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Old 02-22-2007, 04:23 PM
Dross Dross is offline
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Default Phase III Study of Avastin(R) Plus Chemotherapy Shows Improved Survival

Avastin (bevacizumab) is a specially designed antibody that binds to a protein called vascular endothelial growth factor (VEGF). VEGF is the most important protein in a process called angiogenesis, the act of growing new blood vessels. The idea is that by removing all the VEGF with the Avastin, tumors will not be able to grow new blood vessels or at least the blood vessels that they make will be more normal and make it easier for treatments to reach the cancer. In non-small cell lung cancer (the non-squamous variety), Avastin has been proven to extend survival modestly when combined with standard platinum doublet chemotherapy.

Genentech, Inc. announced that a Roche-sponsored Phase III study evaluating two different doses of Avastin (bevacizumab) in combination with gemcitabine and cisplatin chemotherapy met the primary endpoint of prolonging progression-free survival (PFS) in patients with previously untreated, advanced non-squamous, non-small cell lung cancer (NSCLC), the most common form of the disease. Both doses of Avastin (15 mg/kg or 7.5 mg/kg every three weeks) significantly improved PFS compared to chemotherapy alone, as assessed by trial investigators. Although the study was not designed to compare the Avastin doses, a similar treatment effect in PFS was observed between the two arms. No new safety signals related to Avastin were observed in the study. More than 1,000 patients from outside of the United States participated in the trial, known as AVAiL (BO17704).

"In addition to supporting Avastin's benefit in advanced lung cancer, these results demonstrate Avastin's potential when used in combination with a different chemotherapy regimen," said Hal Barron, M.D., Genentech's senior vice president, Development and chief medical officer. "We will continue to analyze these data to better understand the benefit and relative safety of each arm and these findings will be presented at an upcoming medical meeting."

Based on an improvement in overall survival, the U.S. Food and Drug Administration (FDA) in October 2006 granted a supplemental approval for Avastin in combination with carboplatin and paclitaxel for the first-line treatment of advanced NSCLC. The U.S. approval is based on results of the Phase III E4599 trial that studied a 15 mg/kg dose of Avastin administered every three weeks. The 15 mg/kg dose was selected based on the outcome of a randomized Phase II study evaluating two different doses of Avastin in combination with carboplatin and paclitaxel chemotherapy.

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Old 07-07-2007, 09:51 PM
gdpawel gdpawel is offline
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Default The Microvascularity Viability Assay

Anti-angiogenesis drugs work by blocking the activity of VEGF to prevent the growth of new capillaries into the tumor and thereby sustain tumor growth. VEGF causes angiogenesis by attaching to special receptors, and this action starts a series of chemical reactons inside the cell.

Avastin directly binds to VEGF to directly inhibit angiogenesis. 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 like Avastin which works by blocking VEGF (Avastin "sensitive" tumors). It potently inhibits the formation of new blood vessels.

There is a "functional profiling" Microvascular Viability Assay for anti-angiogenesis-related drugs. A major modification of the DISC (cell death) assay allows for the study of anti-microvascular drug effects of standard and targeted agents. 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 Microvascularity Viability 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.

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.

Source: Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007
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Old 09-19-2010, 08:46 PM
gdpawel gdpawel is offline
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Default Bibliography relevant to AngioRx/Microvascular Viability assay (MVVA)

1. Weisenthal, L. M. Patel,N., Rueff-Weisenthal, C. (2008). "Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood." J Intern Med 264(3): 275-287. [url]http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2008.01955.x/full

2. Weisenthal, L., Lee,DJ, and Patel,N. (2008). Antivascular activity of lapatinib and bevacizumab in primary microcluster cultures of breast cancer and other human neoplasms. ASCO 2008 Breast Cancer Symposium. Washington, D.C.: Abstract # 166. Slide presentation at: [url]http://tinyurl.com/weisenthal-breast-lapatinib

3. Weisenthal, L. M. (2010). Antitumor and anti-microvascular effects of sorafenib in fresh human tumor culture in comparison with other putative tyrosine kinase inhibitors. J Clin Oncol 28, 2010 (suppl; abstr e13617)

