Dr. Cheson , ASCO, and
Panel on DRAs
What about Testimonials?
Evaluating Nagourney's Claims
and Potential Biases |
Reply from the
The importance of identifying drug
resistance | CMS Panel Report |
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.
The importance of identifying drug
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
The practice of CDRA is not standard for several reasons:
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.
Assays on single
agents do not inform about how drugs may work together
synergistically in the body.
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
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
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
"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. ... "
CMS Panel: Strength of Evidence Presented
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." 
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
"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
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) 
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
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 
What about the testimonials from individual
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
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
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. 
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.
on review of the CMS transcripts , 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.
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  CMS
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.' 
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
Survival signals within the tumour
microenvironment suppress drug-induced apoptosis: lessons learned
from B lymphomas. Endocr Relat Cancer. 1999 Mar;6(1):21-3.
- How do the assays account for combined effects of different drugs in the body - the dosing of the agents, and the
interactions between metabolites of the parent drugs?
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
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.
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
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. 
=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.
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.
(We believe that Oncotech provides this test.)
Summary of CMS Proceedings:
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
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
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.
Topic Search - PubMed
Treatment Group Refutes ASCO's Stance
Chemotherapy Resistance Testing - jco.org
References and Resources:
Cell Culture Drug Resistance Testing (CCDRT),
by Larry M. Weisenthal, MD, PhD - virtualtrials.com
Pretesting Tumors - Long derided, test-tube screening for cancer-drug sensitivity slowly gains acceptance -
Principles of Chemotherapy - Ray Page, DO, PhD -
Medical coverage of Human Tumor Assay Systems - CMS
VOL1 | CMS
VOL2 | Summary
1999 Medicare/Medicaid transcripts
Patients' Perspectives on: Cell Culture Drug Resistance Assays -
Ex-Vivo Apoptotic (EVA) Laboratory Assay Wallace
I. Sampson, M.D., F.A.C.P - qwatch
IMPATH Drug Resistance Assay (DRA) - Impath
Oncotech - Extreme Drug Resistance (EDR) assays - oncotech.com