(This week we conclude, with references, the article we began last week on the dangers associated with the class of drugs known as angiogenesis inhibitors.).

One of the most pressing concerns surrounding current angiogenesis inhibitors is the fact that they are associated with an increased risk of thrombosis (blood clots). Why does this happen? UCLA Prof. Luisa Iruela-Arispe's study in the August 24, 2007 issue of Cell throws light on this urgent question.

"I believe the survival function of VEGF signaling is mediated from both outside and inside the cell. When we block it from the inside, the outside signaling cannot compensate. But when we block it from the outside, maybe the inside signaling can compensate. That would explain the lesser side effects found when using drugs such as Avastin, which block the extracellular signaling."

This aspect of angiogenesis inhibitors troubles Iruela-Arispe. Avastin, like most angiogenesis inhibitors, is generally infused systemically (i.e., given via a vein directly into the bloodstream). But Iruela-Arispe, who continues to believe in the therapeutic potential of angiogenesis inhibitors, thinks they could be made safer and more effective if they were delivered in a more tumor-focused way. "There is enough smoke in the sky here to make me feel there may be a fire," she added, ominously.

Personally, I share her concerns. Over the past six years, in this newsletter, I have frequently expressed skepticism about many of the best-publicized 'targeted' drugs. My reluctance to jump on the targeted therapy bandwagon has been based on my reading of the medical literature. Simply put, the current approach, at least with the present generation of anti-angiogenic drugs, is not particularly effective. As to toxicity, while these drugs were initially promoted as non-toxic magic bullets, there is now accumulating evidence of toxicity and sometimes lethal side effects.

The interested reader can find dozens of my articles on targeted therapies by searching for terms such as Avastin, Erbitux and Iressa at my Web site, www.cancerdecisions.com.

Avastin

Since Dr. Iruela-Arispe cited the example of Avastin, let us look briefly at its track record of safety and effectiveness. In February 2004, the US Food and Drug Administration (FDA) approved Avastin (whose scientific name is bevacizumab) for advanced colorectal cancer. On October 11, 2006, FDA further approved the drug for use in combination with carboplatin and paclitaxel, for advanced or recurrent non-small cell lung cancer (NSCLC).

Approval for lung cancer was based on what FDA officials called a "significant improvement in overall survival (OS)" (Cohen 2007). An Eastern Cooperative Oncology Group (ECOG) study showed that in patients who had received no prior chemotherapy, the overall survival was 10.3 months in those receiving conventional chemotherapy vs. 12.3 months in those also receiving Avastin. One little-publicized fact was that women given Avastin showed no survival benefit at all - which will doubtless come as a shock to the families of the many women who have been given the drug nonetheless. Also notice that the test group had received no prior chemotherapy, which makes them more likely to achieve a favorable outcome: those whose disease is progressing despite having previously received chemotherapy start off in a less favorable category.

Meanwhile, about one-quarter of those receiving the combined therapy faced severe or life-threatening adverse events. Patients receiving Avastin had a four times greater chance of pulmonary hemorrhage, for example. They also faced a significantly heightened risk of gastrointestinal perforation and hemorrhage, central nervous system infarction, gastrointestinal perforation, and myocardial infarction.

The most common adverse events in patients receiving Avastin are weakness, pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, mouth sores (stomatitis), constipation, upper respiratory infection, difficulty breathing (dyspnea), extreme rashes (exfoliative dermatitis), and protein in the urine (proteinurea), according to the FDA (Cohen 2006).

All this for the possibility of two months' increased survival. And this is not to mention the stress engendered by the expense of the drug: Avastin costs approximately $8,800 per month.

The phrase 'targeted therapy' certainly has a nice ring to it. But the fact that these drugs can cause so many devastating adverse effects yet still be called 'targeted' represents a triumph of public relations over science.

--Ralph W. Moss, Ph.D.

References:

Berenson, Alex. A cancer drug shows promise, at a price that many can't pay. New York Times, Feb. 15, 2006.

Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist. 2007;12:713-718.

Cooke, Robert. Dr. Folkman's War: Angiogenesis and the Struggle to Defeat Cancer. New York: Random House, 2001.

Correa CR, Litt HI, Hwang WT, et al. Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer. J Clin Oncol 2007;25(21):3031-7.

Folkman J, Merler E, Abernathy C, Williams G. Isolation of a tumor factor responsible for angiogenesis. J Exp Med. 1971;133:275-88.

Hooning MJ, Botma A, Aleman BM, et al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst. 2007;99:365-375.+-

Irwin, Kim. Study finds blocking angiogenesis signaling from inside cell may lead to serious health problems. UCLA Press Release, August 23, 2007. Available at:
http://www.eurekalert.org/pub_releases/2007-08/uoc--sfb082207.php

Lee S, Chen TT, Barber CL, et al. Autocrine VEGF signaling is required for vascular homeostasis. Cell. 2007;130:691-703.

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