Targeted Cancer Therapy Improved With Ex-Vivo Chemosensitivity Analysis

Researchers at Rational Therapeutics and Todd Cancer Institute (Long Beach, Calif.) have reported clinical results obtained with a laboratory technique (Ex-Vivo Analysis of Programmed Cell Death - EVA-PCD(TM)) that accurately identifies patients who are candidates for targeted cancer therapy.

A team led by Robert Nagourney, M.D., laboratory director of Rational Therapeutics and medical director of the Todd Cancer Institute at Long Beach Memorial Medical Center, report that ex-vivo laboratory analysis accurately identified non-small cell lung cancer (NSCLC) patients likely to benefit from the EGFr inhibitor, Erlotinib (Tarceva(TM)). The team's findings are published in the official proceedings of the 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO), held June 1-5 in Chicago.

"While targeted EGFr-TKI therapy has proven effective in treating advanced non-small cell lung cancer, response rates remain low in randomly selected patients," said Dr. Nagourney. "We have found that the EVA platform can help doctors select those patients most likely to benefit from the new generation of targeted anticancer therapies."

The researchers used ex-vivo analysis (EVA) to examine tissue from NSCLC patients as part of an IRB-approved assay-directed clinical trial. Patients found sensitive to the EGFr inhibitors received oral Erlotinib at 150mg/day as first line therapy. All of the patients selected responded to this oral therapy, with several achieving long-term remissions. This outcome demonstrates that patients whose cancer cells undergo programmed cell death in the laboratory due to EGFr inhibitor exposure are those who respond to targeted Erlotinib (Tarceva(TM)) therapy. The research team's findings are summarized in an abstract titled, "Clinical Responses to EGFr-TKI's Characterized by Drug-Induced Cell Death in Human NSCLC Primary Cultures" (ASCO Abstract # 07-AB-34058-ASCO).

Traditional anticancer drugs are toxic to both cancerous and normal cells. In contrast, targeted anticancer drugs target cancer cells with specific mutations. While such drugs hold promise, their use requires new methods to enable doctors to accurately and consistently identify patients whose particular type of cancer expresses the drug's specific target.

Dr. Nagourney explains, "Efforts to administer targeted therapies in randomly selected patients often result in low response rates at significant toxicity and cost. While researchers continue to develop molecular probes to select candidates, the ex-vivo platform used in this study serves as a functional profile capable of examining the nuances of cellular response to drugs. To exploit the full potential of targeted anticancer therapies, physicians will need laboratory tests that match patients to specific drugs. We believe the EVA PCD platform is such a test."

The Todd Cancer Institute at Long Beach Memorial Medical Center is the first cancer program in the nation to apply assay-directed therapy as the first-line treatment for advanced solid tumors. The Center is currently hosting clinical trials for cancers of the lung, colon, stomach, pancreas and prostate.

One of those has been Phase II assay-directed therapy in previously untreated, measurable, Stage IV NSCLC. Patients who had high activity for erlotinib in vitro and received first line single agent erlotinib had a 100% response rate.

(Genetic Engineering and Biotechnology News, June 1, 2007).

Read the news article that this opinion was posted about:
Lung Cancer Therapy Could Be Guided By Pre-Treatment Blood Test

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Re: Targeted Cancer Therapy

posted by Gregory D. Pawelski on 22 July 2007 at 8:22 pm

Dan Von Hoff was the most prominent member of the 2004 ASCO technology assessment panel on Cell Culture Assays. Before that time, he told people how the "old" clonogenic assay was the next great thing. However, if one thought he was trying to tell people that the "old" clonogenic assays should be studied in a research setting, is totally false. According to his mass mailings, he was trying to sell his assays outside the confines of a clinical trial.

He is one of the greatest organizers of clinical trials in the history of clinical oncology. Yet he virtually did not successfully organize and complete a single randomized trial to test "assay directed" versus "physician's choice" chemotherapy. Yet he sold his assays, not as a clinical trial, but as a service to patients. Then when his own pet technology was finally discredited, he spoke out against the use of cell culture assays in patient management. If he can't do it then no one else should be able to do it either. I'm glad no one took him up on it.

If the so-called respectible Journals (the ones that fail to adhere to guidelines on conflict of interest) won't publish articles because they have a lock-up on information, don't lay blame on me. If trials show that an assay-directed group actually did better than a physician's choice group, but because these are small and non-randomized studies, it is concluded that efficacy hasn't been proven.

