1. Avastin works by choking off the blood vessels that provide a tumor with oxygen and nutrients (angiogenesis). Angiogenesis is essential for the growth and metastasis (spread) of cancer. A growing tumor requires nutrients and oxygen, which helps it grow, invade nearby tissue, and metastasize. To reach these nutrients, the tumor builds new blood vessels. In fact, growing tumors can become inactive if they can't find a new supply of nutrients.

Angiogenesis starts when cancer cells produce a variety of growth factors and other activators (biologic molecules that begin a process). Growth factors cause endothelial cells (the cells that line blood vessels) to produce chemicals that break down the nearby tissue and the extracellular matrix (the spaces between cells). Then, the endothelial cells divide into more cells and begin building new blood vessels. Other elements, such as stromal cells (cells that form connective tissue), provide structural support for the new blood vessels.

Because angiogenesis is necessary in the growth and spread of cancer, each part of the angiogenesis process is a potential target for new cancer therapies. The assumption is that if a drug can stop the tumor from receiving the supply of nutrients, the tumor will "starve" and die. However, there are so many agents out there now, doctors have a confusing array of choices. They don't know how to mix them together in the right order.

Avastin (bevacizumab) is a monoclonal antibody, a type of genetically engineered protein. Monoclonal antibodies are substances made in the laboratory that recognize and then attach to specific proteins on the outside of cancer cells. They may be used to stimulate the immune system to attack cancer cells or to deliver radiation, chemotherapy, or other biologic therapies more directly to a tumor.

Avastin directly binds to a protein in the body called vascular endothelial growth factor (VEGF), which spurs the growth of blood vessels. Angiogenesis is dependent on VEGF. Avastin directly binds to VEGF to directly inhibit angiogenesis (microvasculature regression). Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. VEGF can cut off the supply of vessels that spring up to feed a tumor, but there is some uncertainty how Avastin works, or if it can get "inside" a cell.

VEGF is an important activator of angiogenesis. Like the name indicates, VEGF causes endothelial cells to grow. Research has shown that oncogenes (genes that help cancer cells grow), cytokines (substances produced by the immune system), and hypoxia (a low-oxygen environment, which is common in tissues around solid tumors) can all directly or indirectly activate VEGF, thereby starting angiogenesis.

VEGF causes angiogenesis by attaching to special receptors (proteins on the "outside" of cancer cells that act like doorways), and this action starts a series of chemical reactions "inside" the cell. Because VEGF is so important to angiogenesis, it is a target of new cancer treatments. Avastin blocks a receptor for VEGF. Erbitux is also a monoclonal antibody but directed at a different protein. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF.

PTK/ZK (vatalanib) is a small molecule tyrosine kinase inhibitor with broad specificity that targets all VEGF receptors (a multi-VEGFR inhibitor), the platelet-derived growth factor receptor, and c-KIT. It is a multi-VEGFR inhibitor that inhibits the activity of all known receptors that bind VEGF.

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.

Posted at 5:14PM on Jan 27th 2007 by Gregory D. Pawelski

2. Thank you, that was very informative!

Posted at 10:42AM on Jan 28th 2007 by Alex Weyermann

3. Mr. Pawelski,

That was very informative information and well said so that the average non-medical person could understand! Thank you for taking the time to post that! I just wish it would have been explained to me prior to agreeing to the therapy for my father’s colon cancer. We were handed print-outs from the nurses that gave general drug information along with side affects that include the general chemo side effects such as nausea, vomiting, hair loss etc. But we were NEVER informed of the more serious and fatal side effects until it was too late. I suppose you can say that Avastin worked too well in our case. After my father came out of emergency surgery where they removed his entire colon this week, we were then told of the serious side effects and how Avastin worked. Needless to say, Avastin not only cut off the blood supply to the tumor, it also cut off the blood supply to the colon entirely causing the tissue to die. This placed my father in a very critical situation....Surgery after Avastin is causing him not to heal now, Avastin caused him to loose his colon, and Avastin has caused the fluid around his heart and given him blood clots in the lungs (this is what the doctors tell us). To me Avastin is not worth the $5000/per dose price tag it comes with. Drug manufactures and Doctors should speak honestly and openly about how the drug works and about ALL the possible outcomes prior to prescribing and administering a drug. Where is the compassion in the medical world these days... Do doctors not remember or believe that “their” patients are our loved family members? I am sure the doctor remembers to tell his/her father about the side effects BEFORE giving him such a dangerous drug. Maybe we should have the drug makers put the warnings on those cute little ink pens instead of the company’s mascot and drug names so they can remember what can go wrong while writing these prescriptions/therapies. Which is more important to remember .... the drug company mascot or the fatal side effects?

Posted at 10:07AM on Feb 11th 2007 by Daughter

4. The below information applies to gastrointestinal perforation/wound healing complications when Avastin is given as adjuvant chemotherapy (after surgery).

