Ovarian Cancer Treatment Improved By Novel Medication

[gpawelski]

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.

[gpawelski]

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 in 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 AngioRx™ Microvascular Viability / Angiogenesis Assay, 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 AngioRx™ Microvascular Viability / Angiogenesis Assay 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.

http://weisenthalcancer.com/Professionals%20Pages/AngioRxProfessional.htm

[gpawelski]

Effective novel assay-directed drug combination for relapsed ovarian cancer

Two studies reported that the drug combination of Gemzar + Cisplatin identified chemosensitivity analysis that was effective for treating women with relapsed ovarian cancer.

While both drugs are commonly used to treat an array of tumor types, the combination of these two in the treatment of relapsed ovarian cancer patients, including those with platinum resistance, was highly novel.

In the first study, researchers at Rational Therapeutics in California, investigated the results of heavily pretreated patients with relapsed ovarian cancer. The results revealed that the Gemzar + Cisplatin combination achieved a 70% response-rate, with more than 20% of the patients achieving complete remission.

Equally noteworthy was the fact that the patients whose cancer cells demonstrated sensitivity to the drug combination in the laboratory assay were the same patients who benefited the most from therapy.

They were able to achieve positive outcomes for patients, many of whom had virtually no other options, and do this by simply using available drugs more effectively.

The second study, conducted by researchers at Case Western Reserve University, Ohio, and University Hospitals of Cleveland, similarly confirmed the high response-rate for the Gemzar + Cisplatin combination in treating ovarian cancer.

These results further verify the value of drug sensitivity testing in identifying treatment options for all cancer patients who are candidates for chemotherapy. Such results could provide the basis for assay-directed therapies in a wide variety of cancers.

The Gemzar + Cisplatin combination was first identified at Rational Therapeutics and applied by Dr. Robert Nagourney in 1995 to treat heavily pretreated patients with advanced ovarian cancer. The patients, having failed all available therapies, received assay-directed therapy.

Based on the encouraging results from the two studies, a national clinical trial of the Gemzar + Cisplatin combination in treating relapsed ovarian cancer, by the Gynecologic Oncology Group, with support from the US National Cancer Institute, was instituted.

Source: Gynecol. Oncol. 88 [1], 2003

[gpawelski]

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.

[sandrawall]

What about the drug Paclitaxel for treating ovarian cancer?

[gpawelski]

In past two decades, taxanes have emerged as front-line chemotherapy agents in several types of human cancers. Paclitaxel for ovarian cancer epitomizes this notion and is the current standard front-line therapy along with carboplatin. Having already learned about the efficacy of paclitaxel in ovarian cancer (only 30% according to the FDA), future areas of active exploration include finding the optimal dosing schedule (like low-dose), investigating newer and potentially better forms of paclitaxel (like Taxotere and Abraxane), and identifying the optimal route of administration (IV vs IP).

In a survey from the 4th International Ovarian Symposium in 2007, it was found that physicians switched from dispensing the drugs that experienced the largest cuts in profitability, paclitaxel and carboplatin, to other high-margin drugs, like Taxotere (docetaxel) and Abraxane.

No form of first-line chemotherapy has been proven superior to the single agent alkylators (including orally-administered agents like Leukeran or Melphalan) which were utilized in the '60s and '70s. It has not been shown that platinum-based combination therapy is superior to single agent alkylator therapy. No substantial benefit has been found in giving ovarian cancer patients this therapy. Clinicians have found that the toxic effects of this treatment can cause a lower quality of life for these patients.

Taxol does not improve standard first-line ovarian cancer treatment. Studies in Lancet (August 17, 2002) suggest that for initial treatment of women with ovarian cancer, widely used standard drugs are equally as effective as treatments that include Taxol and Carboplatin and may be considered the preferred treatment as they have fewer side effects. The results of these studies doesn't mean that Taxol has not role in the treatment of ovarian cancer, but they allow doctors and ovarian cancer patients to have choices according to each individual's needs.

Two large, unrefuted studies (GOG-132 and ICON-2) showed that single agent carboplatin was at least as good and in some respects better than platinum/Taxol. Paclitaxel (Taxol) plus carboplatin failed to achieve superiority over carboplatin alone in the ICON-3 study. Based on clinical trials, results showed no difference between single agent platinums (cisplatin or carboplatin) versus platinum/Taxol (GOG Trial #132, ICON3), the British National Institute for Clinical Excellence (NICE) determined that platinum/Taxol should no longer be considered as standard therapy.

A myriad number of choices exist in the management of ovarian cancer patients. Doxil, Etoposide, Gemcitabine (Gemzar), and gemcitabine-based combinations, including gemcitabine + platinum combinations (gemcitabine circumvents tumor cell resistance to platinum in some cases by preventing the tumor cells from repairing platinum-induced DNA damage). But not all patients derive benefit from gemcitabine + platinum administered on an empiric basis, because it only works against some tumors. But when it works, it often works very well.

Additional possibilities are Melphalan, Hexamethylmelamine, 5FU (including Xeloda), Oxaliplatin, Gemcitabine + Oxaliplatin, Vinorelbine + Oxaliplatin, gefitinib (Iressa), pemetrexed (Alimpta), ifosfamide + cyclophosphamide (plus or minus gemcitabine), Mitomycin c, and others. In ovarian cancer a greast many drugs can be and should be tested.

Chemosensitivity Assays Have a Role in the Management of Recurrent Ovarian Cancer

Julian C. Schink, MD, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Gynecologic Oncology Program, Northwestern Prentice Women's Hospital, 250 East Superior Street, Suite 05-2168, Chicago, IL 60611.

Abstract

In this era of personalized medicine, patients with recurrent ovarian cancer deserve better than the 25% response rate that is associated with drugs selected based on clinical information alone. In the past decade, marked laboratory improvements have enabled chemosensitivity assay testing to yield a 0.70 correlation with response, and to accurately predict progression-free and overall survival. Compelling retrospective data supporting the use of this technology cannot be ignored while waiting for a cooperative group to test whether chemosensitivity assay should be used to direct salvage therapy.

Prognostic factors for women with recurrent ovarian cancer include histology, CA125 level, radiographic versus clinical disease, and treatment-free interval. Surely, with the aid of laboratory information, patients can hope for more than creative inspiration. Similarly, criticisms of the retrospective nature of most of the data supporting the benefit of chemosensitivity assays ignore the fact that the concept of platinum-sensitivity was based on and adopted entirely from retrospective analyses.

In the past two decades the number of drugs with documented activity against ovarian cancer has increased dramatically, but the selection criteria has remained unchanged. The concept of platinum resistance is a gross siimplification of a complex biologic system and cannot remain the primary selection criterion for choosing salvage chemotherapy.

In colon cancer, the value of Kras testing to predict the benefit of using cetuximab was readily accepted based on a single retrospective study. Trastuzumab was adopted for the treatment of HER1-positive breast cancer based initially on retrospective data. With more than a dozen NCCN-acceptable treatments for recurrent ovarian cancer, and only the platinum-free interval to guide decision-making, the results of assay studies support including chemosensitivity assay results in salvage therapy decision-making whenever feasible.

Using highly technical scientific and engineering principles, chemosensitivity assay testing has evolved in the past decade to produce clinically reliable results that predict progression-free and overall survival. The opportunity to personalize therapy in the setting of recurrent platinum-resistant ovarian cancer through using assay-directed therapy should not be overlooked. Patients deserve the best prospect for treatment response, and chemosensitivity assay testing offers the chance to avoid ineffective therapies (J Natl Compr Canc Netw 2011;9:115-120).