No one has ever said or represented that cell culture assays have been proven to be efficacious in randomized trials, just that the tests are accurate and that accuracy has always been the standard used to evaluate tests. But, just because trials may have never been done, this should not be the reason for an medical oncologist to refuse to have the tests performed.

The current clinical trial of the EDR assay should not be designed as a self-fulfilling prophecy (to disprove the merits of this approach) but should legitimately seek an answer to the questions regarding the role of assays. They should be simple head to head comparisons between different assay endpoints in a real world, cooperative group setting, to determine whether the assays are of value. Then you can actually design a trial which has the best possibility of actually improving treatment results.

Thank goodness for America's private laboratories.

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Re:Pawelski

posted by hchcec on 23 July 2007 at 5:23 pm

"No one has ever said or represented that cell culture assays have been proven to be efficacious in randomized trials, just that the tests are accurate and that accuracy has always been the standard used to evaluate tests."

This is false. Pawelski believes tests are approved based on accuracy and not efficacy. This is not true. And, bte, who wants to pay $3500 for a test that has never been proven to be effective?

"But, just because trials may have never been done, this should not be the reason for an medical oncologist to refuse to have the tests performed. "

Huh? Design the test. Bring it on. You could say the same thing about homeopathy. I guess you want docs to advise patients to use homeopathic "remedies", too.

"Thank goodness for America's private laboratories."

Nice statement. But it's meaningless and their anecdotes are meaningless if they are hyping unproven tests as they regularly do.

(Sorry, my name is not Michele.)

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Re: Charlatans Like Michelle H. (hchcec)

posted by Gregory D. Pawelski on 24 July 2007 at 9:03 am

The issue isn't about the "accuracy" of cell culture assay tests, they have been "proven" accurate. The issue is about what criteria should be used to judge the tests. The tests themselves are a direct threat to the income of private practice oncologists and they are a threat to the research protocols of academic oncologists. So these groups want to see an unprecendented evaluation of "efficacy" as they do for newly "patented" cancer drugs.

A California Medicare contractor spent a whole year studying the issue of these tests. They got lots of negative feedback from lots of academic and private practice people. They also got positive feedback. Most importantly, they evaluated the tests by the criteria used to evaluate all other tests and concluded that the tests should be covered. So now virtually all Medicare patients, anywhere in the country, can have these tests and Medicare will pay for them.

Likewise, California Blue Shield has had two separate, extensive technology reviews, where all points of view and all data were considered. On both occasions, the impartial board of expert physicians voted unanimously in favor of reimbursement, despite active opposition from certain oncologists and oncology organizations.

It is totally wrong to portray this as being something where there is unanimity of opinion. In point of fact, in every situation where a neutral panel of adjudicators had the opportunity to hear both sides of the story, the decision came down in favor of coverage of these tests as a reasonable and scientifically supportable medical service.

So, it is by no means arguing in favor of snake oil and on the side of charlatans, as Michelle H. (hchcec) wants to portray this.

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Re Pawelski

posted by hchcec on 25 July 2007 at 8:53 pm

"The tests themselves are a direct threat to the income of private practice oncologists and they are a threat to the research protocols of academic oncologists."

Ah, conspiracy. (I should stop right here as anything that follows in his post is, well, biased.) Of course, oncologists and researchers are only in it for the money and, yet, the assay sellers are not. Sure.

This is an example of a Placing Blame Elsewhere Logical Fallacy. You have no evidence for your statement, so you blame the those who examine the evidence; they're greedy evildoers. Also known as the exaggeration fallacy, it is committed when an argument tries to include additional causal influences which are ultimately irrelevant to the matter at hand. We can say that committing a fallacy of exaggeration is a consequence of failing to heed Ockam's Razor, which states that we should prefer the simpler explanation and refrain from adding "entities" (causes, factors) which are not specifically necessary.

Cell Culture Testing, which is not empirically validated in relation to clinical response is not covered by the vast majority of large insurers. A novel testing technique is not automatically assumed to correlate with clinical performance simply because it measures cell survival or death in vitro.

And this comment from a leader in the field:

"In response to the statement, 'The extreme drug
resistance assay accurately identifies ineffective chemotherapy and helps the oncologist avoid unnecessary treatments and toxicity', Markman wrote, 'It is unquestionable that oncologists use these assays to assist in the positive selection of chemotherapeutic agents. Therefore, it is highly relevant to ask if the use of such an assay improves quality of life, reduces toxicity, improves
survival, or reduces cost. In the absence of actual data .it is INAPPROPRIATE to make claims .'"

