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[gdpawel]

Phase II trials of Avastin (bevacizumab) for the treatment of aggressive brain cancer have shown promising results, said Genentech, makers of the drug, who presented their findings at the 12th Annual Scientific Meeting of the Society for Neuro-Oncology that took place between 15th and 18th November, in Dallas, Texas.

Avastin (bevacizumab) is a monoclonal antibody that inhibits the growth of tumours by blocking the production of new blood vessels (angiogenesis) that would feed the tumour. The drug, which has been described as a "blockbuster" cancer drug, was one of the first clinically available angiogenesis inhibitors in the US.

Given alone or with irinotecan chemotherapy in a randomized, multi-center, phase II trial, the drug showed an encouraging six-month progression-free survival (PFS) and objective response rate in patients with the most common and aggressive type of brain cancer, relapsed glioblastoma multiforme (GBM).

According to the American Cancer Society (ACS), only 3 per cent of patients with GBM survive longer than 5 years, and this figure has not altered in 25 years. The Society estimates that in 2007 there will be 20,500 new cases of brain cancer and 12,740 brain cancer deaths in the US.

36 per cent (31 out of 85) patients treated with Avastin alone, and 51 per cent (42 out of 82) treated with Avastin combined with chemotherapy, lived without the disease advancing within six months, reported Genentech, who said the results were "assessed by independent radiological review".

Genentech researchers said they observed no new or unexpected safety events related to Avastin.

Dr Timothy Cloughesy, lead researcher of the study, and director of the Neuro-Oncology Program of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA) said that:

"Historical estimates suggest that only 15 percent of patients with this aggressive type of brain cancer live without their cancer progressing within six months."

"The findings suggested that at six months, more patients had lived without their cancer advancing when Avastin was administered as a single-agent or in combination with chemotherapy, than what we would normally expect," he added.

In this phase II, open-label, multicenter, randomized, non-comparative study, Cloughesy and colleagues enrolled 167 patients with GBM whose cancer had relapsed. They were randomized to either an Avastin alone or Avastin with irinotecan chemotherapy group, and all patients had received prior temozolimide. The treatment was administered every other week for up to two years (104 weeks).

The main outcome measure was PFS, which was defined as the "absence of any event of cancer progression or death". The researchers also assessed overall survival and safety.

As well as the six-month PFS rates of 36 and 51 per cent in the Avastin only and Avastin with chemotherapy groups, the results also showed that:
Preliminary estimates of tumour response were seen in 21 per cent (18 of 85) of patients treated with Avastin only.

The figure for Avastin with chemotherapy was 34 per cent (28 out of 82).

Adverse events linked to Avastin were similar to previous trials.

The most common severe (grade 3 or higher) toxicities in the Avastin only group were: hypertension (8 per cent), and convulsion (6 per cent).

The figure for the Avastin plus chemotherapy group were: convulsion (13 per cent) and neutropenia (9 per cent); neutropenia is a condition where there is a low count of neutrophils, a type of white blood cell.

Grade 1 and grade 3 intercranial (brain) hemorrhage occurred in 2 participants in the Avastin only group.

One patient had a grade 4 hemorrhage in the Avastin plus chemotherapy group.

Two deaths were linked to adverse events in the Avastin only group, and one in the Avastin plus chemotherapy group.
So far, the findings have turned out better than the researchers expected and have prompted the company to spur efforts to discuss the findings with the US Food and Drug Administration (FDA) and find out what the next step should be in getting the drug to this new group of patients.

The trial is still ongoing and final figures for safety and other efficacy results will be available in 2008, said the researchers.

Avastin was first approved by the FDA in February 2004, to treat metastatic colorectal cancer in combination with chemotherapy. Since then it has been approved for particular types of lung cancer. There are currently over 300 trials worldwide assessing the drug's potential to treat over 20 different types of tumour.

[url]http://www.medicalnewstoday.com/articles/89186.php[/url]

[gdpawel]

In normal tissue, new blood vessels are formed during tissue growth and repair, and the development of the fetus during pregnancy. In cancerous tissue, tumors cannot grow or spread (metastasize) without the development of new blood vessels. Blood vessels supply tissues with oxygen and nutrients necessary for survival and growth.

Endothelial cells, the cells that form the walls of blood vessels, are the source of new blood vessels and have a remarkable ability to divide and migrate. The creation of new blood vessels occurs by a series of sequential steps. An endothelial cell forming the wall of an existing small blood vessel (capillary) becomes activated, secretes enzymes that degrade the extracellular matrix (the surrounding tissue), invades the matrix, and begins dividing. Eventually, strings of new endothelial cells organize into hollow tubes, creating new networks of blood vessels that make tissue growth and repair possible.

Most of the time endothelial cells lie dormant. But when needed, short bursts of blood vessel growth occur in localized parts of tissues. New capillary growth is tightly controlled by a finely tuned balance between factors that activate endothelial cell growth and those that inhibit it.

About 15 proteins are known to activate endothelial cell growth and movement, including angiogenin, epidermal growth factor, estrogen, fibroblast growth factors (acidic and basic), interleukin 8, prostaglandin E1 and E2, tumor necrosis factor-, vascular endothelial growth factor (VEGF), and granulocyte colony-stimulating factor. Some of the known inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 ( and ß), interleukin 12, retinoic acid, and tissue inhibitor of metalloproteinase-1 and -2. (TIMP-1 and -2).

