Avastin in Adjuvant Setting

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Avastin in Adjuvant Setting

by Gdpawel on Mon Mar 17, 2008 12:00 AM

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In cancer medicine, it's not a case of throwing "targeted" drugs at the problem. It's knowing "what" targeted drugs and "how" to use them in "individual" patients (not average populations). The problem is that few drugs work the way oncologists think they do and few of them take the time to think through what it is they are using them for.

Case in point with Avastin is a perfect example. Serious adverse events, including fatal events, of tracheo-esophageal (TE) fistula have been reported in association with use of Avastin clinical trials of small cell lung cancer (SCLC), non small cell lung cancer (NSCLC) and esophageal cancer.

Avastin should be permanently discontinued in patients with tracheo-esophageal (TE) fistula or any gastrointestinal fistula. There is limited information on the continued use of Avastin in patients with other fistulas. In cases of internal fistula not arising in the GI tract, discontinuation of Avastin should be considered.

The interesting caveat about Avastin with colon cancer - gastrointestinal perforations. If Avastin is given within at least 28 days following major surgery (or before), it results in an abscess formation. This is due to the impaired wound healing induced by Avastin.

By Avastin working like it's supposed to work, not only does it cut off blood supply to the tumor, it also cuts off blood supply to the colon entirely causing the tissue to die. Avastin can cause you to loose your colon. What's distubring is oncologists' comment that this is common with Avastin, but is never mentioned until it is too late.

Most bowel perforations with Avastin have been in cases where there is tumor going right through the wall of the colon. Avastin causes the tumor to melt away, leaving a hole. With Avastin, the tumor dissolves, but scar tissue won't form because it can't make a blood supply.

The same thing applies to bowl perforations with Avastin in advanced ovarian cancer. Advanced ovarian cancer commonly involves bowel walls. The problem is a direct result of the drug's ability to kill tumor cells that have replaced healthy bowel tissue, leading to a dead area that then perforates.

With conventional chemotherapy, as the tumor melts away, new connective tissue forms a patch. But Avastin can inhibit the growth of capillaries into newly forming tissue, as well as in tumor tissue. If one does not have any known bowel involvement, one would probably be okay.

And now, Avastin is one of the most popular drugs used in combination with Camptosar (CPT-11) for brain tumors. In a small percentage of patients, Avastin can cause neurological side effects ranging from headaches and blurry vision to potentially fatal seizures and brain swelling.

VEGF normally protects the specialized cells that create a seal between the brain and spinal column and thus prevent fluid from leaking into the brain. When VEGF was blocked in mice, these cells died and the animals developed brain swelling. Researchers suspect that Avastin's side effects in humans may be caused by a similar phenomenon.

Whiz bang therapies often get a pass on toxicities because they are just so darn cool (Herceptin and CHF in the adjuvant setting is another example). Again, the problem is that few drugs work the way oncologists think and few of them take the time to think through what it is they are using them for.

Meanwhile, it's hard to tell a medical oncologist (and patient) to ratchet back on the anti-VEGF drug they're using when the disease setting is stage IV lung, ovarian, or pancreatic cancer. Therapy-related, late onset sequelae are becoming a very real problem.

The True Costs And Benefits Of Avastin

by Gdpawel on Wed Jul 09, 2008 12:00 AM

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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

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