Indeed. And the claims Pawelski makes are false. And the Medicare decision was a small local one, not national, as suggested.

PLUS,

One standard for Medicare coverage decisions is general acceptance in the medical community, while acceptance by individual health care providers, or even a limited group of health care providers fails to meet this standard (PIM Chapter 13.7.1). One laboratory under NHIC jurisdiction had hundreds of referring Medicare providers in 2005, requesting over 2,000 assays for ovariancancer alone (the incidence in the Medicare population is circa 10,000). NHIC must view these referrals as showing a tenable standard of practice and not an individual provider or small group However, to NHIC s knowledge there has never been anational organization s guideline that sensitivity testing is required for chemotherapy decisions, and this LCD shall in NO WAY be construed as making any such suggestion."

http://www.weisenthal.org/medicare_lcd_final.pdf

Hey, I hurt my back. I rest for 1 week, do some light exercise, and recover a another week later.
OR
I go to a chiropractor and feel better in 14 days. Medicare covers chiropractic. So what?

There is NO proof that these very expensive assay tests are beneficial.

Who's this Michele H?

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Private Researchers Have Put Chemosensitivity Analysis To The Test!

posted by Gregory D. Pawelski on 25 July 2007 at 10:57 pm

For over ten years, GOG, CCG, SWOG, ECOG, NSABP, and CALGB have never accepted the challenge to compare their results with Ex-Vivo Chemosensitivity Analysis. More important, the concept of testing a test needs to be in the context of other tests like ER/PR, CT or PET scans.

PET scans were not approved because they saved lives in a controlled clinical trial that compared the outcome of patients who received care with or without the benefit of a PET scan. They were approved because their performance characteristics (sensitivity/specificity) are reporducible, favorable and provide useful information to treating physicians.

Chemosensitivity analyses have performance characteristics that are reproducible, favorable and provide useful information to treating physicians. What's more, the information is the result of a clinical trial in which NSCLC patients underwent an assay as part of a Phase II assay-directed trial (IRB-approved). It so happens that these patients were found more sensitive to Tarceva than to other forms of chemotherapy, all of which were tested for the same $3,500 price.

If costs well in excess of $1,000 to do EGFR mutation and FISH for amplification. All of which tells you whether or not to give Tarceva (one drug). Chemosensitivity analyses more often find MSCLC patients sensitive to other compounds and combinations and can recommend these all from one assay. It costs a lot more to give a single cycle of chemotherapy than it does to test all of the possible options.

The evidence supporting a doctor's use of therapy may be far less solid than the evidence supporting chemosensitivity analysis. If a physician uses chemotherapy for NSCLC, does he/she give second-line chemotherapy to patients with good performance status who fail first-line therapy? If so, there is only one study to support it, Docetaxel. There is also one non-inferiority trial for Alimta. If the physician does anything other, he/she is not adhering to the evidence. I'm sure there are dozens of practices that fail to meet these lofty evidence standards.

Michelle H. (hchcec), you haven't the foggiest idea! It is entirely inappropriate to regard the randomized clinical trial as being the "gold standard" for judging whether a treatment does more good than harm. After thirty-six years of holding back the "war on cancer," it is time to move on to a better, more efficient paradigms of cancer treatment.

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Re Pawelski

posted by hchcec on 26 July 2007 at 3:12 pm

No studies were identified that provided direct evidence comparing outcomes for patients treated either by assay-guided therapy or contemporaneous empiric therapy in the previous post.

Why?

There are none. (This is why national Medicare policy and all major health ins. cos do not cover this experimental, unproven test and have not for many, many years. This is becoming quite troubling as the assay salesmen are forced to blame the insurers.)

Let's see the evidence. Instead of attacking oncologists and researchers. Let's see the evidence from the assay salesmen. If they want the taxpayer to pay $3500 for the test, should we see some, any, evidence of benefit?

Science cares not about anecdotes from web sites and assay bloggers. it's scientifically meaningless.

Where's the data?

Where?

( BTW, that name thing? it's getting a little disturbing...)

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Michelle H. (hchcec)

posted by Gregory D. Pawelski on 26 July 2007 at 11:13 pm

Michelle H. (hchcec) is condemning "personalized" cancer medicine. Wonder what Andrew C. von Eschenbach thinks about that? He has made it his career ambition to bring "personalized" cancer medicine to the forefront.

At the FDA, he is presiding over a transformation in medicine as scientists come to understand diseases in a more detailed way that could improve doctors' ability to treat patients. Much of what has been done previously has been based on the antiquated model of empiricism (the so-called evidence-based medicine).

