New Paradigms of Cancer Treatment

gdpawel · Last edited by gdpawel on Wed Nov 23, 2005 2:00 am; edited 1 time in total

Gene Expression assays are panels of markers that can predict the likelihood of cancer recurrence in various populations. Chemotherapy Sensitivity and Resistance Assay is a test for drug activity against a tumor. Pharmacogenomic testing is a test to identify patients who are likely to have the most (or least) toxicity.

By testing the gene expression markers of a patient, oncologists can identify those patients unlikely to benefit from adjuvant chemotherapy from those that would. If the patient needs adjuvant chemotherapy, by testing the patient's tumor cells and testing the patient toxicity tolerance, the oncologist can select drugs that have a higher probability of being effective for an individual patient rather than selecting drugs based on the average responses of many patients in large clinical trials.

What a cancer patient would like ideally, is to know whether they would benefit from adjuvant chemotherapy (something gene expression assays may be good at). If so, which active drugs have the highest probability of working (something chemosensitivity testing is very good at) and are relatively non-toxic in a given patient (something pharmacogenomic testing should be good at).

Whether a patient would benefit from adjuvant therapy depends on two things: (1) whether the tumor is "destined" to come back in the first place and (2) whether the tumor is sensitive to drugs which might be used to keep it from coming back.

The gene expression markers (assays) actually can be calibrated to provide information both about the possibility of recurrence and also chemosensitivity. The problem is dissecting one from the other. Studies to date have just looked at whether people had a recurrence.

You can identify gene expression patterns (via assays) which correlate with this. But it can be hard and even impossible to tell what exactly you are measuring: is it intrinsic aggressiveness of the tumor? sensitivity to adriamycin? sensitivity to cyclophosphamide? sensitivity to taxol? sensitivity to tamoxifen? You find a gene expression panel which correlates with something, but picking apart the pieces is hard.

You can begin to do this if you combine gene expression studies with cell culture studies. Use the cell culture as the gold standard to define the difference between sensitivity and resistance. Then see which pattern correlates with which for individual tumors and individual drugs. It can theoretically be done (and certainly will be done, over time), but it's not easy.

And then you come to the 1,000 pound gorilla of a question: What effect will the different individual drugs have in combination in different, individual tumors? This is where cell culture assays will always be able to provide uniquely valuable information. But it's not one versus the other. The best thing is to combine these different tests in ways which make the most sense. One month's worth of herceptin + avastin costs $8000. That's without any docetaxel and blood cell growth factors and anti-emetics. If nothing else, we can't afford too much trial and error treatment.

caryam · New User Joined: 04 Jun 2005 Posts: 9

great post, gdpawel, this is something that has been on my mind for a while now...what is incredible to me is that my dog, who died of cancer four years ago, was able to get a full battery of chemo-sensitivity tests from his veterinary oncologist for a measly $150, but my wife, who has been battling stage IV cancer for the last three years hasn't even been given the option.

There is something seriously amiss. What amazes me is the money that could be saved by the big HMOs if they would just bother to embrace these newer technologies, and the vast amount of un-needed pain and suffering that might be avoided by patients who are taking high doses of toxic chemicals that might not have ever had a chance of giving them any benefit in the first place. The disparity between what we are learning in research labs around the globe, and the time it actually takes to trickle down to Oncology as it's practiced in the clinic, is disheartening to say the least.
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-Cary

gdpawel

Some of these technologies are already present, some have been available for over fifteen years, some will be out shortly. The three that I list are so complementary to each other. We are getting a rapidly-expanding list of treatments which are partially effective in a minority of cancer patients, ineffective in a majority of them, remarkably effective in a few, isolated patients, while being enormously expensive. The fastest way to improve things is to match treatment to the patient, like these technologies can and will do.

There are over 100 different therapeutic drug regimens which any one or in combination can help cancer patients. The system is overloaded with drugs and underloaded with the wisdom and expertise for using them. We have produced an entire generation of investigators in clinical oncology who believe that the only valid form of clinical research is to perform "well-designed," prospective, randomized trials in which patients are randomized to receive one empiric drug combination versus another empiric drug combination. The problem is not with using the prospective, randomized trial as a research instrument. The problem comes from applying this time and resource-consuming instrument to address hypotheses of trivial importance (do most cancers prefer Coke or Pepsi?).

