Since most lymphoma are initially sensitive to almost all chemotherapy drugs, what is the rationale for using
drug resistance assays on previously untreated patients with lymphomas?
REPLY: Many tumors are initially sensitive to chemotherapy. Ovarian cancers have in
excess of an 80% response rate, even in the advanced stage, yet only 29% of
patients remain alive at 5 years( i.e. the other 71% relapse and succumb to
their illness).
Similarly, 70% or more of women with metastatic breast cancer respond to
chemotherapy yet few (<5%) are cured.
With regard to NHL, the CR rate is up to 90% yet only 50-70% of patients
remain in durable CR, depending upon prognostic categories.
If we use our experience in childhood ALL the point becomes clearer. In our
25 year follow up (15 years at time of initial report; Leukemia, 1995)
children with ALL found sensitive to chemotherapy had an 80% Event free
survival (EVS) as opposed to only a 20% EVS in the resistant group. This
despite virtually all of the children achieving a CR with initial therapy.
The principle being that by administering the most "active therapy" administered at the time of "first-line" therapy, the degree of
cytoreduction will be optimal.
COMMENT:
The ALL study (name and full text not provided) does not appear to
compare outcomes of the children based on selection of therapy
guided by the DRA, which, presumably, is the reason some patients ask for
this test.
Copying from the Physician information page of the sponsor's
website: After fifty years of experience with cytotoxic drugs, why is there no widely accepted laboratory method to select chemotherapy for individual patients?
From this text it appears that DRA is being offered as a way to
"rationally" select therapy agents, and not to predict
survival and chemo-sensitivity in general.
We'd all love to see reliable data (from controlled
prospective clinical trials)
proving the clinical utility of the
assays for patients with lymphoma - how it helps to improve outcomes
by informing selection or avoidance of treatment agents.
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.
Quoting from the CMS transcripts: 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
Since signals in the microenvironment of the tumor are known to contribute to resistance to cell death, how do the predictive assays account
for these factors in cells outside the body?
REPLY: The laboratory assays have been calibrated against clinical outcomes. They
are not designed to, nor do they, recreate the human body in a test tube.
They cannot take into account immune response, and certain PK/PD factors
that do contribute to response. This is one of the reasons why the assays
have performance characteristics in the range of 80-90% sensitivity and
specificity and not 100%. However, in over 1600 peer-reviewed published
clinical correlations, ASSAY SENSITIVE PATIENTS RESPONDED MORE OFTEN THAN
ASSAY-NEGATIVE PATIENTS (P <0.00000001)
COMMENT:
No specific
study is cited in the reply.
We
do not know what is meant by "calibrated against clinical
trials." , and assume that by "clinical correlations" the
provider means observed associations for a broad range of
cancers. As above, according to the testimony of Dr. Burk, you can easily set up a study
by patient selection to predict an
outcome when the outcome (resistance to treatment) is very
predictable. Randomized studies protect against this kind of
error.
What clinical data do you have - specific to my type of lymphoma - that the assay will predict resistance to specific chemotherapy
protocols
REPLY: There is a wealth and growing (see Ugurel, S Clin Canc Res. Sept 15th, 2006) body of evidence that supports the scientific basis of these assays. While we have accumulated excellent published prospective data in Lung, Ovarian, Breast, CLL and ALL (and now melanoma), not every disease at every stage of every subcategory has been prospectively studied.
COMMENT:
The provider does not cite a prospective controlled clinical trial, which,
again, is the foundation of evidence-based medicine. Referring to the "wealth and
growing body of evidence" reminds of the comments made by Dr. Burke's at
the CMS hearings:
"You have to talk a specific disease, a specific treatment, how does the test do? Not a conglomeration of diseases and treatments together."
How do the assays account for combined effects of different drugs in the body - the dosing of the agents, and the
[interactions of the] metabolites of the parent drugs?
REPLY: Formal synergy analyses in thousands of patients
account very well for drug
interactions.
COMMENT:
The provider has not provided a reference for the "Formal
synergy analysis."; and the reply is not specific to lymphoma
or consistent with the testimony of experts at the CMS hearing:
"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?"
Unfortunately, individual cases (testimonials) cannot be
considered evidence. If so, the development of drugs and tests would be very
easy indeed
REPLY:
It may be useful to examine what the actual dictates of evidence based
medicine are.
"Evidence based medicine is not restricted to randomized clinical trials and
meta-analyses. It involves tracking down the best external evidence with
which to answer our clinical questions" ."some questions about therapy do
not require randomized trials (successful interventions for otherwise fatal
conditions)."
Sackett DJ (Professor NHS Research and Development Centre for Evidence Based
Medicine, Oxford, UK) et al BMJ, 1996
In conclusion: The evidence supporting the use of cell death assay is compelling and
growing. Individuals must determine the threshold that satisfies their
evidence standards.
COMMENT: Regarding the profound limitations of observed
associations, we cite the comments of Dr. Steven Bratman, a
nationally regarded expert in the field of alternative medicine:
"We now know that a host of "confounding factors"
can easily create a kind of optical illusion, causing the appearance
of efficacy where none in fact exists. The double-blind study is thus
much more than a requirement for absolute proof of efficacy (as is
commonly supposed) — it is a necessity for knowing almost anything
about whether a treatment really works." altmedconsult.com/
Importantly, for the reader, we ask: What would be the impact on medical
progress if the observations of the sponsor (with obvious financial
conflict of interest) were sufficient to win
marketing approval for drugs, or in this case: unproven tests to guide clinical
decisions?
What are the dangers to patients, present and future, for waving
standards of evidence for tests that guide treatment decisions?