He wants to see that doctors will be able to intervene with medical treatments more effectively to a specific patient's illness. Doctors treated illnesses based on how well "average" people have responded to a given treatment. Now they can develop a tailored (personalized) response built around understandings of the patient, the treatment and the disease.

I am enamoured by his belief that much of what has been done has been based on a model of empiricism, but now, doctors should be able to intervene with medical treatments more effectively matched to a specific patient's illness (individualized treatment). The era of empiric treatment should come to an end. We should put much more emphasis on matching the treatment to patient, through the use individualized testing.

Medicare coverage is available for Chemosensitivity (Resistance) Testing for a tumor specimen from a Medicare patient obtained anywhere within the United States, but submitted for testing by one of the approved laboratories located within California. Medicare bills for this testing are billed through NHIC because the test is conducted by one of the approved laboratories in California.

The same tortured syntax was evident when Michelle H. (hchcec) stopped using the name Michelle and started using hchcec on the same repeated blogs sometime in the fall of last year (like a blog groupie). Everybody caught on. Perhaps she should take the paper bag off her head and let everybody else on this blog know who she is, instead of hiding behind a symbol. Condemning the messenger instead of having any rational thought on the message does drift too far from reality.

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Re Pawelski

posted by hchcec on 27 July 2007 at 5:12 pm

In fact, I do not condemn the science. I do condemn the internet blogger who pushes unproven therapies.

I do not condemn (never have) individualized testing that shows benefit , e.g. Oncotype Dx. What MUST be condemned is these chemotherapy assay bloggers who take advantage of the vulnerable, who tell them their oncologist is living in the past, who claim they care nothing about anything except $$, and who keep therapies off the market so money is kept in their pockets.

Ridiculous, unsubstantiated, fear mongering of the worst kind.

The non-scientist assay blogger wants cancer patients to spend $3500, often travel to CA, and hope a test can help them when there's not one study (and you'll notice Pawelski presents none - never has) to show any benefit whatsoever. But, perhaps the assay bloggers pocket the cash and hope they are of help. Are they? No one knows. Why? They despise the scientific method. Why? Because, so far, those studies have not shown any benefit. Therefore, just attack the scientific method. Very convenient. Oh, yes. And put a few anecdotal stories on your web site to entice. No research. Just anecdotes.

Sort of like those Mexican clinics who offer "hope."

(Why haven't I ever given my real name? Truthfully, I do all the time, but not in response to Mr. Pawelski. An internet search will find thousands upon thousands of entries by this individual on cancer support sites, telling patients that they, in his words, may end up "in a mortuary" earlier than need be if chemotherapy assay testing is not performed. This has been going on for years. Finally, last year, his claims had to be answered. But, it had to be done anonymously (with good data, of course) as I found the sheer volume of posts disturbing.

Chemotherapy assay testing holds promise, but is unproven. The are not covered by Medicare nationally (one small local area does) and NO major health insurance co. covers the test.

Isn't it time to chill out?

"Although the concept behind CSRAs (chemotherapy sensitivity and resistance assay is compelling, unfortunately, there does not appear to be a single assay that is ready for routine use in a clinical setting. This is likely due to problems in the technical success and yield of the assays, the lack of adequate prospective evaluation of CSRAs in clinical trials, and the tendency of CSRAs to "recommend" treatments that would have been given based on the results of research published from clinical trials.

Decisions about which chemotherapy regimen you receive should be based on discussions with your oncologist about how the results of clinical trials pertain to your situation. At this time, CSRAs should not be used to select the choice of chemotherapy. Because the concept of customizing chemotherapy is important, participation in research studies that evaluate the accuracy of laboratory testing of tumor specimens to predict chemotherapy response is encouraged."

http://www.plwc.org/portal/site/PLWC/menuitem.169f5d85214941ccfd748f68ee37a01d/?vgnextoid=8ef241eca8daa010VgnVCM100000ed730ad1RCRD

(Mr. Pawelski will now attack ASCO in his next post, but not his own lack of data.)

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Michelle H. (hchcec)

posted by Gregory D. Pawelski on 27 July 2007 at 11:12 pm

Contrary to Michelle H. (hchcec) and her perverse idioms and phrases, drug sensitivity assays measuring "cell death" of three dimensional microclusters of live "fresh" tumor cells have been found to offer clinical utility.

