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The Cancer Advisory Panel for Complementary and Alternative Medicine (CAPCAM)
convened on May 21, 2001, at the Pooks Hill Marriott, Bethesda, Maryland.
Richard Nahin, Ph.D., M.P.H., Executive Secretary of CAPCAM, called the
meeting to order at 9:05 a.m.
On this page
- Call to Order and Meeting Procedures
- Introductory Remarks
- Virulizin
- Discussion
- Recommendations
- Rand Best Case Series for Cam Treatment of Cancer
- Update on NIH Initiatives for CAM and Cancer
- Public Comment
- Adjournment
CAPCAM
Members Present
- Michael Hawkins,
M.D., Chair
- Peter L. Choyke,
M.D.
- Ian D. Coulter,
Ph.D.
- David J. Hufford,
Ph.D.
- Ralph W. Moss,
Ph.D.
- Susan K. Quella,
R.N.
- Debasish Tripathy,
M.D.
- Jeffrey D. White,
M.D, Ex-Officio Member
AD
HOC Members
- Xin Chen, M.D.,
Ph.D.
- Susan Holloran
- Leanna Standish,
N.D., Ph.D.
- James E. Williams
NIH
Staff Present
- Richard Nahin,
M.P.H, Ph.D.
- Marc Pitts, M.B.A
- Mary Ann Richardson,
Dr.PH
- Stephen Straus,
M.D.
- Shan Wong, Ph.D.
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I.
Call to Order and Meeting Procedures
The meeting
was called to order by Richard Nahin, M.P.H., Ph.D., Executive Secretary
of CAPCAM. Dr. Nahin reviewed the rules concerning confidentiality and
conflict of interest, and polled the members for acceptance.
II. Introductory Remarks
Dr. Michael
Hawkins, chair, asked members to introduce themselves. Dr. Hawkins then
explained that the first presentation would be by Lorus Therapeutics,
Inc. on Virulizin®, a cancer therapy. The committee would then focus
on whether the treatment falls within the realm of CAPCAM; whether the
work was promising enough to continue; and if so, whether CAPCAM should
play a role.
Top
III.
Virulizin
Dr. Jim
Wright, president of Lorus Therapeutics, introduced the company and the
history of Virulizin®. He explained that the goal of Lorus was to
build the leading biopharmaceutical company specializing in research and
development of efficacious therapies with low toxicity for management
of cancer. He then explained that Virulizin®, which is extracted from
bovine bile, was first introduced by a Romanian veterinarian in the 1980s
who had noticed that certain animals, and certain animal organs, seemed
resistant to cancer.
Dr. Donald
Braum then discussed the cell biology behind Virulizin®. He explained
that Virulizin® is a pyrogen-free, liquid, clinically non-toxic biological
response modifier (BRM) that exerts its anti-tumor effects by enhancing
the cell-mediated immune response to tumor cells. Virulizin® is obtained
from bovine bile by a standardized process involving solvent extraction
and heat hydrolysis and is provided for IM (intramuscular) injection.
The immunostimulatory function of Virulizin® is achieved by direct
macrophage activation. Virulizin® stimulates the production of TNF
(tumor necrosis factor) in combination with LPS (lipopolysaccharide) from
monocytes and macrophages. Its stimulatory function is not inhibited by
prostaglandins, hence it is distinct from many other activators.
Dr. Braum
then briefly introduced the pancreatic cancer study, which indicated that
Virulizin® promoted a trend towards increased killing in the blood
by monocytes. The company had also begun to see a trend towards increased
blastogenic response, and an increase in lymphocyte-based killing. Dr.
Braum reiterated that Virulizin® is a well-tolerated drug that does
not contribute to patient morbidity. He also touched on the possibility
of Virulizin® being effective in the treatment of other diseases,
such as endometriosis and atypical micro bacterial infections.
Dr. Straus
asked whether Virulizin® required organic and inorganic compounds;
Dr. Chen asked for more information about the veterinarian who had the
idea to use bile. Dr. Moss then inquired whether Lorus had looked at oral
administration of Virulizin®, and the response was that although it
could certainly be explored, it did not look like a promising mode of
administration.
Dr. Aiping
Young presented the information on pre-clinical animal testing. Virulizin®
showed significant inhibition of growth of human tumors injected in mice.