Clinical research into the chemotherapy of advanced ovarian cancer has produced no progress dating back to the 1960s. To this date, no form of first-line chemotherapy has been proven superior to the single agent alkylators (including orally-administered agents) which were utilized in the 1960s. Government and academic clinical investigators have failed to support the individualization of chemotherapy through laboratory testing, in favor of attempts to identify "one size fits all treatments" through trial and error testing which has consumed tens of thousands of human lives. This entire effort has been a colossal failure and a colossal waste of human and financial resources.

Chemosensitivity testing for instance, has been shown to correlate strongly with patient response to chemotherapy and with long-term patient survival after treatment with chemotherapy. What has been missing until most recently are data to show that basing treatment decisions on the results of chemosensitivity testing improves clinical outcomes. This is simply because the investigators who control the clinical trials system have been entirely non-supportive of clinical trials to compare assay-directed chemotherapy to standard, one-size-fits-all chemotherapy. Some day this will change. The failure of 30 years' worth of clinical trials research into "one-size-fits-all" therapy will eventually force a consideration of new approaches. But it will be years before the results of such trials are available. Too late for treatment decision which must be made today.

Neil Love, M.D. reported in a survey of breast cancer oncologists based in academic medical centers and community based, private practice oncologists. The academic center-based oncologists do not derive personal profit from the administration of infusion chemotherapy, the community-based oncologists do derive personal profit from infusion chemotherapy, while deriving no profit from prescribing oral-dosed chemotherapy.

The results of the survey show that for first line chemotherapy of metastatic breast cancer, 84-88% of the academic center-based oncologists prescribed an oral dose drug (capecitabine), while only 13% perscribed infusion drugs, and none of them prescribed the expensive, highly remunerative drug docetaxel.

In contrast, among the community-based oncologists, only 18% prescribed the oral dose drug (capecitabine), while 75% prescribed infusion drugs, and 29% prescribed the expensive, highly remunerative drug docetaxel. The existence of this profit motive in drug selection has been one of the major factors working against the individualization of cancer chemotherapy based on testing the cancer biology.

This is not to imply that the academic center-based oncologists are without their fair share of collective guilt. They were misguided in not recognizing that they were trying to mate notoriously heterogeneous diseases into one-size-fits-all treatments. They devoted 100% of their clinical trials resources into trying to identify the best treatment for the average patient, in the face of evidence that this approach was non-productive. However, such unsuccessful experiments will never be viewed as such by the thousands of people whose careers are supported by these experiments.

I don't think Dr. Love had any clue to the meaning of his own data. He just thought it was interesting how community oncologists differed in their prescribing preferences from the academics. He didn't, however, connect the dots. He didn't note the reimbursement implications of prescribing an oral dose drug on one hand and an infusion drug on the other hand, and he didn't appreciate how his data constituted a smoking gun with respect to what has been going on in the world of cancer chemotherapy.

The Community Oncology Alliance (COA) says that the government is reducing payment for cancer care under the new Medicare bill (MMA). However, that's not what they are doing. They are simply reducing overpayment for drugs. The government can't afford to overpay for drugs, in an era where all these new drugs are being introduced, which are fantastically expensive.

The costs of a month's worth of the new drugs Herceptin and Avastin average $8,000. This is not reimbursement or overreimbursement for services; this is simply the cost of the drugs. The thing about drugs like Herceptin and Avastin is that they are pretty much taken chronically, in some cases perhaps for years. The "old" drugs would typically just be given for six months or so.

So cancer patients have a choice. Keep overpaying their oncologists and not have access to new generations of cancer therapeutics. Or keep payments in line with actual costs and perhaps have something left over to help pay for the new drugs.

leo · Site Admin Joined: 23 Sep 2004 Posts: 1574

Gdpawel,

You seem to be very bitter about Oncologists. I understand what you've been through with your wife, but that does not mean all Oncologists are money-driven and just do not invest in what you openly promote: chemosensitivity testing. Maybe it will work in the future. So far there are no results indicating that this should be done, however you keep on pounding all boards with this idea, creating a sense that patients are receiving the wrong treatment. You do not, however, have the appropriate training and insight into the biology that is behind this, and I am sure you've never done any laboratory research to understand how difficult and time-consuming this is. From a distance it may be very simple to implement chemosensitivity testing, but if this worked, wouldn't you think it would be done by now ?

