Ovarian Cancer Treatment Improved By Novel Medication

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A new study appearing in International Journal of Gynecological Cancer states that Avastin, a biologic anti-cancer agent that prevents tumor growth by interfering with the formation of new blood vessels, may have the potential to improve the efficacy of standard combination chemotherapy in ovarian cancer.

Studies have continued to investigate the activity of novel medications in combination with standard therapy to improve overall and disease-free survival in ovarian cancer patients.

Avastin has been studied clinically and was recently approved as a treatment for metastatic colon cancer and non-small cell lung cancer. Currently, Avastin is also being studied as a treatment to improve patient survival rates for breast and kidney cancers.

Since Avastin has a unique mechanism of action and a favorable safety profile, the medication is not associated with unreasonable levels of toxicity. However, previous studies have reported that gastro-intestinal perforations and hypertension may be a consequence of treatment involving Avastin.

According to Dr. Bram Goldstein, co-author of the study, the results from their research suggest that the combination of Avastin and standard therapy for the treatment of ovarian cancer may be promising, particularly with regard to safety and efficacy.

Source: Vol. 17 Issue 4 of International Journal of Gynecological Cancer.

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Angiogenesis is essential for the growth and metastasis (spread) of cancer. A growing tumor requires nutrients and oxygen (angiogenesis), 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.

Tumor growth is dependent on angiogenesis. Angiogenesis is dependent on VEGF. Avastin directly binds to VEGF to directly inhibit angiogenesis. Avastin works by choking off the blood vessels that provide a tumor with oxygen and nutrients. Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. Tumors which secrete relatively low levels of VEGF might be more susceptible to an agent which works by blocking VEGF.

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. Avastin, used by itself and in combination with other drugs, shows that the angiogenesis-blocker boom is on. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to 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. 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.

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 patient's cancer.

Drugs like Avastin can be tested with a bio-marker test called EGFRx, because the target of Avastin is not the cells themselves, but rather a hormone (VEGF) secreted by the tumor cells. The Avastin complexes with free VEGF and blocks its action. The EGFRx bio-marker can discriminate between the activity of different targeted drugs and identify situations in which it is advantageous to combine the targeted drugs with other types of cancer drugs.

A major modification of the DISC (cell death) assay allows for this study of anti-microvascular drug effects of standard and targeted agents, such as Avastin, Nexavar and Vatalanib. The assay is based upon the principle that microvascular (endothelial and associated) cells are present in tumor cell microclusters obtained from solid tumor specimens. The assay which has a morphological endpoint, 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 an individual cancer patient. 2. Exposing viable tumor cells to anti-neoplastic drugs. 3. Measuring absolute in vitro drug effect. 4. Finding a statistical comparision 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.

It is the only assay which involves direct visualization of the cancer cells at endpoint, allowing for accurate assessment of drug activity, discriminating tumor from non-tumor cells, and providing a permanent archival record, which improves quality, serves as control, and assesses dose response in vitro.

This kind of technique exists today and might be very valuable, especially when active chemoagents are limited in a particular disease, giving more credence to testing the tumor first. After all, cutting-edge techniques can often provide superior results over tried-and true methods that have been around for many years.

Reference: Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007.

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ZURICH—Roche Holding AG said its cancer drug Avastin showed positive results in the treatment of advanced ovarian cancer, further improving the prospects of one of the Swiss pharmaceutical company's best-selling drugs.

Roche, which earlier registered a setback with Avastin in the treatment of stomach cancer, said a late stage trial found that the drug—in combination with chemotherapy plus maintenance use of Avastin—increases the time women live without the disease becoming worse.

"We are greatly encouraged by these results," said Pascal Soriot, Chief Operating Officer of Roche's pharma division. "Women with this disease still have a poor outlook and we are committed to working with the relevant health authorities to make Avastin available to these patients," he said.

Ovarian cancer is the sixth most commonly diagnosed cancer in women and the eighth leading cause of cancer death among women world-wide, according to the American Cancer Society. Annually, an estimated 230,000 women are diagnosed with ovarian cancer around the world and around 140,000 die from the disease.

Analysts welcomed the positive result of the phase III study, which showed that women who continued using Avastin alone after receiving Avastin in combination with chemotherapy lived longer without the disease worsening, compared to those who received chemotherapy alone.

"2010 is going to see a slew more Avastin data," said Bernstein analyst Jack Scannell, referring to two ongoing studies that test Avastin in prostate cancer and in early-stage colorectal cancer. "We think there is a decent chance the prostate cancer trial will succeed, ... but we have very low expectations for Avastin in colorectal cancer," he said.

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Temsirolimus (Torisel) is a kinase enzyme inhibitor, which works by blocking the action of the abnormal protein that tells the cancer cells to multipy. It was FDA approved for the treatment of renal cell carcinoma.

The barrier to entry (approval) is much lower in renal cell cancer with numerous targeted therapies now approved for a relatively small niche indication, including Nexavar, Sutent, Torisel, Afinitor, Votrient and Avastin.

Doctors can legally prescribe drugs for any use. Off-label uses of cancer drugs are those therapies other than those for which drugs have received approval from the FDA. Off-label use is the practice of prescribing pharmaceuticals for an unapproved indication.

The FDA does not have the legal authority to regulate the practice of the medicine and the physician may prescribe a drug off-label. Some drugs are used more frequently off-label than for their original, FDA-approved indications. Frequently, the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs.

The FDA wants to alter rules for cancer drug cocktails. Rather than mixing and matching approved drugs, scientists want to develop combinations designed to work in tandem to block cancer. What better way for a pharmaceutical to identify a potential population of cancer patients that it thinks will benefit from its drug and then conduct a randomized clinical trail among this group.

Some have suggested to use assays to identify a potential targeted population of ovarian cancer patients that it thinks will benefit from the Avastin and Torisel combination, and then conduct a randomized clinical trial among this group. The Microvessel Viability Assay (MVA) is such a test to tell who is going to benefit. There are not perfect combinations of drugs, there are simply combinations that work for certain patients.

According to cell function analysis, by clinical oncologists involved with cell culture assay testing, Avastin appears to better deliver the effects of other classes of durgs. Avastin facilitates vascular access of cytotoxics to tumors. In other words, Avastin may facilitate vascular access of Torisel.

Conventionally, oncologists rely on clinical trials in choosing chemotherapy regimens. But the statistical results of these population-based studies might not apply to an individual. For many cancer, especially after a relapse, more than one standard treatment exists.

There are so many excellent agents for ovarian cancer, but mass confusion for oncologists in knowing how too use them, and cell culture assay testing can be very helpful.

It will take combination antivascular therapy to make a big difference, but this is definitely coming and it's the most promising thing on the near term therapeutic horizon.