4. Weisenthal, L., H. Liu, Rueff-Weisenthal, C. (2010). "Death of human tumor endothelial cells in vitro through a probable calcium-associated mechanism induced by bevacizumab and detected via a novel method." Nature Precedings 28 May 2010. from [url]http://hdl.handle.net/10101/npre.2010.4499.1
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Old 11-16-2010, 12:54 PM
gdpawel gdpawel is offline
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Default Avastin Regrowth (Rebound)

When you get rid of VEGF with Avastin, the body cranks out other types of blood vessel growth/survival factors. A research article in The Journal of Clinical Investigation explains tumor vascular regrowth following withdrawal of an anti-VEGF agent.

Rapid vascular regrowth in tumors after reversal of VEGF inhibition.

[url]http://www.jci.org/articles/view/24612

What may limit the effectiveness of Avastin is that 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.

Also, there are other proangiogenic factors that can affect whether Avastin works or not, FGF, PDGF, ephrin A1, angioprotein 1, IL8, etc. You need to attack these other targets as well. That is why we need combination anti-angioRX. If you can achieve this, then you don't really need the other drugs, which don't get into the tumor so well. Angiogenic attack provides true selective toxicity, something which is sorely lacking with all of the other treatments.

It could be vastly more important to measure the net effect of all processes (systems) instead of just individual molecular targets (like VEGF). The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one or a few targets or pathways.

There are many pathways to the altered cellular (forest) function, hence all the different "trees" which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indiviudal trees.

VEGF-targeted drugs are poorly-predicted by measuring the preferred target VEGFR. They can be well-predicted by measuring the effect of the drug on the function of live cells.

Many of these fine drugs (and Avastin is a miracle drug for the few) cry out for validated clinical biomarkers as pharmacodynamic endpoints and with the ability to measure multiple parameters in cellular screens to help set dosage and select people likely to respond. Many molecular diagnostics approved often have been mostly or totally ineffective at identifying clinical responders to various therapies.

If you find one or more implicated proteins in a patient's tumor cells, how do you know if they are functional (is the encoded protein actually produced)? If the protein is produced, is it functional? If the protein is functional, how is it interacting with other functional proteins in the cell?

All cells exist in a state of dynamic tension in which several internal and external forces work with and against each other. Just detecting an amplified or deleted gene won't tell you anything about protein interactions. Are you sure that you've identified every single protein that might influence sensitivity or resistance to a certain class of drug?

Assuming you resolve all of the preceeding issues, you'll never be able to distinguish between susceptibility of the cell to different drugs in the same class. Nor can you tell anything about susceptibility to drug combinations. And what about external facts such as drug uptake into the cell? You're not going to accomplish this using genetic tests.

Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease. The biologies are very different and the response to given drugs is very different.

The major obstacle in controlling cancer drug prices is the widespread inappropriate use of anti-cancer drugs. As the increasing numbers and types of anti-cancer drugs are developed, oncologists become more and more likely to misuse them in their practice. There is seldom a "standard" therapy which has been proven to be superior to any other therapy. What may work for one, may not work for another.

Literature Citation:
Eur J Clin Invest 37 (suppl. 1):60, 2007
Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117
"Cure: Scientific, Social, and Organizational Requirements for the Specific Cure of Cancer" A. Glazier, et al. 2005

It is going to take combination antivascular therapy to make a difference, as Weisenthal, et al had shown at the 2008 ASCO Breast Cancer Symposium.

[url]http://cancerfocus.org/forum/showthread.php?t=3152
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Old 11-16-2010, 12:55 PM
gdpawel gdpawel is offline
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Default What's Wrong with Avastin?

By Dr. Robert Nagourney

Nothing really. Itís a wonderful drug that incorporates the brilliant insights originally articulated by Judah Folkman, MD, at Harvard University. Dr. Folkman reasoned that:

Cancers require oxygen and nutrients

These would need to be delivered by a blood supply

Tumors would avidly seek their own blood supply via humoral factors.

