CAM & Life Style > Drug Resistance Assays? (Nagourney) 

Examining the Claims

Background  | Dr. Cheson , ASCO, and CMS Panel on DRAs 
What about Testimonials?
Evaluating Nagourney's Claims and Potential Biases | Reply from the Sponsor 
The importance of identifying drug resistance | CMS Panel Report | Related Articles

A cell drug resistance assay (CDRA) is a lab test performed on a biopsy specimen containing living cancer cells.  It's used to determine the sensitivity or resistance of the malignant cells to individual chemotherapy agents. 

Depending on how well the tumor cells respond to each chemotherapy agent, they are rated as sensitive, resistant or intermediate. The concept here is that you are better off using a chemotherapy drug that your tumor reacts to strongly than one your tumor resists.  Also see The importance of identifying drug resistance

The assay is used for suggesting unusual combinations of chemotherapy, which may not be among those commonly used for a particular cancer based on empirical evidence obtained in clinical trials. 

We are concerned that using CDRA may be especially inappropriate for previously untreated lymphomas because most subtypes of the disease are typically sensitive to all chemotherapy agents.

The practice of CDRA is not standard for several reasons:

1. Tumor cells taken from the body and put in a petri dish are profoundly changed and behave differently than cells in the body.  Therefore assays testing the sensitivity of tumor cells to a single agents may not accurately predict the sensitivity to the agent or it's metabolites in the body.

2. Assays on single agents do not inform about how drugs may work together synergistically in the body. 

3. There are no prospective clinical trials demonstrating the clinical utility of these tests, and 
   weaknesses in the existing evidence cited by experts, with the exception of DiSC assay for CLL.  

Experts have cited many problems with the studies done to validate the clinical utility of the tests:

Dr. Bruce Cheson on CSRAs for Lymphomas:

BETTY: CSRA stands for a procedure where various drugs are – first, done in a special laboratory, they examine the tumor, and then a selection of drugs are then analyzed to see which drugs would work best with that tumor. Have you mentioned CSRA? And what do you think about it?

DR. CHESON: The fact that I didn’t mention it tells you what I think about it. There really are no studies which demonstrate that this is really effective in any cancer and particularly in lymphoma. 

Part of the problem is we rarely treat lymphomas with single drugs.  And therefore these sorts of assays, these chemosensitivity assays, aren’t very good at predicting response to combinations. 

And in fact, they’re not really good at predicting response to anything. They’re better at predicting resistance than they are response. 

The other problem is the testing that they do – once you take a tumor out of someone and you put it in a laboratory situation, it’s no longer the same tumor that it was in the patient. 

So there really are no studies in lymphoma that show the results of doing chemosensitivity assays accurately predict outcome and more successfully direct therapy, so that patients will do better. And we don’t do it and in fact I strongly recommend against doing it. It’s fairly useless information. 

Source: LOOKING AHEAD: Novel Therapies in Non-Hodgkin Lymphoma Dr. Bruce Cheson,
December 13, 2005 5:00 PM

Transcript: http://www.leukemia-lymphoma.org/graphics/National/Dec13NHLFormattedTrans.pdf  

Reply by ASCO Assessment Working Group

Treatment Group Refutes ASCO's Stance on Chemotherapy Resistance Testing 

IN REPLY:  Dr Nagourney strenuously objects that the American Society of Clinical Oncology’s (ASCO’s) Technology Assessment Working Group did not adequately distinguish between assays measuring tumor growth inhibition versus cell death.  - jco.org | jco.org PDF
 
"Dr Nagourney is simply mistaken in suggesting that diagnostic accuracy indices (sensitivity, specificity, and positive and negative predictive values) are sufficient for establishing a test’s utility.  
 
As outlined by the Institute of Medicine,1 tests are clinically 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.  