Gastrointestinal perforation (the development of an abnormal break in the wall of the stomach, intestines, or colon) occurred in an increased incidence in patients treated with Avastin. These episodes often resulted in an abscess formation. This may be due to the impaired wound healing induced by Avastin. Therefore, it is recommended that Avastin not be given within at least 28 days following major surgery. In addition, the surgical incision should be fully healed prior to initiation of Avastin. This is a severe complication.

The typical presentation of wound breakdown and gastrointestinal perforation is abdominal pain (often severe) with associated constipation and/or vomiting. Therefore, any severe abdominal pain should be regarded as an emergency. Obviously, discontinuation of Avastin is warranted in these instances.

However, your father received Avastin as neoadjuvant chemotherapy (before surgery).

Posted at 7:11PM on Feb 12th 2007 by Gregory D. Pawelski

5. There was some information put out by Genentech about advanced ovarian cancer patients experiencing gastrointestinal perforations with Avastin. It said that it was higher than expected number. The problem could be 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.

Ovarian cancer commonly involves bowel walls. With conventional chemotherapy, as the tumor melts away, new connective tissue forms a patch. So bowel perforations are rare. But Avastin can inhibit the growth of capillaries into newly forming normal tissue, as well as in tumor tissue. So this would be a complication. If one does not have any known bowel involvement, one would probably be ok.

It was suggested that none of the other "targeted" drugs like Erbitux, Iressa or Tarceva work the same way and should not share the problem seen with Avastin. Again, this was with "advanced" cancer patients.

Posted at 8:56AM on Feb 14th 2007 by Gregory D. Pawelski

6. The risk of serious GI side effects remains low with Avastin

In clinical studies, the incidence of GI perforation (perforation, fistula formation, and/or intra-abdominal abscess) was 0.9% for bevacizumab-treated NSCLC patients compared with 2.4% for those with colorectal cancer.

This is new data:

http://www.medscape.com/viewarticle/550583

and it's possible that cancer patients have not been informed because the data was not there. Clinical trials are often not large enough for physicians to make this determination, yet the public demands FDA approval of effective medications. It's only when large #s of patients receive the medication, after approval, that side effects are seen.

We should not be so quick to accuse doctors and researchers of a lack of openness and honesty. They wait for the data just as you and I do.

Posted at 7:09PM on Feb 14th 2007 by hchcec

7. There are good sides and there are bad sides to all drugs. What needs to be learned, and obviously sometimes the hard way, is how do drugs work. This is particularly true when they are biologics, they can be working in ways and speed that we arn't used to. It is a learning process and it can be a painful one, but we just need to learn how to use it.

Avastin is indeed associated with wound dehiscence, a rupture of a surgical wound to discharge its contents. The vascular inhibitory effects are predisposed to these complications. The mechanism of action may more reflect the Vascular Permeability Factor effects rather than the anti-angiogenesis effects. Maybe Avastin wasn't the cause of this complication. Avastin as a single agent is relatively ineffective in most tumor types, other than Renal cancer, a disease known to be driven by the VHL->HIF1a->VEGF pathway. Beyond that, it appears better to deliver the effects of other classes of drugs.

Some of these new "smart" therapies often get a pass on toxicities because they are "sexy." So darn cool! Herceptin in the adjuvant setting is an example. There are tumors that are Her2/neu positive which don't respond to Herceptin. There are tumors which are estrogen receptor positive which don't respond to Tamoxifen. There are tumors which are c-kit positive which don't respond to Gleevec. The problem is that few drugs work the way we think and few physicians take the time to think through what it is they are using them for.

Posted at 11:16PM on Mar 1st 2007 by Gregory D. Pawelski

8. I'd be interested in knowing what you mean when you say that these therapies get a pass on toxicities? With few patients entering clinical trials and ill patients urging approval of these drugs, perhaps you want many more years and many more patients entered in clinical trials before approval?

Also "few drugs work the way we think and few physicians take the time to think through what it is they are using them for."

So, if I go to my oncologist today, I should go with the understanding that it is likely that he or she does not know why I'm getting my chemotherapy or how it works?

Could you elaborate?

Thank you.

Posted at 8:25AM on Mar 2nd 2007 by hchcec

9. Any number of oncologists' training and practice does not include studying and understanding the cancer cell and its relationship to the rest of the body's cellular mechanics and communication. Cellular biology is a very complex and fascinating body of knowledge which a number of private clinical scientists appreciate and understand. They are the "geeks" of cancer medicine (the M.D./Ph.D's). They are constantly looking for ways to reverse that cell physiology and in a non-toxic way as possible. Continued development of better cancer drugs is driven by increased understanding of cancer cell biology. Their goal is to develop agents that are effective at killing tumor cells while sparing normal cells in the process. Perhaps if these physicians did rotations like medical students do, they would develop more of an understanding and appreciation of what it is they are doing.

Posted at 4:55PM on Mar 2nd 2007 by Gregory D. Pawelski