Cancer Decisions - Free Newsletter

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AVASTIN MORE EFFECTIVE THAN CHEMO ALONE FOR COLORECTAL CANCER

There was some surprisingly positive news at the 2003 meeting of the American Society of Clinical Oncology (ASCO). A new drug called Avastin (bevacizumab) has been shown to lead to a prolongation of survival in patients with advanced colon cancer. Avastin is a new kind of drug that works by attacking the blood supply of tumors. Technically, it is a monoclonal antibody directed against vascular endothelial growth factor (VEGF). VEGF (pronounced 'vedge-eff') was discovered by a young Italian-American scientist, Dr. Napoleone Ferrara, working at Genentech, the company that intends to market Avastin. VEGF is a protein secreted by cells that are chronically starved of oxygen, and many cancers exist in just such a state of oxygen depletion. By binding to specific receptors on nearby blood vessels, VEGF stimulates the outgrowth of new extensions to these vessels, a process called 'angiogenesis'.

Avastin, originally called simply anti-VEGF, was designed by Genentech scientists to inhibit new blood vessel formation in tumors, and thereby inhibit tumor growth. This is in accord with the philosophy of Judah Folkman, MD, of Harvard University, who pioneered the study of angiogenesis in cancer.

In the ASCO presentation it was shown that Avastin prolonged survival when added to a standard three-drug chemotherapy regimen. The gain is only measured in a few months, but still it was significant, since this was the first time that an anti-angiogenic drug has been shown to actually prolong survival.

The lead investigator of the study, Herbert Hurwitz, MD, of Duke University, showed that when Avastin was combined with the irinotecan/fluorouracil/leucovorin (IFL) regimen, there was significant prolongation of survival and more tumor shrinkage than with chemo alone (Abstract #3646).

Patients treated with the Avastin combination had a median survival of 20.3 months compared to 15.6 months in those treated with chemo alone. This represented a gain of 4.7 months. The time to disease progression (a less important marker) was also increased by 4.4 months. Tumors were reduced in size by at least half in 45 percent of patients who received Avastin-IFL compared to just 35 percent in patients who received IFL alone.

Overall, more patients receiving Avastin-IFL responded to treatment than those receiving standard chemotherapy (44.9 percent vs 34.7 percent) and the response was maintained for longer in those patients who received the combination (10.4 months vs 7.1 months). All of these differences were statistically significant.

There are some side effects that are exacerbated when Avastin is added to chemo. The incidence of elevated blood pressure was significantly higher among the Avastin patients than those getting just chemo (22.4 percent vs. 8.3 percent), although it is said that this high blood pressure problem could be well managed with medication.

Gastrointestinal perforation, although a rare occurrence, seems to have also been increased by the addition of Avastin to IFL. Six patients (1.5 percent) who were treated with Avastin developed perforations, as opposed to none of the patients treated with standard chemotherapy. As a result of such perforations, one patient died, and five patients had to be removed, at least temporarily, from the study.

Breast Cancer Results Were Not Good

The findings, of course, were excellent news for Genentech. The company's stock (DNA-NYSE), which had been ailing, has doubled in value since the announcement, and presently stands at over $74 per share.

The latest results came as a big surprise to both scientists and investors. In September, 2002, the company had announced disappointing results with Avastin in the treatment of advanced breast cancer. At that time, Genentech said its Phase III study of Avastin in patients with breast cancer did not meet its primary endpoint, which was a 50 percent prolongation of the time till the disease progressed. That study involved 462 women who received either Avastin plus the drug Xeloda (capecitabine), or Xeloda alone. The overall tumor response was actually better in the Avastin group than in the Avastin-chemo group, but this increased rate of tumor shrinkage did not translate into an increase in progression-free survival or in one-year survival for a sufficient number of patients.

Genentech is now initiating two randomized controlled trials in kidney (renal cell) cancer. The Cancer and Leukemia Group B (CALGB), and the National Cancer Institute, are studying first-line treatment of metastatic renal cell cancer, and Genentech will study the same cancer in patients who have received prior treatment with another chemotherapy combination. Enrollment also continues in several Eastern Cooperative Oncology Group (ECOG) studies with Avastin, including a Phase II/III trial in metastatic non-small cell lung cancer and a Phase II/III first-line metastatic breast cancer trial. A Phase III trial in relapsed, metastatic colorectal cancer in which Avastin is being combined with oxaliplatin (Eloxatin™)/5-FU/Leucovorin recently completed enrollment. Further information on these trials can be obtained at the US government website, www.clinicaltrials.gov

In this era of rapid FDA approval of dubious drugs it is certainly refreshing to see results from a rigorous clinical trial, with overall survival as the main endpoint. However, impressive as these results are, some caveats are necessary. First of all, these results have been presented only in abstract (and press release) form; study of the full peer-reviewed paper may modify conclusions.

Second, do not expect this four-five month advantage to necessarily hold up in the general population. In clinical trials, patients are highly selected for certain favorable characteristics. For instance, they were excluded from this trial if they had been treated in any other way within the last 12 months, if they had metastasis to the central nervous system, or if they had significant atherosclerotic vascular disease. Many patients with colorectal cancer in the real world would be disqualified using these criteria. Thus, Avastin may not work as well in the general population as it does in highly selective clinical trials.

DEPARTMENT OF CORRECTIONS

In last week's newsletter I referred to a clinical trial of Erbitux and Taxol when I meant Erbitux and Taxotere.

--Ralph W. Moss, Ph.D.

References:

Glade-Bender J, Kandel JJ, Yamashiro DJ. VEGF blocking therapy in the treatment of cancer. Expert Opin Biol Ther. 2003 Apr;3(2):263-76.

Hassan, Joe. Angiogenesis Inhibitor and Standard Chemotherapy Superior to Chemotherapy Alone in Colorectal Cancer. December 26, 2002 (ASCO news release).

Reuters. Genentech colon cancer drug extends life. May 19, 2003. At:
http://www.asco.org/ac/1,1003,_12-002122-00_18-0027793-00_19-0027794-00_20-001,00.asp

Reuters. Genentech's Avastin breast cancer trial fails to meet primary endpoint.
September 10, 2002. At:
http://www.asco.org/ac/1,1003,_12-002123-00_18-0020282-00_19-0020283-00_20-001,00.asp

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IMPORTANT DISCLAIMER

The news and other items in this newsletter are intended for informational purposes only. Nothing in this newsletter is intended to be a substitute for professional medical advice.