The results were most striking when Virulizin® was used in combination
with standard chemotherapeutic drugs such as DTIC against melanoma, Gemcitabine
against pancreatic adenocarcinoma, and Taxol against breast adenocarcinoma.
In some studies, partial to total regressions of the cancer were observed
during prolonged treatment periods. Both acute and chronic toxicity studies
in mice indicated that Virulizin® injected intramuscularly was very
well tolerated by the animals. Mutagenicity studies with Virulizin®
were also negative.
Dr. Guy
Ely then gave an overview of the Phase I/II and Phase II clinical trials
of Virulizin®. The trials consisted of three studies -- CO1, CO2,
and USO1 -- performed on cancer patients with solid tumors (108 patients);
pancreatic cancer (61 patients); and malignant melanoma (52 patients).
The general results included superior tolerance & safety, extension
of median survival, and improved quality of life.
Meta-analysis
of the three studies compared subjective responses to Virulizin® and
Gemcitabine. Over a four week course, Virulizin® results were at least
equal to Gemcitabine, but with better quality of life and less pain. A
summary explained also that Gemcitabine patients were pre-selected for
pain control; and it is already known that patients with less pain in
pancreatic cancer have longer life span. The Gemcitabine patients were
chosen only if pain was under control by 10 days.
Dr. Ely
summarized the results of the meta-analysis conclusions for all three
studies: the amount of adverse events were small; the most conservative
estimates of survival were better with Virulizin® than in a similar
patient population receiving Gemcitabine; the survival experience of Virulizin®
patients was significantly better; the median survival rates were comparable;
and the subjective response values were maintained for at least four weeks.
Ms. Quella
asked which quality of life standards were used in the analysis. The answer
was Spitzer.
Dr. Ely
then explained his reasons for approaching CAPCAM. Lorus Therapeutics
wishes to run a pivotal Phase III, open-label, multi-center, randomized
study of Virulizin® administered intramuscularly (3 cc injections
3x per week) plus best supportive care, versus best supportive care alone
in patients with advanced pancreatic cancer who have failed or are intolerant
to chemotherapy. The goal is to understand Virulizin® better. The
planned study would require about 250 patients and take approximately
2 ½ years to complete. The end points of the Phase III study would be
survival, quality of life, and clinical benefits.
Top
IV.
Discussion
Dr. Straus
asked about a comparison to another study and the answer was addressed
by Dr. Chen. Dr. Moss asked about the antioxidant qualities of ox bile.
Dr. Braum stated that it hadn't been studied yet, although there are indications.
Dr. Standish asked about possibly studying oral administration of Virulizin®.
Dr. Wright and Dr. Young said that while that could be explored, Virulizin®
made in other ways turned out to be toxic. The current process separates
out toxic components, but must be administered through IM injection.
Dr. Hawkins
then began the discussion on whether Virulizin® falls under the rubric
of CAPCAM criteria. Ms. Holloran asked whether results for Virulizin®
could be further quantified. Dr. Braum emphasized the issue of quality
of life, as drugs for metastatic cancer are very difficult to tolerate.
Dr. Moss said he'd love to see the drug approved and available, but he
was having trouble conceiving of it as a so-called natural product. He
wanted to be assured that supporting it wouldn't break purview. Dr. Hufford
countered that the committee did not have strictly-defined criteria for
what constitutes complementary and alternative medicine (CAM), and that
he believed it fit. He also stated that the committee must be careful
not to discount therapies because the science behind them is well-developed.
Ms. Holloran asked that the committee look at CAM therapies not just by
what they are, but how they act in patients. She stated that non-toxicity
was an important criterion for CAM. Mr. Williams asked how a product of
this type gets to this table, as that may give some indication of whether
it is CAM or not. Dr. Nahin answered that Virulizin® was brought to
CAPCAM's attention by the National Cancer Institute (NCI), which couldn't
agree on whether or not it was CAM. Dr. Hawkins asked him to summarize
the disagreement, and Dr. Nahin answered that the question revolved around
how much of the product was natural and how much was processed. Mr. Williams
asked if there are any pure products being tested, and Dr. Hawkins replied
that there are some purer products, but not being tested by CAPCAM. Dr.