His groundbreaking work ultimately lead to the discovery of VEGF, as well as the FDA approval of Avastin, the monoclonal antibody that binds and inactivates circulating VEGF in patients. The problem isnít with Avastin, itís with the practice of oncology Ė the clinical trial process and the muddied waters that surround clinical utility of any drug, new or old.

There are no perfect drugs. There are simply drugs that work for certain patients. VEGF down-regulation is an attractive and highly appropriate therapy for a subset of cancer patients with many different diagnoses whose tumors use the VEGF pathway to their advantage. Avastin combined with carboplatin and taxol has improved the survival of lung cancer patients. Avastin plus folfox has improved survival for colon cancer patients. Avastin plus chemotherapy improves the survival of some breast cancer patients. The problem is that it doesnít improve the survival of all breast cancer patients.

When the FDA rules on the clinical utility of a drug, they use a broad-brush approach that looks at the global outcomes of all patients, determining whether these glacial trends reflect a true climate change. The problem is that while Bethesda, Maryland may not be noticing significant changes in ocean levels, people who live on the Maldives are having a very different experience. As these scientists ponder the significance of Avastin, some breast cancer patients are missing out on a treatment that could quite possibly save their lives.

One breast cancer patientís life saving therapy is anotherís pulmonary embolism without clinical benefit. Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one Avastin after another. Our solution to this problem has been to investigate the VEGF targeting agents in each individual patientís tissue culture, alone and in combination with other drugs, to gauge the likelihood that vascular targeting will favorably influence each patientís outcome. Our results to date in patients with non-small cell lung cancer, colorectal cancer and even rare tumors (like medullary carcinoma of the thyroid) suggest this to be a highly productive direction for future development.

[Dr. Nagourney is medical and laboratory director at Rational Therapeutics, Inc., in Long Beach, California, and an instructor of Pharmacology at the University of California, Irvine School of Medicine. He is board-certified in Internal Medicine, Medical Oncology and Hematology.]
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Old 11-23-2010, 11:43 AM
gdpawel gdpawel is offline
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Default Tumours grow their own blood vessels

Published online 21 November 2010 | Nature | doi:10.1038/news.2010.623

[url]http://www.nature.com/news/2010/101121/full/news.2010.623.html

About the most key statement in the article (when it comes to treatment) is, "most people agree that a single pathway is not going to do it." When you get rid of VEGF with Avastin, the body cranks out other types of blood vessel growth/survival factors.

The problem with Avastin is the same thing that was a problem with AZT for HIV/AIDS. Early results, then rapid resistance. Solution was combination therapy to attack different targets. With cancer, it's going to take combination antivascular therapy to make a difference.

Tumor vasculature needs VEGF to survive. Avastin removes VEGF, killing blood vessels. But other proangiogenic factors can substitute: FGF, PDGF, ephrin A1, angioprotein 1, IL-8 etc. We need to attack these other targets, as well.

If you can achieve this, then you may not even need the other drugs, which don't get into the tumor so well. But angiogenic attack provides true selective toxicity, something which is sorely lacking with all of the other treatments.

Perhaps Avastin "sensitive" tumors secrete relatively low levels of VEGF. Tumors which secrete relatively low levels of VEGF might be more susceptible to an agent which works by blocking VEGF.

As the article mentions "vascular mimicry," something I've written about on the board previously, 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 angiogenesis, co-option of existing blood vessels and vasculogenic mimicry. All must be inhibited to consistently starve tumors of oxygen.

While vasculogenic mimicry - some types of cancers form channels that carry blood, but are not actual blood vessels - with co-option, instead of growing new blood vessels, tumor cells can just grow along existing blood vessels. This process cannot be stopped with drugs that inhibit new blood vessel formation.

The consistent and specific cure or control of cancer will require developing and using a set of drugs, given in combination, targeted to patterns of normal cellular machinery related to proliferation and invasiveness.

A sufficient number of independent methods of cell killing must be employed so that it is too improbable for a cancer cell to evolve that can escape death or inactivation. It must examine every cell in the body and must do so for a prolonged period of time.