Even though Medicare had been reimbursing for cell culture drug "resistance" tests since 2000, it wasn't until Medicare contractor National Heritage Insurance Company (NHIC) spent a year reviewing everything about the technology, did they abandon the artificial distinction between "resistance" testing and "sensitivity" testing and are providing coverage for the whole FDA-approved kit. Their decision had been made that the assay is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis.

And contrary to Michelle's lack of understanding, Medicare coverage is available for this test from a Medicare patient anywhere within the United States, when their tumor specimen is submitted for testing by one of the approved laboratories located within California. Medicare bills for this testing are billed through NHIC because the test is conducted by one of the approved laboratories in California, just like the Oncotype DX test is reimbursed.

Good peer-reviewed papers exist on cell culture assays but the literature on them have not been understood by many NCI investigators and by NCI-funded university investigators (which maybe is why Michelle doesn't understand it herself), because their knowledge has been based largely on a failed assay technique that was hasn't been used in most private labs in over fifteen years (the old clonogenic assay that Von Hoff tried to sell, not as a clinical trial, but as a service to patients).

Many of the comments posted by Michelle have used the fine art of selective quotation to make me appear to hold positions which I do not hold. I suggest readers who may be unnecessarily alarmed by her quotations to read my information in its entirety. A scientific communication should be judged on the quality of its content, not by alarmist Quakewatch attitudes.

Educating those who have the ears to listen is not always an easy task. Medicine is often so slow to change, it ends up taking creative and independent individuals to start the real changes. One needs to start somewhere, helping patients conceptualize cancer more accurately, so they could better understand the way to approach their choice of treatment regime. I have to range the web to combat misinformation about cell culture assay tests by charlatans like Michelle H. (hchcec).

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Re Pawelski

posted by hchcec on 28 July 2007 at 10:50 am

The Medicare decision is local. I've said this many, many times. No national org. approves of these totally unproven tests. Pawelski's declarations cannot change the facts:

One laboratory under NHIC jurisdiction had hundreds of referring Medicare providers in 2005, requesting over 2,000 assays for ovariancancer alone (the incidence in the Medicare population is circa 10,000). NHIC must view these referrals as showing a tenable standard of practice and not an individual provider or small group However, to NHIC s knowledge there has NEVER been a national organization's guideline that sensitivity testing is required for chemotherapy decisions, and this LCD shall in NO WAY be construed as making any such suggestion."
-------------------------------------------------------------Medicare statement

The internet blogger Pawelski sees conspiracies everywhere: in me, in Medicare, in Blue Cross, in Aetna, in researchers, in your onclogist.

He sees enemies everywhere. I think there's treatment of that.

Pawelski:

"greed and certitude in the power of the dollar have once again clouded judgement. Not everyone is willing to sell his principles so cheaply. The persons making these decisions are not friends of cell culture assays, but they are smart and cynical enough to accept baksheesh from the very persons whose technology they are bent upon discrediting. It's DEATH BY CLINICAL TRIAL.."

These tests are not approved by ANY NATIONAL organization They are expensive, and 10 years later...they remain unproven.

To say anything else would be intellectually dishonest.

(I'm beginning to wonder if the these assay companies pay internet bloggers to do their work for them. Research: NO. lobbying: YES!

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Re Pawel

posted by hchcec on 29 July 2007 at 7:05 am

PAWELSKI:

"Drug sensitivity assays do not harm patients in any way except in terms of COST. [Is he saying it harms them in terms of cost. The answer is yes. Who pockets that money?] Every cancer patient SHOULD have his/her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data. Research and application of drug sensitivity assays are being encouraged by growing patient demands, scientific advances and medical ethics. Drug sensitivity tests are not a luxury but an ABSOLUTE NECESSITY, and a powerful strategy that CANNOT be overlooked. Having some foreknowledge of a given agent's expected result before its administration would benefit the individual patient."

http://www.emaxhealth.com/forums/showthread.php?p=9610

Pawelski is wrong. Endlessly blogging this does not make it so. In response to the blogger Pawelski (who has never worked in the field of cancer research, is not an M.D., has never advised patients directly, yet does so only over the internet where he has gone unchallenged-until now) comes this:

"Review of the literature does not identify ANY CSRAs for which the evidence base is sufficient to support use in oncology practice.

