (via PubMed) through April 2009, using the following search terms: (avastin OR bevacizumab) AND (pancreas OR pancreatic), limited to English-language studies involving human subjects. The search yielded 118 references, 42 of which were retrieved. In addition, literature searches were conducted in EMBASE and the Cochrane Central Register of Controlled Trials using the same search terms. Reference lists of pertinent articles were also reviewed, as well as abstracts from recent meetings of the American Society of Clinical Oncology (ASCO). The search was updated in July 2009, and no additional Phase III studies were found.
Selection criteria: All Phase III trials evaluating bevacizumab for patients with advanced adenocarcinoma of the pancreas are included. No comparable data are available on the use of bevacizumab in earlier stages of the disease, so this topic is not addressed further in this Assessment.
Main results: Results are available on two Phase III trials. The first, Cancer and Leukemia Group B (CALGB) 80303, compared gemcitabine with or without bevacizumab in 590 patients with locally advanced or metastatic adenocarcinoma of the pancreas. The trial was stopped early in June 2006 after a protocol-specified interim analysis with 64% of the information on overall survival and 436 deaths, or 93% of the deaths expected at final analysis. The CALGB Data Safety Monitoring Board concluded that a futility boundary had been crossed, i.e., it was unlikely that significant differences between treatment arms in overall survival would be detected with further follow-up. No statistically significant difference in progression-free survival was found.
The second Phase III trial, published in April 2009, compared gemcitabine and erlotinib with or without bevacizumab. Adding bevacizumab to gemcitabine and erlotinib did not yield a statistically significant increase in overall survival. A statistically significant increase of 1 month was reported in progression-free survival.
Author's conclusions and comments: Adenocarcinoma of the pancreas is a grim disease with limited life expectancy after diagnosis, even after the best treatment current practice can offer. Multiple drugs have been tested as combination therapy with gemcitabine for advanced disease, including both more traditional chemotherapies such as cisplatin and newer, targeted therapies such as erlotinib. Unfortunately, the impact of these additional therapies has been limited or nonexistent. In this type of clinical situation, even small net benefits are often accepted. Bevacizumab was considered promising because it targets vascular endothelial growth factors (VEGF), which stimulate angiogenesis and are thought to play an important role in pancreatic cancer, and because of an apparently positive effect in a Phase II trial. Unfortunately, the results of two Phase III trials, one of which was stopped early because of the lack of an effect on overall survival and the second of which was recently released, show no incremental benefit in overall survival.
The findings on progression-free survival were inconsistent, although the earlier Phase III trial was cut short. The more recently published trial did report a statistically significant difference in progression-free survival: median of 4.6 months in patients receiving bevacizumab plus gemcitabine and erlotinib versus 3.6 months in the group receiving only gemcitabine and erlotinib. However, few details were given on the methods used to assess progression-free survival, which may be subject to greater measurement error than overall survival. Data on quality of life would also be helpful to assess the value of this difference, but none were reported. In a disease such as advanced pancreatic cancer, where, unfortunately, life expectancy is short and secondary treatments used after failure of the first course have shown limited efficacy and often are not used, overall survival is the most meaningful primary outcome.
Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether the use of bevacizumab in patients with advanced adenocarcinoma of the pancreas meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria.
1. The technology must have final approval from the appropriate governmental regulatory bodies.
The U.S. Food and Drug Administration (FDA) has approved bevacizumab for first- or second-line treatment of metastatic colorectal cancer; for first-line treatment of unresectable, non-squamous, non-small cell lung cancer; for patients who have not received chemotherapy for metastatic, HER2-negative breast cancer; and, as of May 5, 2009, for patients with glioblastoma, with progressive disease after prior therapy. Bevacizumab has not been approved by the FDA for use in pancreatic cancer.
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
Sufficient scientific evidence is available on the use of bevacizumab for patients with advanced adenocarcinoma of the pancreas in the form of two Phase III trials.
3. The technology must improve the net health outcome.
The addition of bevacizumab to a treatment regimen does not increase overall survival among patients with locally advanced or metastatic disease.
4. The technology must be as beneficial as any established alternatives.
The established alternatives provided a benefit compared to the previously used regimens (gemcitabine vs. fluorouracil and erlotinib plus gemcitabine vs. gemcitabine alone). The addition of bevacizumab does not provide additional benefit in terms of the primary outcome of interest, overall survival.
5. The improvement must be attainable outside the investigational settings.
Whether the addition of bevacizumab to chemotherapy regimens for advanced pancreatic adenocarcinoma improves health outcomes has not been established in the investigational settings.
For the above reasons, use of bevacizumab for patients with advanced adenocarcinoma of the pancreas does not meet the TEC criteria.