Given the current state of the art, cell-based in vitro drug sensitivity testing (with functional profiling) could be of significant clinical value. One aspect of a functional profiling assay is that microvascular viability can measure dead microvascular cells in tissue, fluid and peripheral blood specimens to identify potential responders to anti-angiogenic drugs (Avastin, Nexavar, Sutent) and to assess direct and potentiating anti-angiogenic effects of tyrosine kinase targeted therapy drugs (Tarceva, Iressa).
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Old 12-02-2010, 12:43 PM
gdpawel gdpawel is offline
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Default Alcohol as an anti-angiogenic enhancer and potentiator

Very high doses of antioxidant polyphenols found in red wine - such as resveratrol - shut down and prevent cancerous tumors by cutting off the formation of new blood vessels needed for tumor growth. Phenolics contained in red wine possess antioxidant and antimutagenic properties.

Polyphenols are antioxidant compounds found in the skin and seeds of grapes. When wine is made from these grapes, the alcohol produced by the fermentation process dissolves the polyphenols contained in the skin and seeds. Red wine contains more polyphenols than white wine because the making of white wine requires the removal of the skins after the grapes are crushed.

It's the alcohol itself rather than a particular type of drink or pill that GSK can try to concoct that is responsible for the reduction. Resveratrol has been shown to inhibit growth of many types of cancer cells in clinical specimens of human neoplasms and peripheral blood. Extracts of grape (resveratrol) can elicit protective responses, some mediated by the KEAP-1, NRF-2 pathway.

What is remarkable is tha if there is resistance to the anit-angiogenesis drug Avatin (in vitro), it is thought tha alcohol has a membrane effect, basically putting the cells to sleep so that it doesn't think it requires a blood supply. Avastin, with alcohol (as an anti-angiogenic enhancer and potentiator), the abrogating effect of the alcohol upon VEGF reduces the secretion of VEGF by the tumor cells.

It both reduces VEGF and makes Avasting work better, possibly overcoming tumor resistance to Avastin. In the presence of Avatin, it has a lethal 1-2 combination which knocks out the new vessels which are dependent on VEGF for survival.

The arbitrary distinction between commercial therapeutics and nutritional substances has created an unnecessary barrier between conventional therapists and those who practice complimentary care. A growing cadre of physicians is developing expertise in natural product therapeutics in parallel to their traditional training.

Chinese herbal and Indian ayurvedic medicine instruct physicians in the appropriate use of natural therapies. An explosion of interest in resveratrides, curcuminoids and terpenes are fueling a rebirth of interest in these naturopathic approaches.

Source: Journal of Internal Medicine, Volume 264, Number 3, September 2008 , pp. 275-287(13)
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Old 03-11-2011, 11:53 AM
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Default When Combined with Taxol or Platinum, Avastin Associated with 3-fold Risk of Death

Cancer patients who receive the targeted therapy bevacizumab (Avastin) in combination with chemotherapy are at increased risk of serious side effects that may lead to death, according to a meta-analysis of 16 clinical trials that was conducted by researchers at Stony Brook University School of Medicine in New York. The results were published February 2, 2011 in JAMA.

The risk of fatal adverse events varied by the type of chemotherapy agents used with bevacizumab, lead author Dr. Vishal Ranpura and his colleagues reported. There were also suggestions that the risk might vary by tumor type and bevacizumab dose, but the study did not have the statistical power to provide a definitive answer in either case.

More than 10,200 patients were enrolled in the randomized trials included in the analysis. Overall, fatal events were relatively rare, occurring in 2.5 percent of trial participants who received bevacizumab, compared with 1.7 percent of patients who did not—an approximately 50 percent increase in risk. However, the increased risk was more than threefold higher in patients who received bevacizumab in combination with platinum or taxane chemotherapy agents, such as carboplatin and paclitaxel, respectively.

The most common fatal event, accounting for nearly one-quarter of the total, was hemorrhage. Neutropenia, a decrease in a specific type of white blood cell that can put patients at increased risk of infections, was next, followed by perforations of the gastrointestinal tract, blockages of the pulmonary arteries, and cerebrovascular events such as stroke.