Clinical utility can be determined by mapping a causal chain from diagnostic accuracy through changes in management to impact on outcomes.2  
 
There is a lack of clarity about how CSRA results influence management decisions and there is insufficient evidence documenting their effect on patient outcomes.3  ... 
 
... It is certainly each practitioner’s prerogative to order CSRAs or any other medical test. 
 
However, it is important to specify to the patient what the treatment would be in the absence of the assay and to be clear about if and how the information will be used to inform treatment decision making. The alternative is to risk our credibility with our patients and the public whose trust is critical to our mission. ... "  

jco.org (full text)

CMS Panel: Strength of Evidence Presented

DiSC assay for CLL "We found 22 of 119 patients had extreme drug resistance in vitro, and none of these patients responded. So here is one of the things that we would speak to, which was independent validation in a completely different set of circumstances in a different laboratory, and we find exactly the same thing, extreme drug resistance, no response." [4]

Patient selection bias - If you select patients with a disease type and stage that is unlikely to respond to treatment, and use these patients as validation of a test to predict failure of chemo agents, the study results become questionable.  This was cited as one type of weakness in the supporting studies, and why the studies could not be considered "science." 

"The composition of the study, the study population, makes a difference in the observed accuracy. A sample with only extreme cases, i.e., the predictors are extreme values of their range, will be easier to predict than a sample with many intermediate cases, the predictions are mostly in the middle of their range. 

For example, for women with breast cancer who have many positive lymph nodes, their outcomes are fairly easy to predict. Women with metastatic disease, their outcomes are pretty easy to predict. It isn't a hard task to do. 

What is hard to do is to predict the women with small tumors and with no lymph node involvement or metastatic involvement, that's really tough to do. 

So, if you just pick an extreme population, it turns out those are pretty easy predictions to make, but it turns out that most patients aren't in the extreme, so it's relatively un-useful. Okay? Thus, the sample must be representative of the real world in which the test is to be used. ~ Dr. Burke (CMS transcripts) [4]

Translation: The significance of the data depends on the study population. You can easily set up a study to predict an outcome when the outcome (resistance to treatment) is very predictable.

Validation by different labs  If you have the same tests done in different labs do you get the same results? We did not see evidence that this kind of corroboration was done to establish the credibility of the test to replicate findings.   

Studies were not disease- and treatment-specific: "You have to talk a specific disease, a specific treatment, how does the test do?  Not a conglomeration of diseases and treatments together." ~ Dr. Burke [4]

 

What about the testimonials from individual patients?

We note that Dr. Nagourney provides patient testimonials on his website promotion of DRAs. 

For the undecided reader: Is smoking proven safe when a life-long smoker never get a cancer?  Would it be accurate and ethical for a tobacco company to provide accounts like this as evidence of tobacco safety?

The evidence that smoking increases our risk of developing a cancer comes from comparing the incidence rates of cancers among those who smoke and those who do not - a controlled study on a very large population. Note: this evidence did not come from the sponsors of tobacco products.

Credible scientists, regulators, and most physicians know that it's not possible to prove causality, utility, or risk from case reports. There are many additional problems with testimonials that we list here.  

Are weakly substantiated clues better than no clues? 

Having a biopsy is not without risks.  But even when a patient is having a biopsy for other reasons, making clinical decisions based on the results of a drug resistance assay can be potentially helpful or harmful; and at this time we don't have information from controlled clinical trials to tell us which. 
 
Since most lymphoma are initially sensitive to almost all chemotherapy drugs, it's difficult to see even a rationale for the use of drug resistance assays prior to first line treatment. 

For patients with chemo-refractory disease the concern is that the assay will merely distract patients from looking at investigational or approved targeted therapies, such as monoclonal antibodies, and radioimmunotherapy - which are proven effective alternatives to chemotherapy for lymphomas. 

Despite the answers provide by the sponsor to our questions, we remain concerned about the use of drug resistance assays (DRAs) to guide treatment selection for lymphomas; and question the ethics of promoting DRAs  prior to demonstrating the clinical utility of these tests. The sponsors should first do the controlled prospective studies.