LF
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Disclaimer: this information is for informational purposes only. It is not medical advice.

gdpawel

Leo

You sound trite right-wing in your rhetoric. Hypothetical statement "A" plus hypothetical statement "B" must mean statement "C." You should get a hold of yourself before insinuating adjectives onto people. The survey by Love was truly a "holy cow!" moment.

Ask a physician like Dr. William R. Grace, a board certified community practicing oncologist, with nearly two decades in academic oncology as Chief of Medical Onoclogy and Cancer Research, why he utilizes chemosensitivity testing in his practice for over ten years now, if assay-testing is not a "ready for prime-time player" yet. Given his experience with apoptotic CSRA's, noting their accuracy in predicting clinical outcomes, defining unique chemotherapeutic synergies and their frequent curative value in many adult malignancies which all current literature would deem incurable, why would he say that it would be unethical for him not to use apoptotic CSRA's in his practice?

The standard always used to evaluate any type of medical test has always been the correlative and predictive "accuracy" of the test. How well does a Bacterial Culture and Sensitivity Test predict for clinical success or failure of penicillin therapy? Not only is test accuracy (not efficacy) the established standard for evaluating every single test used in medicine, it is also the precise standard used by the FDA in approving a test kit for Cell Culture Drug Resistance Testing (assay-testing). The FDA didn't require proof of "efficacy" (as it has never required proof of "efficacy" for any medical tests).

Having some foreknowledge of a given chemo agent's expected result before its administration would benefit the individual patient. The cost of drugs is enormous. Patients are followed with serial CT scans, MRI's and even Pet Scans, just to see if a tumor is growing or shrinking. Not to mention the hospitalizations for toxicity, bone marrow tranfusions, etc. The point is, the cost of ineffective therapy is truly enormous and assay-testing is particularly good at identifying ineffective therapy.

Patients armed with knowledge can demand the treatment that works and be empowered. The human cost, not to mention the financial and emotional costs are too great.

leo · Site Admin Joined: 23 Sep 2004 Posts: 1574

GD,

First of all, bacteria are completelly different from human cells. So if you think that culture and sensitivity for bacteria can be applied 100% to human cells you are wrong. Also if you see one physician practicing by doing things that are not standard of care (doing tests and treating people based on absolutely no scientific evidence), you can not assume that what he/she is doing should be done by all physicians. All you've done so far is try to discredit Oncologists and Scientists who work hard to come up with better treatment.

LF
_________________
Leonardo F - Webmaster Cancer Forums
Disclaimer: this information is for informational purposes only. It is not medical advice.

gdpawel

The American Society of Clinical Oncology (ASCO) tries to point out that as outlined by the Institute of Medicine, tests are useful only if the information they produce leads to patient management changes that improve outcomes, such as longer survival, better quality of life, or fewer adverse events. Until the controlled, randomized trialist approach has delivered curative results with a high success rate, the choice of physicians to integrate promissing insights and methods like Chemotherapy Sensitivity and Resistance Assays (CSRAs), remains an essential component of this kind of treatment advocacy.

As ASCO points out, because the number of available chemotherapeutic agents has increased enormously over the past few years, the emphasis on the rationale for these assays has never been stronger. As the number of possible treatment options supported by completed randomized trials increases, the scientific literature becomes increasingly vague for guiding physicians. Almost any combination therapy is acceptable in the treatment of cancer these days.

Physicians are confronted on nearly a daily basis by decisions that have not been addressed by randomized trial evaluation. Their decisions are made according to experience, new basic science insights, bias or personal preference, philosophical beliefs, etc.. With all these uncertainties, would it be wrong to make a clinical decision based on CSRAs? Should it be denied to patients who walk in the door asking for it? Patients who want this testing, after a thorough discussion about the peer-reviewed studies and experience that supports it, should not be hindered by restrictive ASCO policy. I never heard that ASCO has been knighted a regulatory agency.