The benefits of bevacizumab can outweigh the risks of its use in a proportion of patients, explained Dr. Shenhong Wu, the study’s senior author, but the finding should prompt closer scrutiny of how bevacizumab is used. Oncologists, he said, “should have a healthy respect for the toxicity of this drug and the possibility that it can cause fatal events.”

The finding of an increased risk of serious events in patients treated with bevacizumab “is generally consistent with what’s known about the drug,” said Dr. Helen Chen of NCI’s Division of Cancer Treatment and Diagnosis. “What is clear [about bevacizumab] at this point is that the patients’ susceptibility to serious adverse side effects from bevacizumab can have a lot to do with the tumor setting and comorbidity.” Certain tumor types can predispose patients to an increased risk of certain events, she continued, such as bleeding in patients with advanced lung cancer.

Avastin can increase the risk of bleeding and prevent wound healing, so patients with recent surgeries or who cough up blood should not receive Avastin. It also increases the chances of getting a blood clot and can raise blood pressure and cause protein to spill into the urine. Patients with squamous cell carcinoma should not get Avastin due to a much higher risk of bleeding in the lungs.

Dr. Cary Presant of the Wilshire Oncology Medical Group, who is also a clinical professor of medicine at the USC Keck School of Medicine, believes that the study’s finding will likely affect clinical practice. “I do believe…that [bevacizumab] usage will go down,” he said. “This obligates every physician who wants to use [bevacizumab] to have a conversation with their patients about fatal events, and it will lead to less use of this drug in cases where the beneficial effects are more marginal.”

The strongest evidence of benefit with bevacizumab still seems to be in treating patients with metastatic colorectal cancer, Dr. Presant continued. “But some patients with lung [or] breast cancer might be inclined to choose not to receive it because the benefits are not as great.”

An antiangiogenic agent that binds to vascular endothelial growth factor (VEGF), bevacizumab was the first FDA-approved drug designed to target the blood supply that feeds tumors. In addition to being approved for the treatment of colorectal cancer, the monoclonal antibody is approved to treat lung cancer, kidney cancer, and glioblastoma.

Bevacizumab is also approved to treat metastatic, HER2-negative breast cancer. In December 2010, however, the FDA announced it was beginning the process of withdrawing that approval for breast cancer based on results from several post-market clinical trials that failed to show an improvement in overall survival and which, the agency stated, did not “provide a sufficient benefit in slowing disease progression to outweigh the significant risk to patients.” Genentech, which manufactures bevacizumab, has asked for a public hearing on the FDA’s withdrawal decision.

In an accompanying JAMA editorial, Dr. Daniel Hayes of the University of Michigan Comprehensive Cancer Center noted that treatment with bevacizumab can run as high as $100,000 a year, yet there is still substantial uncertainty around appropriate use of the drug in cancer care.

“Why, despite the impressively solid preclinical data and the promising early clinical results, has bevacizumab not been more successful in improving overall survival?” he wrote. Improvements in median overall survival were seen in only three of the pivotal trials on which the FDA based its approvals. In two of the trials, survival increased by less than 3 months.

“Careful review of response rates to bevacizumab suggest that bevacizumab works well, but only in selected patients,” Dr. Hayes wrote further. Despite being broadly tested in numerous clinical trials, he continued, “few insights are available about specific subgroups of patients who may benefit.”

In a statement responding to the JAMA study, Genentech noted that “the majority of our clinical studies include collection of blood, tumor tissue, and DNA for biomarker analysis as part of a comprehensive biomarker program.” To date, although some studies have reported a correlation between certain markers and outcomes of bevacizumab-based therapy, no markers have undergone the rigorous validation studies needed for use in the clinic, Dr. Chen stressed.

Genentech has proposed a phase III clinical trial of bevacizumab in HER2-negative breast cancer that would have a biomarker component. Based on a retrospective analysis of a previous trial, the company explained in a document filed with the FDA, the new trial would assess whether plasma levels of the protein VEGF-A are indicative “of a more substantial benefit” with bevacizumab.