Straus said that a pure product could be under our purview, and Dr. Hawkins
pointed out that all products must be processed in some fashion to get
quality controls and get them into clinical trials. Dr. Hawkins gave his
opinion that he was comfortable with the mixture under discussion as CAM,
and Dr. Coulter concurred, pointing out that this is always a grey area.
Dr. Coulter also expressed that his real interest was in what CAPCAM could/should
do to support this product.
Dr. Hawkins
asked if there was further discussion regarding Virulizin® as CAM.
Dr. White said he sees similarities with other CAM products, based on
the bile originator. Ms. Holloran asked whether Virulizin® could be
used as a preventative, and Dr. Braum answered that it should be possible
in cases where there is a high prognosis of recurrence and long therapy
is expected, such as endometriosis and HIV patients with a high likelihood
of cancer. Dr. Hawkins pointed out that long-term administration is problematic
if only IM injection is available. Ms. Holloran stated that using Virulizin®
as a preventative would add to its value for CAPCAM, as conventional medicine
has so little to address this. Dr. Moss pointed out that Virulizin®
is a palliative, not a cure. But he added that he does consider it CAM.
Dr. Hawkins then polled the members, and there was general agreement that
Virulizin® could qualify as CAM.
Dr. Hawkins
then directed the committee to consider what it could do to help. Dr.
Moss emphasized that CAPCAM shouldn't jump in to give money when other
money is available. Dr. Nahin pointed out that among the recommendations
that they could make would be an RFA; helping Lorus Therapeutics apply
for other monies, including applying through regular channels at NIH;
requesting applications to aid research; helping as program officers to
get a high-quality application for peer review; helping to set up the
process for patients to apply for next trial.
Dr. Standish
inquired as to who was currently funding the planned Phase III trial,
to which Dr. Wright responded that they'd had trouble finding investors,
because of the natural component of Virulizin®. In particular, their
proprietary purification process wasn't enough to get funding - people
worried about hoof and mouth, and other diseases. He asked whether CAPCAM
had ideas to overcome this problem. Dr. Ely emphasized the amount of patients
clamoring for this product, and their inability to provide it at this
point. Dr. Ely explained that Lorus Therapeutics needed to attract a large
pharmaceutical company for worldwide distribution, but the pharmaceuticals
wanted a complete analysis of components, which would hold up a Phase
III trial. Dr. Tripathy agreed that this was the Catch 22 of nonpurified
products. Ms. Holloran said that this is an institutional problem, and
a fundamental CAM problem, that those with disease feel an urgency that
the institutions can't address. She asked how the committee could come
to grips with this. Mr. Williams asked about the estimated cost of the
Phase III trial, and Dr. Wright said $10 million. Dr. Hawkins agreed that
a Phase III study was necessary and the time was right. Dr. Standish asked
if it would be possible for project officers at NCCAM to produce a high
quality RO1 application that could be co-funded by CAPCAM and NCI. Dr.
White didn't think that was the most efficient route, and that other routes
would provide more opportunity/push for drug. Dr. Hawkins recommended
the Cancer Therapy Evaluation Program route instead, as CTEP is a scientific
association and can more easily accommodate a cooperative group study.
Dr Braum pointed out that the pancreatic cancer patient population may
be too small for a cooperative group effort. Dr. White asked whether they
could do a melanoma treatment in Phase III as well. Dr. Ely stated that
the data is ready on pancreatic cancer, but not on other types, because
as a small company they could only afford small clinical trials.
Top
V. Recommendations
Dr. Hawkins
recommended that Dr. White contact CTEP to work on a solution to Lorus
Therapeutics' problem. Dr. White added that his office at NCI has an active
search out for Phase II and III clinical trials, for funding within this
fiscal year, and that the application deadline is July 2. Dr. Tripathy
pointed out that working through CTEP would allow for the trials to be
open to any group, not only co-ops, and since Lorus already has several
investigators ready with patients, this would let them still proceed.
He also expressed some concern that supportive care alone may not be enough
to attract patients. Ms. Holloran asked about the funding at CTEP, but
Dr. Hawkins explained that the value of the program is as a mechanism
to run trials. Dr. Standish asked if CTEP had any CAM experts on their
panels, and Dr. White answered that some outside ad hoc members may have
CAM experience, but that appropriate people are also added as necessary.
