Avastin Approved for Breast Cancer?

FDA Approves Cancer Drug Despite No Increase in Survival

But is this drug worthy of approval? A review of the transcript of the FDA’s own Oncologic Drugs Advisory Committee suggests a number of unsettling aspects, including:

• Survival – The drug did not increase overall survival in the breast cancer patients tested.

• Toxicity – More patients died toxic deaths who received Avastin in combination with paclitaxel than those who received paclitaxel alone. In addition there were more life threatening adverse events (side effects) in those breast cancer patients who received Avastin.

• Problems With the Clinical Trial that Led to Approval – There were a number of issues with the clinical trial highlighted by the FDA including lack of data, the subjective nature of the findings, missing information, and protocol violations.

• Committee Voted “No” on Approval – The FDA’s own Oncologic Drugs Advisory Committee voted not to approve Avastin for breast cancer 5-4. Inexplicably, FDA bureaucrats overturned the decision of its own Advisory Committee.
http://www.cancermonthly.com/iNP/view.asp?ID=209

Here is an example of a cancer trade group and its peer review venue. It is highlighted in a recent video by the Healthcare Channel, questioning a drug's use in breast cancer.
http://blogs.wsj.com/health/2007/12/11/avastin-for- breast-cancer-the-pre-history/

The idea that approving drugs based on population studies has its limits. What may or may not work for the average population may not apply to the individual. Avastin killed more patients than the control arm. Avastin doesn’t have to be used in every breast cancer patient. Taxol doesn’t have to be used in every breast cancer patient (it seems like they do).

The clinical trial was done using Avastin in combination with Taxol. Doctors are faced with a problem of whether to use Taxol and forgo Avastin, or to use some other conventional drug for initial therapy in order to use Avastin.

Avastin is a “large molecule” monoclonal antibody. It can be tested with a EGFR biomarker assay because the “target” of Avastin is not the cells themselves, but rather a hormone (VEGF) secreted by the tumor cells. Avastin complexes with free VEGF and blocks its action.

Having a good tumor-drug match not only would improve survival rates, it would be cost-effective, and the high cost of the newer cancer therapies reinforces the necessity of choosing the right therapy the first time around.

The tumors of different patients have different responses to chemotherapy. It requires individualized treatment based on testing the individual properties of each patients’ cancer.

Post edited by: gpawelski, at: 2008/03/29 17:24

Problems With the Clinical Trial that Led to Approval – There were a number of issues with the clinical trial highlighted by the FDA including lack of data, the subjective nature of the findings, missing information, and protocol violations.


This doesn't make sense

Isn't it ridiculous?

The True Costs And Benefits Of Avastin

What may limit the effectiveness of Avastin is that there are multiple ways by which tumors can evolve that are independent of VEGF and independent of angiogenesis. Tumors can acquire a blood supply by three different mechanisms: angiogenesis; co-option of existing blood vessels; and vasculogenic mimicry. All must be inhibited to consistently starve tumors of oxygen.

Instead of growing new blood vessels, tumor cells can just grow along existing blood vessels. This process, called co-option, cannot be stopped with drugs that inhibit new blood vessel formation. Some types of cancers form channels that carry blood, but are not actual blood vessels. Drugs that target new blood vessel formation also cannot stop this process, called vasculogeneic mimicry. The realization is that starving tumors by shutting off their blood flow requires that all three mechanisms be addressed.

It could be vastly more important to measure the net effect of all processes (systems) instead of just individual molecular targets (like VEGF). The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one or a few targets or pathways.

There are many pathways to the altered cellular (forest) function, hence all the different "trees" which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indiviudal trees.

VEGF-targeted drugs are poorly-predicted by measuring the preferred target VEGFR. They can be well-predicted by measuring the effect of the drug on the function of live cells.

Many of these fine drugs (and Avastin is a miracle drug for the few) cry out for validated clinical biomarkers as pharmacodynamic endpoints and with the ability to measure multiple parameters in cellular screens to help set dosage and select people likely to respond. Many molecular diagnostics approved often have been mostly or totally ineffective at identifying clinical responders to various therapies.

If you find one or more implicated proteins in a patient’s tumor cells, how do you know if they are functional (is the encoded protein actually produced)? If the protein is produced, is it functional? If the protein is functional, how is it interacting with other functional proteins in the cell?

All cells exist in a state of dynamic tension in which several internal and external forces work with and against each other. Just detecting an amplified or deleted gene won’t tell you anything about protein interactions. Are you sure that you’ve identified every single protein that might influence sensitivity or resistance to a certain class of drug?

Assuming you resolve all of the preceeding issues, you’ll never be able to distinguish between susceptibility of the cell to different drugs in the same class. Nor can you tell anything about susceptibility to drug combinations. And what about external facts such as drug uptake into the cell? You're not going to accomplish this using genetic tests.

Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease. The biologies are very different and the response to given drugs is very different.

The major obstacle in controlling cancer drug prices is the widespread inappropriate use of anti-cancer drugs. As the increasing numbers and types of anti-cancer drugs are developed, oncologists become more and more likely to misuse them in their practice. There is seldom a "standard" therapy which has been proven to be superior to any other therapy. What may work for one, may not work for another.

Literature Citation:
Eur J Clin Invest 37 (suppl. 1):60, 2007
Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117
"Cure: Scientific, Social, and Organizational Requirements for the Specific Cure of Cancer" A. Glazier, et al. 2005