Source: NCI Cancer Bulletin February 8, 2011 • Volume 8 / Number 3

Taxol + Carboplatin + Avastin

Paclitaxel (Taxol) has a cancer-promoting risk. It increases fivefold the production of Interleukin - 8 (IL-8), a cellular communication molecule that initiates the growth of new blood vessels to feed a growing cancer. IL-8 is under the control of an inflammatory regulating protein called nuclear factor-kappa Beta (NF-kB). When NF-kB is enhanced, it increases the production of IL-8, and thus Paclitaxel (Taxol) fails to stop the growth of new blood vessels that feed a growing cancer, failing to prevent recurrence.

Adding Avastin, which only goes after VEGF-sensitive cancer cells, you need to go after other pro-angiogenic factors which can substitute for VEGF: FGF, PDGF, ephrin A1, angioprotein 1, IL-8, etc. And with Taxol promoting an increase of IL-8, how effective is it with Avastin?

With Taxol increasing the production of a cellular communication molecule that initiates growth of new blood vessels to feed a growing cancer, seems to add to Pachmann, et al's study of Taxol-induced circulating tumor cells (CTCs). Taxol is worse off than anyone has ever realized (highly resistant, initiates cancer blood vessel growth, increases circulating tumor cells, and not the least, very toxic).

Source: Cell Function Analysis
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Old 03-11-2011, 11:53 AM
gdpawel gdpawel is offline
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Default Techniques that match patients to active therapies

[Dr. Robert A. Nagourney is medical director at Rational Therapeutics and instructor in Pharmacology at the University of California, Irvine School of Medicine. He posted on his blog about the issue surrounding Avastin.]

We previously wrote about bevacizumab (Avastin) and its approval for breast cancer. The early clinical trials revealed evidence of improved time to disease progression. This surrogate measure for survival benefit had, over recent years, gained popularity, as time to disease progression is a measure of the impact of a given treatment upon the patientís response durability. It was hoped and believed that time to progression would be an early measure of survival.

Unfortunately, the survival advantage for the Avastin-based therapies in breast cancer has not met statistical significance. As such, careful review by the oncology drug committee of the FDA lead to a unanimous decision to remove Avastinís indication in breast cancer. Avastin has not been removed from the market, but instead, cannot be promoted or advertised, nor do insurers necessarily reimburse it. This decision, however, will have a very big impact on Medicare patients and many others who are in managed care programs (HMOs).

There are no villains here. Instead, dedicated physicians empowered to scrutinize the best data could not prove beyond any doubt that the drug improved survival. The time to progression data was favorable and the survival data also trended in a favorable direction. But, the final arbiter of clinical approval ó statistically significant survival ó was not met.

The physicians who want to provide this for the patients, the company that produces the drug and the patients who believe it offers benefit all have legitimate positions. As Jerome Groopman, MD, once said, in a similar situation with regard to the FDA approval of interleukin 2 (a biological agent with profound activity in a small minority of melanoma and renal cell cancer patients), ďI am confronted with a dilemma of biblical proportions, how to help the few at the expense of the many.Ē

The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials. Our laboratory has been deeply involved in these stories for 20 years. When we first observed synergy for purine analogs (2CDA and fludarabine) with cytoxan, and then recommended and used this doublet in advanced hematologic malignancies (highly successfully, we might add) we were a lone voice in the woods. Eventually, clinical trials conducted at M.D. Anderson and other centers confirmed the activity establishing these treatments as the standards of care for CLL and low-grade lymphoma.

The exact same experience occurred in our solid tumor work when we combined cisplatin plus gemcitabine in pancreatic, ovarian, breast, bladder, lung and other cancers. While our first patient (presumably the first patient in the world) received cisplatin plus gemcitabine for drug-resistant recurrent ovarian cancer in 1995 ó providing her an additional five years of life ó it wasnít until 2006 that the FDA approved the closely related carboplatin plus gemcitabine for this indication.