The committee
voted to take a break (11:40) and resume at 12 noon. At noon, the committee
resumed. Dr. Nahin passed a confidentiality statement for committee members
to sign, and reminded members of the reimbursement travel expense sheet.
He then introduced Dr. Coulter to talk about the Rand Best Case Series
for CAM Treatment of Cancer.
Top
VI.
Rand Best Case Series for Cam Treatment of Cancer
Dr. Coulter
began by discussing the history of best case series studies. These studies
have faced several obstacles: insufficient candidates and/or difficulty
recruiting candidates; barriers in terms of economic costs, time, and
know-how; legal regulations in attaining files and permissions; the challenges
of varying office formats, result statistics, etc. The aim of the Rand
project is to compile data for three CAM providers to determine if there
is sufficient evidence for further study.
The methodology
involves accessing the files of the CAM provider to identify best cases;
contacting patients for permission; comparing with files from a patient's
mainstream provider; reviewing cases for inclusion; and abstracting the
data. Moreover, the RAND procedure involves a complete patient interview
on health-related quality of life. The process relies on a mainstream
medical provider to provide other documentation of diagnosis and treatment.
In particular, it is important to obtain a histological confirmation;
the starting date for CAM; well-documented CAM treatment; a record of
exclusive CAM treatment; and a documented end-point (i.e. remission, reduction
of tumor size, longevity, etc.). RAND has found that as an independent
research provider, it has had more success in accessing files than other
groups with potential conflicts of interest.
A previous
best case series study was done by the National Foundation for Alternative
Medicine in 1999. Of 73 cases, 27 met the inclusion criteria, and 20 cases
were reviewed in the final report. RAND is reviewing this series and using
it to eliminate problems. In this series, extended quality of life was
the most common outcome criteria, with patients more than two standard
deviations from the national statistics.
Dr. Coulter
then went on to discuss the first RAND best case series site, a program
for immuno-augmented therapy in the Bahamas. This therapy involved daily
injections of human-processed blood based on the patients' immune systems,
in an attempt to encourage anti-tumor activity while not inhibiting the
immune system. At this site, there were 23 cases, 17 of which meet the
inclusion criteria. The documentation of prior cancer treatment is fairly
complete, as is the data on chronology of care. Standard protocol for
immuno-augmentation therapy was used. The weakest documentation involves
the immuno-augmentation therapy care, including the initiation date, but
Dr. Coulter believes this can be recovered.
Dr. Moss
pointed out that the survival statistics were very iffy. Dr. Coulter agreed,
and noted that RAND will have its own statistician to assess results.
Dr. Coulter
then briefly discussed the second site, a New York program to study pain
therapies.
Ms. Holloran
questioned the need for best case series. Dr. Nahin said that RAND was
hired to try to provide the type of data that CAPCAM providers have said
they need. If RAND can't get it, it may not be attainable. Dr. Coulter
talked about the time involved, and the need to pick the programs in which
this is attainable. Dr. Tripathy talked about needing to find a fairly
cohesive group of patients. Dr. Coulter stated that their statistician
asked for the same thing, and he agreed it's a problem. Dr. Hawkins posed
the rhetorical question: what are we trying to learn from a best case
series? He explained that CAPCAM needs finished studies to see if they
are worth pursuing further, although none of these studies will be definitive,
since only the best case examples will be used. But he said that trying
to put statistical conclusions on this type of data would slow the process.
Dr. Coulter agreed, saying that they just need good, promising cases that
are documented. Dr. Hufford asked about prospective analysis studies,
as they might be a way to get systematic data if best case study fails.
Dr. Nahin added that they might make a good second phase after best case
study. Dr. Moss explained that historically, one group of patients claimed
something was a cure; and on the other side, fraud was claimed. The best
case study is used to determine whether anything is there before running
a clinical trial. The goal is to find plausibility only. Mr. Williams
noted that patients are quite anxious to find out if anything is there.
Dr. Standish
noted that most cancer patients are using CAM in a complementary way,
and asked how they could assess the addition of CAM therapies. She wanted
to know if there was a way to start investigating the efficacy of that.
