Flawed Analytic Methods and Conflicts of Interest Cited as Factors Behind ASCO Panel Findings
Long Beach, Calif. -- August __, 2004 – A group
of leading chemotherapy experts assembled as the Clinical
Oncologists for Individualized Therapy (COFIT)
refute the findings of the American Society of Clinical Oncology
(ASCO) technology assessment panel regarding
the use of chemotherapy sensitivity and resistance assays (CSRA).
The investigators, led by Robert Nagourney,
M.D., Larry Weisenthal, M.D., Ph.D., Robert Hoffman, Ph.D. and William
Grace, M.D., promote research and application
of a specific class of CSRAs that measure drug-induced cell death.
These assays have been clinically validated
for the selection of optimal chemotherapy regimens for individual patients.
The ASCO panel reported that the use of in-vitro
CSRAs to select chemotherapy should be limited to clinical trials and
not made available for use in oncologic practice.
After reviewing 1,139 published clinical trials, the panel members
selected 12 studies that met their criteria
and based their recommendations on this limited series. Results of the
panel’s
findings are published in this week’s issue
of the Journal of Clinical Oncology -- ASCO’s official publication.
CSRAs are in-vitro laboratory analyses that
use fresh human tumor biopsies to determine which drugs or combinations
have the highest likelihood of response for
individual cancer patients. Conducted and applied correctly, these analyses
enable doctors to individualize and optimize
treatments while minimizing the risk of toxicity from chemotherapy.
Assay-directed therapy is based on the premise
that each patient’s cancer cells are unique and therefore will respond
differently to a given treatment. This is
in stark contrast to standard or empiric therapy, in which chemotherapy
for a
specific patient is based on results from
prior clinical studies.
“While we agree with ASCO’s conclusion that
CSRA research should be a priority, we take issue with the composition
of the panel, the methods for trial selection,
the analytic process and, most fundamentally, with the suggestion that
the
data does not support the utility of these
tests,” said Dr. Nagourney, who serves as Medical/Laboratory Director of
Rational Therapeutics (Long Beach, Calif.),
and has published extensively in the field. “ASCO’s findings could
potentially limit patient access to a technology
that has proven capable of identifying active treatments.”
Dr. Weisenthal added, ”Both BlueCross/BlueShield
and ASCO demonstrated systemic bias and a lack of expertise in
arriving at their conclusions.” Dr.
Weisenthal is a 25-year investigator and author in the field. He serves
as
Medical/Laboratory Director of the Weisenthal
Cancer Group (Huntington Beach CA)
Drs. Nagourney, Weisenthal, Hoffman, and Grace
are among a growing number of oncology specialists who support the
use of a certain class of CSRAs that measure
drug induced cell death. They assert that the ASCO panel’s analysis is
flawed in the following four key areas:
1. Study Selection
ASCO’s recommendations were based on
a review of 12 previously published clinical studies, many of which focused
on older cell growth assay methods. Drug induced
cell -death as a surrogate for apoptosis is the most relevant biological
measure and must not be confused with growth-based
testing. The panel made no attempt to distinguish cell death from
cell growth techniques. While the panel’s
criticisms regarding slow turnaround and low evaluability rates may be
applicable to the older cell-growth tests,
the negative conclusions reached by the panel simply do not apply to newer
cell-death assays. In fact, cell death assay
results have consistently correlated with response, time to progression
and
survival.
2. Composition of the panel
Investigators actively working with CSRAs based
on the cell death endpoints were not represented or even consulted by
the ASCO panel.
3. Conflicts of Interest
While ASCO states that no limiting conflicts
were identified among its panel members, their assessment was performed
under a collaborative relationship with the
Blue Cross and Blue Shield Association (BCBSA). Both insurance groups are
on record for their opposition to the use
of CSRAs. Dr. Weisenthal noted that many of the ASCO panel members
have
built their careers on conducting trials based
on empiric therapy, and have a vested interest in maintaining the status
quo
with respect to how chemotherapy is administered
and that the cooperative oncology groups (which have exclusively
focused their attention on trials of empiric
therapy) have consistently refused to carry out the very same clinical
trials
which the ASCO panel now claims should be
“a priority” (their words). These empiric therapy trials have, in large
measure, proven to have been a “colossal failure,”
according to both Dr. Weisenthal and investigative reports published
outside the oncologic media. This conflict
of interest among the panel members is indicative of a systemic conflict
in the
oncologic community regarding how doctors
are reimbursed for chemotherapy drugs by Medicare and insurance
companies. This conflict has also been the
subject of recent investigative reports in the media.