RECOMMENDATIONS: The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is NOT recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.

http://jco.ascopubs.org/cgi/content/full/22/17/3631?ijkey=b2282e1731e2632d973974656c6ac9fd7392f4d3

And, this devastating statement from an assay researcher:

"We await the results of this and other "assay directed" trials with the hope that the time for successful tailored therapeutics has finally come."

http://jco.ascopubs.org/cgi/content/full/23/15/3641

For internet blogger Pawelski, the time is NOW for you to pay $3500 and fly to California. For the ACTUAL RESEARCHER, studies have to be completed FIRST to prove any effectiveness.

Pawelski creates fear in the cancer patient that chemosensitivity assays are a necessity for cure.

For the researchers ACTUALLY IN THE FIELD, who don't spend hours upon hours searching for cancer support sites to hawk their unproven wares, proof awaits.

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Strong Evidence From Clinical Trials?

posted by Gregory D. Pawelski on 29 July 2007 at 8:50 am

Interesting that Michelle H. (hchcec), so wedded to the flat earth concept, brings up insurance outside of Medicare. The payment provided by Medicare will be sufficiently realistic that all Medicare patients for whom this testing is indicated will be able to get it with only the routine 20% co-payment, as Medi-gap insurance secondaries are mandated to provide payment for co-pays for Medicare-approved services. The tests average in the $2,000 range.

The Blue Shield of California Medical Policy Committee on Quality and Technology, in a meeting on March 2, 1994, unanimously accepted the validity of cell culture drug resistance testing. As Medicare contractor National Heritage Insurance Company (NHIC) found out, cell culture drug sensitivity testing is merely a point a little farther along on the very same continuum upon which resistance testing resides.

The official Blue Shield of California conclusion was drug resistance testing in oncology was accurate and reliable. The information can affect clinical decision making and can lead to the avoidance of ineffective and potentially harmful chemotherapeutic agents. There was sufficient published data to determine their safety, clinical utility, and impact on clinical decision making.

The only tech reviews of cell culture assay tests that were negative were the "closed" reviews (e.g. BC/BS and ASCO). But the two "open" reviews by NHIC Medicare and California Blue Shield were both quite positive. NHIC decided to have their own open review where everyone would have the chance to present their data and make their case, pro and con.

In 1994, Blue Cross of California supported tumor cell drug resistance testing. It can improve results when the tests are used. California Blue Cross used to cover it when California Blue Cross was non-profit. Then they were taken over by Wellpoint, turned into a "for-profit" and abruptly without explanation stopped paying for it. I guess they had to show some kind of profit for their shareholders by denying some coverages. However, numerous people have appealed their cases in small claims court and won (even one in superior court).

I made a lot of money investing in U.S. Health Care, Inc. in the 90's. When I found out how HMO's were notorious for "denial of coverage" to make profits for the corporate executives and shareholders on the backs of injuried and diseased human beings, I liquidated my earnings and donated the proceeds, to justify to myself the wrongs of supporting such an organization.

A number of cell culture assay labs across the country have the Rosetta Stone database from tens of thousands of "fresh" human tumor specimens, representing virtually all types of human solid and hematologic neoplasms, in which were tested a median of 17 drugs and/or drug combinations. If there is ever a time when testing should be done, the current clinical applications of in vitro chemosensitivity testing is ever more important with the influx of new targeted therapies.

According to the FDA, the response rate of patients that follow empirically-based drug regimen guidelines is approximately 20-30%. And according to the NCI, the response rate of the new "targeted" drugs is approximately 10-20%. There is also an inherent conflict of interest when organizations that provide guidelines for treating a disease also receive funding from corporations that benefit financially from the recommended treatment.

Clinical Trials: Are Drugmaker's Studies Biased?

http://www.medicalprogresstoday.com/enewsletters/mpt_ind.php?pid=1595&nid=122

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The Problem With Michelle H. (hchcec)

posted by Gregory D. Pawelski on 29 July 2007 at 9:47 pm

I must be doing something very right. I've gotten the resident quacker-watcher in chief all bent out of shape by her diatribe of conspiracy theories and innuendos. It is a common tactic for Quackwatch people to unload a deluge of meaningless references when they cannot cobble together a cohesive and persuasive original argument based upon logic and the issues at hand. This is indeed fundamentalism with the guiding principle being NCCN, ASCO and JCO.

The reason why the "powers that be" behind the cancer medicine establishment say things like "not ready for prime time" yet and "unreliable" is because both Cell Function Analysis (cell culture assay testing) and Genomic Analysis (micro-array analysis) have not been shown to improve patient treatment outcomes "in prospective, randomized clinical trials" (the 'efficacy' standard).