More Detail: CMS Hearings on CDRA

Comments on the CMS Hearings:

It was challenging to identify the key facts in the transcript of the CMS advisory meeting on Human Tumor Assay Systems (HTAS), primarily because the testimonies included data and presentations for different kinds of tests.  [4]  

We were struck by the opinion of Dr. Burke, a respected expert in the field of study methodology,  who stated that the evidence -  with the possible exception of DiSC for CLL - could not be called science because of the potential for selection bias and the failure to provide disease- and treatment-specific data. 

Based on review of the CMS transcripts  [4], the claims of benefit for the assays are based on insufficient evidence in poorly controlled studies that have not been validated (with the possible exception of DiSC assay for CLL). 

These studies are particularly important to validate, in our view, because of the differences between in vivo (test tube) and in-vitro (body) drug/tumor interactions, and the importance of treatment selection on outcomes.

The importance of identifying drug resistance:

"Dr. Alberts spoke this morning about a clinical situation where he would be referred a  patient from another hospital, and that patient may not, may be unaffected by the primary care, he has relapsed, the tumor is growing, and they send him, they send the patient to him. Doctor, what can you do to help me? In that situation, there may be three or four or five different drugs, single agents, none of which have been determined to have a significant clinical benefit over the other drug in that situation. 

If I am a  patient and if any physician can tell me of the five drugs, Frank, two of those drugs you're resistant to, what has he told me? He's said, I'm not going to use those two drugs, I've saved you from the possibility that you're going to get those two drugs and not benefit from it. It's very, very well documented that these tests are able to identify resistance, and if I'm a patient "  and if my physician in that setting can identify the resistance, I believe he has done me a real service."  ~ MR. KIESNER [4] CMS VOL2

 

CMS Panel: Limitations of Test Tube Analysis:

Dr. Stein:  'Things react differently in the human body than they do in the test tube,'" Stein recalls. Indeed, the tests do not mimic many aspects of human biology-- drug delivery by the bloodstream, for example.' [2] 

TECHNICAL NOTE:  "The suppression of apoptosis is one mechanism by which tumours become drug resistant. Extracellular signals from the germinal centre (GC) of secondary lymphoid tissue can rescue B cells from physiological- and chemotherapy-induced apoptosis." PMID: 10732782

Survival signals within the tumour microenvironment suppress drug-induced apoptosis: lessons learned from B lymphomas. Endocr Relat Cancer. 1999 Mar;6(1):21-3. Review.  PMID: 10732782 

From CMS transcripts: "... But let me - as I recall reading these papers, that none of them [studies] actually routinely were testing two agents simultaneously on one. I mean, the majority of the papers that we read and that Dr. Burken presented single agents. Maybe serially they would test several agents, but not together in one Petri dish routinely. 

DR. FRUEHAUF: Yes. DR. HELZLSOUER: That's the same way, I interpreted them the same way, they were all single agent tests, and not combinations. 

DR. FERGUSON: Yeah. I mean, all the published stuff we saw was single agent.  

DR. HANDELSMAN: The bulk of it was, but not all of it. 

DR. FERGUSON: Okay. Yes?" 

Evaluating Nagourney's Claims and Potential Biases

Dr. Nagourney provides materials to patients. Legally. We note that one of the studies he cites (in a portion copied within) was published in 1933, and he leaves it to the patient to locate the specifics - tables and statistical information are not provided.   And we don't know, for example, what large "clinically correlated databases"  he is referring to, and what is it that the databases says.   

To have faith in the supporting studies they must be reviewed and validated by experts who do not have biases or financial conflict of interest. (See Evaluating Medical Claims and Data.)  

This does not mean that Dr. Nagourney, who sells his assays, is wrong about the value of the tests. It does mean, however, that we cannot rely on the information he provides as much as we would like to. 

