Avastin in the Adjuvant Setting

[gpawelski]

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.