However, none of the available laboratory tests used in the selection of treatments for cancer patients have EVER been tested for "efficacy." This includes estrogen receptor, progesterone receptor, Her2/neu, immunohistochemical staining for tumor classification, bacterial culture and sensitivity testing, CT, MRI and FDG Pet Scans to measure tumor response to treatment.

There is no literature establishing clinical "efficacy" of these laboratory tests. The only data supporting any of them relate to test "accuracy," and there is total lack of information regarding test "efficacy" (randomized trials with outcome measurements for diagnostic tests).

Accuracy means having no errors, correct, exact, precise, or true. Efficacy means producing a desired effect, like tumor shrinkage. Clinical trials test the "efficacy" and not the "accuracy" of a drug. Cell Function Analysis and Genomic Analysis have been proven to be "accurate," but haven't been proven to be "efficacious." But they have been proven "accurate" by the FDA standard for approval.

There are obviously lots of situations where a rational oncologist and patient would conclude that the evidence from an "accurate" test would be of help to guide treatment. No lab in history has had anything other than evidence of "accuracy" to either commend it or condemn it.

The traditional and only criteria on which any laboratory, clinical and radiographic tests have been judged are the performance characteristics (predictive accuracy, sensitivity and specificity) and perceived utility in the judgment of the clinican who orders the tests.

The "powers that be" in cancer medicine are trying to raise the bar of acceptance for laboratory tests to unprecedented levels, by erecting a barrier to protect the paradigm of the best "empiric" treatment for the average patient, as seen in so many non-productive clinical trials. This barrier also discourages discovery of new, effective drug regimens through the use of these assays to guide drug selection. With a greater use of these assays in oncology and the ever increasing list of FDA-approved drugs, it is very likely that the activity of new drugs and new regimens would be identified at a much earlier time than with the current system relying on "empiric" evidence of Phase II trials.

If assay hasn't been proven to be "efficacious" in randomized trials, and an oncologist doesn't want to use the test, that's their privilege, although the patient should certainly have a say in the final decision. Personally, I'd rather have a test done because of its "accuracy" not because of its "efficacy." But, because trials may have never been done should not be the reason for an oncologist to refuse to have the tests performed.

But the only information about cell function analysis that Michelle H. (hchcec) has to go on is her old friends at ASCO who did a closed technology assessment in 2004, judging the "old" clonogenic assays, her friend's pet technology that was discredited long ago. If the so-called respectible Journals (the ones that fail to adhere to guidelines on conflict of interest) won't publish articles because they have a lock-up on information, don't lay blame on me.

The format of point by point rebuttal of every single sentence, line by line is rather boring. It doesn't flow. Although I do read long posts when they are written as thoughtful essays. They maybe long, but very readable. Trying to read someone slicing and dicing and dissecting every sentence I write, is trivial. The point by point, line by line, tit for tat rebuttal style is indeed fundamentalism, with the guiding principle of Quackwatch people.

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Re Pawelski

posted by hchcec on 30 July 2007 at 8:35 am

I already answered the accuracy/efficacy "inaccuracy" from Pawelski. He keeps repeating the mantra that accuracy is all that is necessary for test approval. Scientists and researchers know this is not the case and THAT is one reason why the tests he lobbys for are not approved by any National organization.

See link for my response to his repeated claim:
http://www.medicalnewstoday.com/youropinions.php?opinionid=17011

"The diagnosis and management of infectious diseases rely on the availability of microbiology devices as well as their accuracy and EFFICACY. An inaccurate device that is rushed through the approval process may potentially cause additional harm to a patient suffering from an infectious disease. Marketed devices must provide reliable information. The user of the device must be able to understand the strengths and limitations of a particular device or pharmaceutical as it applies to a particular patient population. Accuracy, efficacy and timeliness are three goals that must be achieved as FDA reform is considered. One should NOT be compromised for the other.

http://www.asm.org/Policy/index.asp?bid=2964

For internet blogger/lobbyist Pawelski, accuracy of his expensive test is ALL that is necessary.

For the scientist, that would be a disaster and would open up a huge can of worms.

Point by point rebuttal requires logic. So does science. Otherwise homeopaths , faith healers, herbalists (chemotherapy assay marketers?) would be licensed to treat cancer.

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Michelle H. (hchcec)

posted by Gregory D. Pawelski on 31 July 2007 at 12:13 pm

The NCI applied cell-death endpoint technology to "cell lines" and concluded that these assays don't work, rather than more appropriately concluding that passaged "cell lines" don't work. The purpose of NCI studies never was to determine if "fresh" tumor assays worked. All of the considerable literature which supports the use of cell culture assays in patient management has been based on true "fresh" tumor (non-passaged) cell assays.