With the absence of effective laboratory tests to guide physicians, many patients do not even get a second chance at treatment when their disease progresses. Spending six to eight weeks to diagnose treatment failure often consumes a substantial portion of a patient's remaining survival, not to mention toxicities. In cases where there are several equivalent treatments available, patients can benefit from CSRA results as a supplement to other clinical data when deciding on a treatment option.

Why is it so necessary to protect the patient from information provided by a perfectly rational laboratory test which is supported by a wealth of entirely consistent data? If used to assist in the selection of a regimen chosen from a series of otherwise reasonable alternatives, then patients will never be harmed and best available evidence strongly indicates that they will often be helped.

You're right Leo, some are slow to change. Many oncologists wouldn't have had any training to read and interpret the results. However, there are many very intelligent people who are working every day to bring this dream that is outlined to become the new reality. Find that self-educated oncologist who will make use of the many available off-label drugs in formulating a custom-designed novel regimen, as well as running tests on the biopsy before selecting the chemo option. After all, cutting-edge techniques can often provide superior results over tried-and-true methods that have been around for many years.

gdpawel

The recent discovery in Sweden of a group of 64 genes that can be used to predict whether women with breast cancer will respond to treatment following surgery moves the infant field of DNA microarray analysis closer to viability as a clinical tool.

After more testing and commercial development, the assay for the new gene cohort will supplement two already existing products called MammoPrint, developed by Agendia in Amersterdam, Netherlands, and Oncotype DX, by Genomic Health Inc. in Redwood City, Calif. MammoPrint searches for a 71-gene group associated with the tumor's risk of recurrence, and Oncotype DX identifies a 21-gene cohort that determines whether the tumor in question will respond better to chemotherapy or hormonal therapy.

Scientists hope to use DNA microarray analyses and two other tests -- chemotherapy sensitivity/resistance assays that identify which drugs affect the tumor, and pharmacogenomic testing that determines how the patient's body will respond to the toxicities each drug produces -- to create treatment plans that fit the tumor and the patient like a glove.

Experts told United Press International the tests should be inexpensive enough to be performed on every breast-cancer patient.

Dr. Christi Iacobuzio-Donahue, assistant professor of oncology and pathology and a researcher on genetic microarrays at Johns Hopkins Medical Center in Baltimore, said a focused array that targets a specific gene group eventually should cost only about $100, and the other two assays should be equally reasonable.

"Gene expression studies are not looking at all 33,000 human genes anymore," Iacobuzio-Donahue said. "Focusing on specific groups is moving the technology into a cost-effective era."

Researchers had different ideas on what would bring genetic testing to the bedside more quickly.

Dr. Anthony Elias, medical director of the Breast Cancer Research Program at the University of Colorado in Boulder, and Dr. Larry Norton, deputy physician-in-chief of breast cancer programs at Memorial Sloan-Kettering Cancer Institute in New York City, said changing genetic assays so they could be performed on the paraffin-embedded tissue specimens -- which commonly are used in pathology labs instead of fresh frozen specimens that need special equipment -- would enable the technology to be used at the community-hospital level, instead of being confined to comprehensive cancer centers and teaching hospitals.

Dr. John Olson, associate professor of surgery and breast cancer specialist at Duke University Medical Center in Durham, N.C., said physicians hesitate to use the tests, because they were developed using cancer patients who had been treated in the past, not tested in clinical trials of using current patients.

Norton said he thought such trials were an excellent idea, but worried the means to mount them might not be available.

"As the ideas explode, the opportunities to do the work are shrinking," he said. "The field is suffering from a lack of funds and the small number of adult patients who are willing to participate in clinical trials."

These experts agreed genetic testing and individualized therapy would be the preferred treatments of the future, and probably could become a reality in five to 10 years.