We now confront an even greater hurdle. With our discoveries, using novel combinations of targeted agents, we are years (perhaps decades) ahead of the clinical trial process. We know that patients evaluated in our laboratory with favorable profiles can respond to some of the newest drugs, many of which have already completed Phase I of clinical trials. It is our fervent belief that we could accelerate the drug development process if we could join with the pharmaceutical companies and the FDA to put these hypotheses to a formal test.

Again, there are no villains here. Patients want, and should, receive active drugs. Doctors should be allowed to give them. The drug companies want to sell their agents and the FDA wants to see good therapies go forward.

The rancor that surrounds these emotionally charged issues will best be resolved when we introduce techniques that match patients to active therapies. We believe that the primary culture platform used in our laboratory, and a small number of dedicated investigators like us, may be the answer to this dilemma.

We will redouble our efforts to apply these methods for our patients and encourage our patients to lobby their health care insurers and representatives to sponsor these approaches. To date, we have been unsuccessful in convincing any cooperative group to test the predictive ability of these selection methodologies. In response, I reiterate that I will gladly participate and, to the best of my ability, support at least the laboratory component of any fair test of our primary culture methodologies.

We stand at the ready for the challenge.
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Old 05-14-2011, 09:49 AM
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Default Study: Medicare Part D Helps Heart Failure Patients

A number of cancer patients die of heart failure, brought on by the intense (over-aggressive cocktail) regimes of chemotherapy.

Taxol (paclitaxel) is an extremely potent chemotherapy drug, often producing a number of side effects in patients, such as cardivascular problems: hypertension or problems with the heart, such as arrhythmias, congestive heart failure or bradycardia. Many patients on chemotherapy become anemic and that can trigger further cardiac complications.

Chemotherapy in general can have a deadly side effect: heart trouble. However, the "antimicrotubules" class of chemotherapy drugs, of which Taxol is a member, is supposed to be relatively rare (they really don't know). The Platins (Carboplatin and Cisplatin) may be much different. Heart problems are more common than people think, affecting up to 25% of cancer patients.

According to MD Anderson cardiologists, many doctors do not adequately monitor their patients or manage their care to minimize the health risk. Chemotherapy can help achieve a clinical response (remission), but treatments can also hurt heart muscle by reducing the hearts ability to pump.

Problems can range from insignificant to so severe that a patient can die from the heart damage rather than the cancer itself. In many cases, cancer treatment heart damage isn't detected until it is advanced because traditional heart imaging tools often miss heart muscle damage.

Medicare Part D may be helping more older Americans with heart failure get medication used to control the disease. A new study of nearly 7,000 older heart failure patients in a big insurance plan found the number of filled prescriptions for standard heart failure medication increased after Part D began in 2006, and the biggest increase was among seniors who previously lacked drug coverage.

The results, which were reported in the American Heart Journal, are the first to show Part D may help more people with heart failure get meds that are recommended to lower the risk of hospitalization and extend lives.

The study examined records for 6,950 people age 65 and older who were enrolled in a Pennsylvania Medicare managed care plan between 2003 and 2007. In the year before Part D began, 534 plan members had no coverage, and 4,600 had coverage with quarterly caps of $150 or $350. The remaining 1,800 had coverage through an employer or union, with no cap, the news service reports.

Among those who had lacked coverage, the average number of scrips filled each year rose from 13 to 19, and the percentage who filled at least one scrip for a beta-blocker increased from 45% in the two years prior to Part D, to 59% in 2006 and 2007. For a beta-blocker plus an ACE inhibitor or ARB, the percentage rose from 21% to 32%. Plan members who previously had drug coverage with quarterly caps showed smaller increases. The percentage filling a scrip a beta-blocker rose from between 55 and 58% to about 63%.

Julie Donohue of the University of Pittsburgh Donohue said that these findings are consistent with a major goal of the (Medicare Part D) policy, which was to reduce financial barriers to medication access among the elderly.

Source: American Heart Journal

Common chemotherapy drug triggers fatal allergic reactions

[url]http://cancerfocus.org/forum/showthread.php?t=2871
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