Note: For the record, we would like Nagourney to be right - we need predictive tests that work - and we think the medical establishment would welcome the evidence too, but so far we cannot assume that he is right based on the testimony of experts that reviewed the data presented at the CMS advisory meetings. [4]

=Nagourney's Information Packet for Patients (excerpt)

"THESE TESTS DO NOT WORK BECAUSE THE HUMAN BODY IS NOT THE SAME AS A LABORATORY TEST TUBE."

While no laboratory test can duplicate the human body, the EVA® assay provides a crucial piece of the clinical response puzzle: namely, the inherent sensitivity or resistance of the cancer cells to drugs through a nonproliferative apoptic measurement.

"CANCER CELLS ARE BEING ARTIFICIALLY GROWN IN A LABORATORY AND WILL NOT BEHAVE IN THE SAME MANNER AS CELLS IN YOUR BODY. "

We do not grow cancer cells. We maintain their viability so that drug sensitivity and resistance can be determined.

"THE DOSAGES GIVEN TO A PATIENT ARE DIFFERENT THAN THOSE USED IN THE LABORATORY."

No laboratory test is a reproduction of the human body. The EVA® assay has been calibrated to reflect responses in patients based upon large, clinically correlated databases.

If you or your doctor have any additional questions or concerns, please feel free to contact Us so that we may respond.

References: 
1. Principles and Practice of Oncology Updates: Vol 7, No. 12, 1933. 
2. DeVita, Hellman, Rosenberg (eds.): Cancer Principles and Practice of Oncology, Fifth edition. Uppincott-Raven Publishers, 1997, Chapter 17, pp 345.

Finally, it's unclear from the CMS transcripts if the assay provided by Dr. Nagourney is the DiSC assay, which seems to have good data in support of it's use for CLL.[4]  (We believe that Oncotech provides this test.)

Summary of CMS Proceedings:

Summary
 
Dr. Mitchell Burken, from HCFA, summarized the presentations from the other presenters and found after his systematic review there is not strong medical evidence supporting the overall clinical utility of HTAS. He further noted that there was rare use of blinding, but there were a higher number of clinical correlations for DiSC and MTT formats and, as a result, HTAS may have a greater potential clinical utility for hematologic neoplasms.

Motions, Discussions and Recommendations

The Chairperson announced that the panel would allow discussion and public comment on each motion as it was offered.

On the first question, the panel voted unanimously in favor of the motion that the advisory committee recommend that the clinical response as well as survival rates be accepted as appropriate measures of clinical utility.

On the second question, the panel voted unanimously in favor of the motion that evidence was presented to this panel supporting these tests with combinations of drugs.

On the third question, the panel voted unanimously in favor of the motion that HTASs demonstrate a clinical utility for directing treatment of CLL, and promise for other solid and hematologic tumors. (Our note: If true, why is this not promoted, and covered by insurance?  Which HTAS test? What group offers the test?  )

On the fourth question, the panel voted unanimously in favor of the motion that if a human tumor assay test result indicates that a neoplasm is resistant to a particular drug, that that may not preclude the use of that drug during the course of that treatment for that neoplasm.

full text 

Further Reading:

References and Resources:

1. Cell Culture Drug Resistance Testing (CCDRT),  by Larry M. Weisenthal, MD, PhD  - virtualtrials.com

2. Pretesting Tumors - Long derided, test-tube screening for cancer-drug sensitivity slowly gains acceptance - sciam.com

3. Principles of Chemotherapy - Ray Page, DO, PhD - cancernetwork.com

4. Medical coverage of Human Tumor Assay Systems -  CMS VOL1 |  CMS VOL2 | Summary 
   1999 Medicare/Medicaid transcripts

5. Patients' Perspectives on: Cell Culture Drug Resistance Assays - yana.org

6. Ex-Vivo Apoptotic (EVA) Laboratory Assay Wallace I. Sampson, M.D., F.A.C.P - qwatch

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