Docetaxel/estramustine plus bevacizumab in patients with hormonerefractory metastatic prostate cancer

We conducted a single-arm Phase II trial evaluating docetaxel/estramustine plus the humanized monoclonal antibody bevacizumab in patients with hormone refractory metastatic prostate cancer. Bevacizumab targets the vascular endothelial growth factor (VEGF) protein, which is thought to be one of the mediators of angiogenesis. The drug was developed several years ago and hit the press in a major way in colorectal cancer, where it actually prolonged survival when added to standard chemotherapy regimens.

We enrolled 72 patients in this trial and although we shouldn’t make too much of efficacy in a single-arm trial, I have been impressed by the high response rate. In our docetaxel/estramustine backbone trial we saw a response rate of 69 percent. Here we are seeing a response rate closer to 79 percent. Starting at a base of nearly 70 percent leaves little room for improvement. I believe any increase is impressive. We are also seeing that patients are staying on this therapy for a while and appear to have their disease under control.

With regard to toxicity, we saw some thrombotic problems, but the question is whether they were higher than what we would see with a drug such as estramustine, which is an estrogenic agent and causes thrombotic problems by itself. An ASCO poster suggested that about five to 10 percent of patients on estramustine have thrombotic problems. That’s approximately the same rate we saw in our trial. We also saw some hypertension, one fatal mesenteric vein thrombosis and one patient who clearly had a bowel perforation. We attributed that to a diverticulosis, although given previous bowel perforations observed in the colon cancer trial, I am not sure we can just write that off. We also saw the common toxicities you see with docetaxel/estramustine — nausea, vomiting, fatigue, hair loss, cytopenias — but nothing else that really stood out from our previous experience with chemotherapy.

I would like to see bevacizumab move forward into a randomized trial to really show if it has efficacy. The design of that type of trial is currently being debated nationally and internationally. A very simple trial would be docetaxel/estramustine with or without bevacizumab. However, that would be a fairly large trial, and before we make such a commitment, we need to consider whether it would be worth doing to see a 10 percent improvement. Others have suggested a trial of docetaxel/bevacizumab versus docetaxel/estramustine. I think estramustine adds a lot of toxicity. If bevacizumab is truly an active drug it might be a good substitute with greater tolerability

Case 4: A 62-year-old man with a rising PSA

One of the patients I saw today in my clinic was a 62-year-old retired railroad worker who was a participant in our bevacizumab trial. He was first diagnosed in 1997 with high-risk disease. He had a prostatectomy and was given radiation therapy and hormonal therapy. When I first saw him, his PSA had just started to rise while he was on hormonal therapy, and his bone scan had become positive. Initially, we took him off bicalutamide and his PSA went down, he had no pain and the PSA stayed down for about six months.

However, after failing several antiandrogens, in 2002 he agreed to participate in our bevacizumab/docetaxel/estramustine study. At that time, his PSA was well over 100 ng/mL and he was experiencing considerable pain. He enrolled in the study and had a dramatic response. His pain was gone after his first dose of chemotherapy and his PSA dropped as low as 2 ng/mL. His bone scan improved dramatically and his CT scan looked normal. He no longer needed narcotics and was able to participate in activities that he had previously avoided because of the pain.

Aside from alopecia, fatigue and neutropenia, he tolerated the therapy very well and received nine cycles over six months. However, toward the end of that time, his PSA began to rise and he was increasingly fatigued. We stopped all therapy in March 2003. He did well for about eight to 12 weeks and then his PSA went up from 6 to 10 to 50 ng/mL within a few months, and he began to have pain again.

Because of his fatigue from docetaxel and some residual neuropathy, we had a long discussion and decided to use mitoxantrone and low doses of prednisone in accordance with the FDA-approved indication. He again responded well: the pain went away and the PSA went down to a very low level. He had no side effects from the mitoxantrone, but we were concerned about the cumulative possibility of cardiotoxicity so we stopped therapy after about six cycles thinking that we had achieved a good response.

Three weeks ago his pain returned and he went back on oxycodone and a lot of short-acting narcotics, and he restarted mitoxantrone. When I saw him today he had completely stopped his short-acting narcotics, and we are starting to taper his oxycodone. I think he is a good example of somebody with chemosensitive disease. He does well as long as he is on chemotherapy; however, whenever we stop his chemotherapy, his disease progresses and his quality of life and his performance status deteriorate along with it.

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Dr Picus is an Associate Professor of Medicine in the Siteman Cancer Center’s Division of Medical Oncology at Washington University School of Medicine in St Louis, Missouri.