Dr. Bruce J. Giantonio is a practicing oncologist at the University of Pennsylvania and the Executive Officer of the Eastern Cooperative Oncology Group (ECOG). He also served as the study chair for two large ECOG trials evaluating bevacizumab (Avastin) in combination with chemotherapy for colon cancer. Dr. Giantonio's personal interests include targeted therapies in gastrointestinal malignancies and new drug development.
OncoLink was fortunate to obtain an exclusive interview with Dr. Giantonio and discuss the evolving role of bevacizumab in colon cancer.
= Julia Draznin Matlzman, MD, Senior Editor
BJG = Dr. Bruce J. Giantonio
OncoLink: Dr. Giantonio, thank you for taking time to speak with us. First off, tell us about ECOG. What is it? Why is it important? Why is it better than any of the trials done at a big academic center like your own, for example, Penn?
BJG: Well, it is not better, it is simply different. ECOG is one of the largest clinical cancer research organizations in the US. It conducts clinical trials in all types of cancers. As the name implies it is a cooperative effort. It was first established in 1955 as one of the first cooperative groups launched to perform multi-center clinical trials. The University of Pennsylvania, although an enormous institution with many resources, is still only one academic center. ECOG allows us to run the same clinical study in multiple high-ranking, large academic institutions simultaneously.
A cooperative group such as ECOG is really a huge network of health care researchers, in both the private and public institutions. Our membership has really evolved from a five member group of institutions primarily on the east coast – hence the origin of the name – to almost 6,000 physicians, nurses, pharmacists, statisticians, and clinical research associates from the US and Canada. Institutional members include universities, medical centers, as well as community clinics. Everyone is committed on working for a common goal of controlling, treating and curing cancer. Our funding comes primarily from the National Cancer Institute (NCI).
One of the great strengths of ECOG is that many of the leaders in oncology are members of ECOG. This provides us with an outstanding group of oncology experts that insures our studies represent some of the most important studies in oncology today. In addition, all of our research results are published in scientific journals and presented at professional meetings, whether positive in their findings or negative, and are subject to the same rigor as all other clinical studies.
OncoLink: The big and long awaited trial that you ran was the ECOG 3200. By the way, is there a rhyme or a reason for this numbering system?
BJG: Yes, the last two digits represent the year the study was approved for development within the group. So, with E3200 we began work on the study in 2000 and it accrued its first patient in 2001. The second number represents the ECOG disease committee that submitted the study. In the example of E3200, the study came from the Gastrointestinal Committee, which has been assigned the number 2. The first number represents the sequence number of the study for the particular committee in that year. Again, with E3200 as an example, it was the 3 rd study to be submitted to ECOG by the Gastrointestinal Committee in the year 2000.
OncoLink: Tell me about E3200.
BJG: This was a randomized phase III trial comparing three different regimens: bevacizumab, oxaliplatin (Eloxatin), 5-fluouracil (5-FU) and leucovorin vs. oxaliplatin with 5-FU and leucovorin without bevacizumab vs. bevacizumab alone in previously treated patients with advanced colon cancer. The last arm of the study was closed early following scheduled independent analysis: it appeared that the patients treated with bevacizumab alone weren't doing as well when compared to those patients treated on the chemotherapy arms of the study.
It is worthwhile to give a little bit of background on bevacizumab because it is a fairly exciting development in caner therapy. Bevacizumab is a humanized monoclonal antibody that binds Vascular Endothelial Growth Factor (VEGF) and inhibits formation of new blood vessels. We have learned that in order for tumors to grow beyond the size of a period, they need to establish their own blood supply to survive. VEGF is a very potent mediator of new blood vessel development. The remarkable thing is that the tumors can make their own VEGF and direct the formation of the tumors blood supply. Bevacizumab can alter that. It acts like a sponge, ‘soaking up' VEGF and preventing it from stimulating the formation of new blood vessels and in theory ‘chokes' the tumor. We are learning that it is a bit more complicated than that, but that is basically how it works.
Several clinical studies have already been performed with bevacizumab, and in one it was found to improve survival when added to first line chemotherapy for advanced colon cancer. This study sought to see if there was a survival benefit to using these combinations in people who were already treated for colon cancer and either progressed or did not respond. The only caveat being is that prior use of the antibody was not allowed. Our primary end point, our main goal if you will, was to evaluate the overall survival of this group.
We treated over 800 patients from 2001 to 2003 and found that the combination arm of bevacizumab, oxaliplatin, 5-FU, and leucovorin was well tolerated and did increase survival in advanced previously treated colorectal patients. The survival benefit, although modest, is significant for this group of patients who may have few alternatives. Of particular importance was the fact that bevacizumab used in combination with this particular chemotherapy regimen improved its efficacy. This is important because it is the most commonly used regimen in treating colorectal cancer in the United States.
OncoLink: The study has been criticized for using an unconventional dose of the bevacizumab. Could you comment on that?
BJG: The dose we tested was 10 mg/kg, and while I wouldn't call it unconventional, it is a higher dose than the 5 mg/kg that was approved for commercial use by the FDA. We considered several factors when we selected the dose of bevacizumab. At the time we designed the study there were limited data on both doses in humans, and what data existed was conflicting: some studies in other cancers suggested that a higher dose was more active while one study in colon cancer suggested the lower dose was more active. Despite the conflict, all the data suggested that 10 mg/kg was active and given that the patient population for E3200 was further along with their disease, we believed the higher dose was justified.
It's important to point out that E3200 does not tell us which is the better dose. Even though we demonstrated an important improvement in survival, we don't know if it would have been worse, the same, or even better had we selected the lower dose.
OncoLink: I guess the next question on everyone's mind is: If bevacizumab is good for first line advanced disease and now for second line metastatic disease, then would it then be good for the kind of colon cancer that is not metastatic but warrants chemotherapy after full surgical resection?
BJG: That is a very important question. There are several very large studies that are being done to answer that question and we need to wait for those results before we can advocate using the drug in those patients being treated with adjuvant chemotherapy. The clinical development of bevacizumab has followed a conventional pattern: we test the drug in advanced disease and then study it in earlier stages of disease. From past experience we know that we can not always make the assumption that success in the advanced disease tests will mean it will work in earlier stages. So, to emphasize my point, we need to wait the results of the ‘adjuvant' studies before we can recommend the drug's use in early stage colorectal cancer.
OncoLink: Some would also wonder if we could start to use bevacizumab as almost like “maintenance” therapy. Is there any thinking for that? We have precedent for this sort of use from Herceptin and Rituxan.
BJG: We don't know yet, and that is a question that needs to be answered.
OncoLink: Are bevacizumab and cetuximab (Erbitux) competing for the same role in colon cancer or do you see them as separate and additive to the treatment of this disease?
BJG: Cetuximab is a fascinating agent. It is a targeted therapy, but unlike bevacizumab it works by turning the 'growth switch' on the cancer cell to the 'off' position. I don't see these agents as competing and it is possible that we will learn they act synergistically when used together. That idea, of combining the cetuximab and bevacizumab, will be tested in another large cooperative group study that will likely begin sometime this year.
OncoLink: What is the future for bevacizumab in colon cancer?
BJG: Bevacizumab is a very exciting new treatment for colorectal cancer, and while we have learned quite a bit in a very short time about its role in treating this disease, there are still a boat-load of questions we need answered. You have touched on many of them already, such as it role in adjuvant therapy, its duration of use, and combining it with other targeted agents. All this makes it extremely important that oncologists offer clinical trials to their patients, and that patients asked about these studies, so that we can continue the momentous progress the last few years have seen. Thank you for this thoughtful interview.