"Personalized medicine is our dream," Elias concluded. "Trials like this (one in Sweden) get us one step closer."

gdpawel · Posted: Mon Nov 21, 2005 1:54 pm Post subject: Anti-angiogenic Therapies

Giving low doses of several drugs every day by mouth. There would be no needles and the side effects are expected to be mild. Unlike standard chemotherapy, which is given in high doses to kill as many cancer cells as possible, the lower-dose regimen is meant to attack the blood vessels that feed the tumor. Tumors create their own supply lines by secreting substances that stimulate the formation of new blood vessels and researchers suspect that frequent low doses of certain drugs may disrupt the growth of those new vessels, starving the tumor.

The treatment includes small daily doses of standard chemotherapy drugs and two other drugs that have been found to inhibit the formation of new blood vessels, called angiogenesis. One is Celebrex and the other is Thalidomide. It is offered only to people who have no other options, who have advanced tumors that standard treatment cannot cure or those for whom standard chemotherapy has quit working.

Women with advanced breast or ovarian cancer are being given smaller, more frequent doses of chemotherapy to reduce side effects. It is hoped that low-dose treatment may help other cancer patients, not just those who are considered terminal. It may work just as well or even better, maybe through this ability to cause an anti-angiogenesis effect.

This approach to treatment is based on something that can frequently occur in people, when a tumor becomes resistant to chemotherapy and high doses stop working. It is believed that angiogenesis plays a role. Angiogenesis is essential to the survival of many tumors. Many chemotherapy drugs, in addition to killing tumor cells, also fight angiogenesis. But, if these medicines stop angiogenesis, chemotherapy should work better than it does. Blood vessel cells are less likely than tumor cells to become resistant to chemotherapy, so if cancer cells become drug resistant, these medicines should still be able to shrink tumors by destroying their blood supply.

The reason chemotherapy was not stopping angiogenesis was that chemotherapy is usually given in big doses, with breaks of several weeks between doses to let the body recover. During the breaks, the tumor's blood vessels could grow back. By giving chemotherapy more often, at lower doses, it might prevent the regrowth of blood vessels and kill the tumor or at least slow its growth.

It is especially important to study low-dose therapies now because they are being used increasingly in clinics. Doses, timing and combinations all need to be worked out. Doctors need to find out whether the treatments can make patients live longer and whether tumors will eventually outsmart the drugs and find ways to survive even without angiogenesis.

For further information about clinical trials, refer to the National Cancer Institute's website: http://cancertrials.nci.nih.gov

The October 2005 issue of Ultrasound in Medicine and Biology reports that researchers at the University of Pennsylvania School of Medicine are studying the use of ultrasound to disrupt the vessels supplying blood and nutrition to tumors, much like cancer treatment utilizing anti-angiogenic therapies. After all, cutting-edge techniques can often provide superior results over tried-and-true methods that have been around for many years.

This approach is in keeping with the latest studies of cancer treatment utilizing antiangiogenic therapies, in which they look for ways to stop the growth of vessels supplying blood and nutrition to tumors, rather than develop methods to kill tumor cells themselves. In the future, treatments with ultrasound either alone or in combination with chemotherapeutic agents could be used to treat cancers.

Nobody believed Judah Folkman when, in the 1960s, he claimed that the growth of cancers could be stopped, even reversed, by blocking the tiny vessels that feed them blood. Over the years, however, he has survived peer rejection of his theory, and gone on to develop drugs that did what he predicted they would do. The angiogenesis-blocker boom is on.

gdpawel · Posted: Fri Dec 30, 2005 11:42 am Post subject: Gene Expression Assays

New Strategy Guides Selection of Best Drugs for Individual Cancer Patients

by DukeMed News

Choosing the best cancer treatments is often akin to throwing darts at a massive corkboard, hoping to hit the desired target. But scientists have now developed a novel method for selecting the most effective anti-cancer drugs based on the patient's unique tumor activity.

The new approach scans the tumor for evidence of widespread genetic changes that drive the tumor's growth and survival. Rather than simply identifying defective genes, the scientists identified altered "pathways" - multiple genes and their proteins - that consistently escape normal regulation in tumors.

Cell signaling pathways are a complex hierarchy of genes, and the proteins they produce, that act upon one another in a tag-team relay to ultimately drive a cell's cancerous activity, said the scientists from the Duke Institute for Genome Sciences and Policy and the Duke Comprehensive Cancer Center.