The NCI used "cell lines" because the major expertise of the investigators who carried out the study was in the creation of lung cancer "cell lines," and they wanted to see if they could perform assays on these "cell lines" to use in patient therapy.

All of the work in the past 15 years in the cell culture field has been carried out largely on three dimensional clusters of cells. Work is done exclusively with three dimensional, floating, tumor spheroids. When you test the cells as three-dimensional spheroids, they are many-fold resistant in vitro, just as they are in vivo (multicellular resistance).

The fact that the NCI studies in SCLC were more positive than those in NSCLC may well be related to the fact that SCLC cells do not grow as monolayers (monolayer cell cultures were used in the NCI studies) but instead grow as floating, three-dimensional spheroids (as is tested in modern, cell culture assay labs).

There are absolutely no findings or conclusions in NCI's NSCLC study which are in any way germane to the vast contemporary literature which strongly supports the clinical use of cell culture assays with cell-death endpoints. Yet, within the academic community, you hear nothing but vaguely-described methods, misleading analysis, and misleading presentation of the data. But that is the "gold standard" of Michelle H. (hchcec).

The standard always applied previously to support the use of all medical tests was the acceptable accuracy of the test and clinical utility in the judgement of the physician ordering the test, supported by clinical logic and common sense. This was also the standard applied by the FDA in its consideration of a kit for cell culture testing.

ASCO's position since 1999 was one of being agnostic about the use of cell culture assays, but appointed a panel to study them. However, in the meantime, they wanted to make certain that they still get paid if they choose to use drugs which performed poorly in the assays. Thus, when the so-called panel came upon their decision, they said that although cell culture assays show promise, they should not be used outside the confines of a clinical trial, thus protecting their income, again.

I don't know where Michelle H. (hchcec) is coming from making totally uniformed statements about cell culture assays? If she were honest (and not hypocritical), she would conclude that neither the ER nor Her2/neu tests are "ready for prime time." What studies were made making comparisons of the treatment outcomes of groups of patients managed with the benefit of the information provided by these two tests compared to the treatment outcomes of patients managed without benefit of the information provided by these two tests? None!

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Selling Cancer Chemotherapy With Concessions Creates Conflicts Of Interest For Oncologists

posted by Gregory D. Pawelski on 01 Aug 2007 at 11:19 pm

More data is emerging showing that there is a continuing problem with the Chemotherapy Concession in America. A system which rewards medical oncologists for being pharmacists. The kaisernetwork.org's Daily Health Policy Report lists two recent New York Times articles that indicate this is precisely how chemotherapy drugs are being selected in the real world of cancer medicine.

Federal laws bar drug companies from paying doctors to prescribe medicines that are given in pill form and purchased by patients from pharmacies. But companies can rebate part of the price that doctors pay for drugs which they dispense in their offices as part of treatment. Doctors receive the rebates after they buy the drugs from the companies. But they also receive reimbursement from Medicare or private insurers for the drugs, often at a markup over the doctors' purchase price.

http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=45527

And another New York Times article about cancer drug reps spelling out to cancer docs the way to profit from their wares, a Dr. Robert Geller, an oncologist who worked in private practice from 1996 to 2005 before leaving to join a biotechnology company, said that cancer doctors knew the profits they could make and in some cases would change treatment regimens or offer unnecessary care to make extra money. "It's clear that physicians stopped making decisions based on what made scientific or clinical sense in lieu of what made better business sense, " he said.

The revelation in the article is about pharmaceutical companies calculating to the penny the profits that doctors could make from their drugs and that sales reps from those companies shared those profit estimates with doctors and their staffs. This information comes from industry documents that have become public in a federal civil lawsuit against the drug makers. These documents show that representatives for the companies actually brought spreadsheets to oncologists' offices to show doctors how much they could make.

http://www.nytimes.com/2007/06/12/business/12cancerside.html?ex=1186200000&en=69a4206ea4760a4f&ei=5070

Absent the use of cell culture assay tests to characterize drug resistance and sensitivity of individual tumors, clinical oncologists have the freedom to choose the drug(s) which are most profitable to the oncologist. However, selling cancer chemotherapy with concessions creates conflicts of interest for those oncologists. Medical oncologists should be taken out of the retail pharmacy business and let them be doctors again.

http://www.healthyskepticism.org/news/2007/Jun.php

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