4. Analytic Method
The panel analyzed CSRAs based on patient outcome
-- a criterion that holds such assays to a standard not met by any
other clinical test in cancer medicine, and
which has seldom been met by the empiric chemotherapy treatments supported
by ASCO. Were the panel to have applied
a more standard measure of performance such as predictive accuracy, the
results of its analysis would have been markedly
different and in favor of the use of CSRAs in clinical practice.
CSRAs offer an objective alternative to the
off-the-shelf, ‘best guess,’ trial and error therapy typically used to
treat
cancer patients,” added Dr. Nagourney. “Assays
based on cell death have proven very effective in identifying novel
treatment combinations for a variety of cancers.
It is unfortunate that organizations such as ASCO have consistently
declined to carry out studies to assess the
value of cell death CSRAs.”
Ironically, as the ASCO panel released its
findings, an international study published in the August 5, 2004 issue
of the
New England Journal of Medicine (AUGUST 5,
2004 reported that cell death CSRAs are effective in identifying gene
expression patters that correlate with clinical
drug resistance. The study, titled “Gene Expression Patterns in Drug
Resistant Acute Lymphoblastic Leukemia Cells
and Response to Treatment” employed a cell death assay to examine
drug resistance at the molecular level.
“My experience with cell death CSRAs is that
they have accuracy in predicting clinical outcomes and defining novel
chemotherapeutic synergies. They also have
frequent curative value in treating many adult malignancies which the current
medical literature has deemed incurable,”
said Dr. Grace. “I believe that it would be unethical for me not to use
such
CSRAs in my practice.”
About Clinical Oncologists for Individualized Therapy (COFIT)
COFIT is a group of leading chemotherapy experts
working to promote research and the clinical application of
chemosensitivity and resistance assays (CSRA)
based upon cell death that have proven effective in identifying active
chemotherapy regimens for individual patients.
COFIT is led by Robert Nagourney, M.D., Larry Weisenthal, M.D.,
Ph.D., Robert Hoffman, Ph.D., and William
Grace, M.D.
Dr. Nagourney is Medical Director of
the Malcom C. Todd Cancer Institute at Long Beach Memorial Center, Long
Beach, Calif.) and Medical/Laboratory Director
of Rational Therapeutics (Long Beach, Calif.). Since 1993, Rational
Therapeutics has conducted more than 3,600
EVA (Ex-Vivo Apoptotic) Assays. Rational Therapeutics also regularly
donates assays to medically indigent patients
via the non-profit Vanguard Cancer Foundation. More information about
Rational Therapeutics is available at http://www.rationaltherapeutics.com.
Dr. Weisenthal is a Board-Certified
Medical Oncologist and Ph.D. pharmacologist who trained at the National
Cancer
Institute. He is Medical/Laboratory Director
of the Weisenthal Cancer Group (Huntington Beach, Calif.). Since 1992,
the Weisenthal Cancer Group has conducted
more than 5,500 cell culture drug resistance assays with cell death
endpoints. More information about Dr. Weisenthal’s
work is available at http://www.weisenthal.org.
Dr. Hoffman received his Ph.D. from
Harvard University and did postdoctoral training at Massachusetts General
Hospital. Dr. Hoffman has been a cancer researcher
for 31 years. He is currently Professor of Surgery at the University
of California San Diego, and Founder
and President of AntiCancer, Inc., a research and development biotechnology
company in San Diego. More information on
AntiCancer, Inc., is available at http://www.anticancer.com.
Dr. Grace is a practicing oncologist
with extensive clinical experience in both cell growth and cell death-based
CSRAs.
He served for 20 years as Director of Cancer
Research and Chief of Medical Oncology at Saint Vincent’s Hospital and
Medical Center (New York City), and as a Trustee
and Spokesperson for the American Cancer Society. He is also
Past-President of the New York State Society
of Oncologists-Hemotologists, and Past-President of the New York
Cancer Society. Professional affilations also
include the American Society of Clinical Oncologists (ASCO) and the
American Society for Cancer Research. He has
authored over 20 publications in immunology and cancer research, and
is ranked as one of the “Best Physicians in
America” by the Consumers’ Research Council of America, Better Living
Magazine and the Castle Connolly Guide to
Best Physicians.