Identifying which pathways are deregulated in each type of tumor - and to what degree - provides a critical tool for enabling physicians to choose the right drugs for each patient, said Joseph Nevins, Ph.D., the senior author of the study, published Nov. 6, 2005, as an Advance Online Publication of the journal Nature.

"Targeting drugs to deregulated pathways provides a means to avoid giving ineffective drugs to the majority of patients," said Nevins. "Instead of prescribing a drug that inhibits the SRC pathway at a tumor that has no SRC deregulation, we can select the right drug for that tumor type." SRC is one of five pathways often deregulated in cancer cells.

The Nevins team developed their strategy by first distinguishing normal cells from cells with genomic "signatures" indicative of cancer. They created artificial cancer conditions by introducing a series of cancer-causing genes, called "oncogenes," into otherwise normal cells. By comparing gene expression patterns in normal cells versus cells harboring oncogenes, they demonstrated that each cellular signaling pathway is associated with a unique pattern of gene expression, its so called signature.

Moreover, the gene expression signatures could be used to actually predict which cells carried the oncogenes and their associated deregulated pathways.

Having validated the approach in cells and then in mice, the Duke team assessed its ability in human tumors, as well. Their first success was distinguishing two types of lung cancer from each other: adenocarcinoma, which originates in the periphery of the lung, and squamous cell carcinoma, which forms in the central chest area. They found the overwhelming majority of adenocarcinomas were deregulated for the oncogene Ras, while only a tiny minority of squamous cell carcinomas exhibited Ras deregulation. Hence, deregulation of the Ras pathway is an important signature of adenocarcinomas but not of squamous cell carcinoma, said Nevins.

The Duke scientists then applied the approach to a series of breast cancer cell lines. They predicted which pathways were likely to be deregulated, then treated the cancer cells with drugs that targeted components of the cancer-causing pathways. Indeed, the pathways predicted to be most highly deregulated were also the most sensitive to drugs that targeted these pathways.

"Until now, there have been very few opportunities to guide the use of therapeutic drugs that target specific cellular components," said Nevins, director of the Center for Applied Genomics and Technology at the Duke Institute for Genome Sciences and Policy.

"But now, we've developed tools to measure the activity of critical pathways, groupings of related genes, and proteins that are activated or silenced in a given tumor, and we can potentially use this information to best utilize the large array of existing drugs."

The ultimate goal of their approach is to provide individualized treatment plans to each patient based on the unique pathway signatures of their tumor, said Mike West, Ph.D., professor of statistics and decision sciences at Duke and a lead author of the study. Pre-defining a tumor's characteristics will arm physicians with the information needed to make effective treatment decisions, he said. If the Ras and Myc pathways are activated in a tumor, for example, then physicians could choose drugs that target only Myc and Ras. If the SRC and E2F3 pathways are highly active, then drugs can be selected that target these pathways.

Because tumors arise from multiple defective genes and their malfunctioning proteins, their treatments must target multiple genes and their pathways, said the researchers. The likelihood that someone will be cured by a single drug is low, and the new approach can guide physicians as to which combination of drugs will most likely produce the best outcome, they said.

"We believe this approach provides a path to identifying not only what combination of drugs might be most effective, but also an approach to selecting the right group of patients for the combination of drugs" said Andrea Bild, the lead author of the study.

"We can gain even more powerful insights by looking at patterns of multiple deregulated pathways in any given tumor," added Nevins. "It's really the combinations of pathways that reveal both important biology and subgroups of patients with quite distinct clinical outcomes."

Nevins said the next step in the research is to validate the new method in samples from cancer patients who have been treated with one of the pathway-specific drugs to determine if the pathway predictors are able to select those patients most likely to respond to the drug. A positive result would then form the basis for a clinical study that would evaluate the effectiveness of the pathway prediction to guide the most effective use of therapeutics.

"If we treat patients with drug A whose pathway A is deregulated, do we see a better response?" said Nevins. "We need a clinical study to assess whether we can enrich patient outcomes, but we are encouraged that this could be an approach to the ultimate goal of personalizing the selection of the best drugs for the individual cancer patient."

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