At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth. Two endothelial growth factors, VEGF and basic fibroblast growth factor (bFGF), are expressed by many tumors and seem to be important in sustaining tumor growth.

Angiogenesis is also related to metastasis. It is generally true that tumors with higher densities of blood vessels are more likely to metastasize and are correlated with poorer clinical outcomes. Also, the shedding of cells from the primary tumor begins only after the tumor has a full network of blood vessels. In addition, both angiogenesis and metastasis require matrix metalloproteinases, enzymes that break down the surrounding tissue (the extracellular matrix), during blood vessel and tumor invasion.

Research has shown that controlling production of new blood vessels can restrict tumor growth, often prolonging the life of the cancer patient. Perhaps the most widely-used anti-angiogenic agent to emerge to date has been the drug Avastin.

Avastin was approved by the FDA for use in combination with intravenous 5-fluorouracil-based chemotherapy for first-line treatment of patients with metastatic colorectal cancer.

However, Avastin has also shown activity in many other solid tumor types such as breast, lung, and ovarian cancer. One of the most popular combinations for brain tumors is Camptosar (CPT-11) and Avastin.

As with most "targeted" therapy drugs, Avastin does not necessarily benefit every patient and it is expensive. Until now, there were no tests that existed to show reliably who would benefit from anti-angiogenic agents.

There has been an bio-marker assay (AngioRx™) developed for microvascular viability to identify potential responders to Avastin, Nexavar, Sutent, and other anti-angiogenic drugs. It was discovered that endothelial cells are present in tumor microclusters and it appears that drug effect upon these cells can be assessed in the new microvascular viability assay.

The assay has a morphological endpoint which allows for visualization of both tumor and microvascular cells and direct assessment of both anti-tumor and anti-microvascular drug effect. CD31 cytoplasmic staining confirms morphological identification of microcapillary cells in a tumor microcluster.

The principles and methods used in the assay include: 1. Obtaining a tissue, blood, bone marrow or malignant fluid specimen from the patient. 2. Exposing viable tumor cells to anti-neoplastic drugs. 3. Measuring absolute in vitro drug effect. 4. Finding a statistical comparison of in vitro drug effect to an index standard, yielding an individualized pattern of relative drug activity. 5. Information obtained is used to aid in selecting from among otherwise qualified candidate drugs.

Confirmatory activities are ongoing. It is being offered currently to selected clients on a research basis and as an adjunct to a standard assay or a tyrosine kinase assay.

Every cancer patient should have his/her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data. Research and application of these tests are being encouraged by growing patient demands, scientific advances and medical ethics. These tests are not a luxury but an absolute necessity, and a powerful strategy that cannot be overlooked.

Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007

[gdpawel]

Drugs commonly mixed with brain tumors are temodar, thalidomide, tamoxifen and accutane. However, Avastin has shown activity in many solid tumor types. One of the most popular combinations for brain tumors is Camptosar (CPT-11) and Avastin.

Avastin targets a protein called VEGF (vascular endothelial growth factor) that stimulates blood vessel growth. Avastin inhibits the growth of tumors by cutting off their blood supply, which deprives them of oxygen and other nutrients.

In a small percentage of patients, however, Avastin can cause neurological side effects ranging from headaches and blurry vision to potentially fatal seizures and brain swelling.

A new study revealed that 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.

The authors of the study suspected that Avastin's side effects in humans may be caused by a similar phenomenon. Why these symptoms occur in only a few patients is not yet known.

Many of these new targeted drug therapies often get a pass on toxicities because they are just so darn cool. 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. The scientist in the lab most likely knows this, but the medical oncologist most likely does not.

As with most targeted therapy drugs, Avastin does not necessarily benefit every patient and it is expensive. Until recently, there were no tests that existed to show reliably who would benefit from anti-angiogenic agents. There is a bio-marker assay (AngioRx™) developed for microvascular viability to identify potential responders not only to Avastin, but Nexavar, Sutent, and other anti-angiogenic drugs.

Every cancer patient should have his/her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data. Research and application of these tests are being encouraged by growing patient demands, scientific advances and medical ethics.

These pre-tests are not a luxury but an absolute necessity, and a powerful strategy that cannot be overlooked.

Literature Citation:
Eur J Clin Invest 37 (suppl. 1):60, 2007.
J. Exp. Med. 2008 doi:10.1084/jem.2052iti5
[url]http://www.jem.org/cgi/content/full/jem.2052iti5v1[/url]

[gdpawel]

Avastin has been approved by the FDA for use as a single-agent for treating glioblastoma (GBM) that has progressed after prior treatment. Avastin is a monoclonal antibody that inhibits the growth of tumors by blocking the production of new blood vessela (angiogenesis) that would feed the tumor.

The effectiveness of Avastin in GBM is based on tumor response. No data have shown whether Avastin improves disease-related symptoms or survival in people previously treated for GBM.

[url]http://www.avastin.com/avastin/patient/gbm/index.html[/url]

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.

Cancer patients may be taking doses of treatments that are possibly well in excess of what they need. Writing in the Journal of Clinical Oncology, Dr. Ian Haines cites an emerging body of evidence showing that many cancer drugs may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses.

He gave one example, Avastin, the dose being used is 15 milligrams per kilogram of body weight, despite other research showing it may work with 3 milligrams per kilogram of body weight. He mentioned that more time should be spent on analyzing drug data after a new medicine is made available.