Dr. Coulter explained that they would need to look at observational studies
to accomplish that. Dr. Standish noted that the conundrum would be defining
the comparison group.
Dr. Hawkins
announced that Dr. Coulter would give a further update on the RAND best
case series study at the next CAPCAM meeting.
Top
VII.
Update on NIH Initiatives for CAM and Cancer
Dr. Mary
Ann Richardson presented an overview on current CAM cancer research at
NCCAM.
There
are two P50 NCCAM-funded cancer centers: Johns Hopkins and University
of Pennsylvania. University of Pennsylvania is focused on hyperbaric oxygen
head and neck cancers. Projects include post laryngectomy complications/quality
of life; angiogenesis and tumor growth; cell adhesion; and nitric oxide
synthesis. Johns Hopkins is focused on breast and prostate cancer, and
the Johns Hopkins projects include oxidative stress in cells; natural
products for pain (rodent model); Phase II PC SPES in prostate cancer;
and prayer on breast cancer recurrence in Africa American women.
Approximately
22 investigator-initiated RO1 and R21 studies are currently underway,
funded through 15 grants. Most of the RO1 and R21 projects are studying
bio-pharmacologic and herbal products, but other areas of study include
alternative system models, manipulation, energy, and mind-body work. Examples
of projects include the following:
- Distant healing
for glioblastoma at the California Pacific Medical Center
- Massage for cancer-related
fatigue at the University of California - San Francisco Osher Center
- Scutellaria
baicalensis for skin cancer at Mt. Sinai
- Mechanisms of herbal
radiosensitization of glioma cells at California Pacific Medical Center
- Ginkgo biloba to
stabilize/prevent cancer at George Washington University
- Shark cartilage
as an angiogenesis inhibitor at Boston Children's Hospital
- Soy isoflavones
for prostate/breast/bone cancer at Stanford
- Soy phytoestrogens
for post menopause HRT at Wake Forest
Several
trials are funded through the NCI established research networks and comprehensive
cancer centers. A phase III trial of shark cartilage extract is underway
at M.D. Anderson Cooperative Research Base and another evaluating a shark
cartilage powder is being finalized for the North Central Cancer Cooperative
group at Mayo. In addition, an evaluation of the Gonzalez complex nutritional
regimen for pancreatic cancer is underway at Columbia.
New research
may result from several initiatives and mechanisms for funding: program
announcement for novel therapies for cancer treatment; supplements to
the P30 comprehensive cancer centers; requests for applications for the
frontier medicine, herb-drug interaction, integrative medicine, and end-of-life
care initiatives; and the standard investigator initiated RO1-R21 mechanism.
Ms. Holloran
asked how the quality of placebo massage could be assessed. Dr. Richardson
acknowledged that this was a common problem for studies of massage and
acupuncture and such, and explained how the problem was being addressed.
Ms. Holloran then asked whether information on the CAM funded studies
were in the public domain. Dr. Nahin stated that under the Freedom of
Information Act, only abstracts were available, as long as there were
proprietary and intellectual property issues. Nothing goes into the public
domain until there is a published study.
Dr. White
addressed the issue of cancer CAM information. There are seven summaries
of research currently available on the website and by phone. A PDQ CAM
editorial board is now forming to review these summaries before posting.
The board will have a variety of expertise and meet about four times a
year, with Dr. White as Editor-in-Chief.
Dr. White
then addressed the new NCI CAM initiatives. A letter RFA for CAM cancer
pilot projects in NCI-designated cancer centers was released, with a goal
of supporting projects with a high likelihood of developing into successful
RO1 applications; of facilitating the development of continuous CAM research
programs; and of encouraging and supporting collaborations between strong
conventional cancer researchers and CAM practitioners and researchers.
This letter RFA received 21 responses.
Another
new NCI CAM initiative was an announcement of March 21 regarding supplements
to NCI's Cooperative Groups and Community Clinical Oncology programs for
randomized Phase II and Phase III trials for CAM interventions in cancer.
Letters of intent for this program are due June 1 and applications are
due July 2.
A promotion
plan for the best case series has included direct mail, interviews, journal
ads, etc. As a result, the program has grown from 12 inquiries in 1999,
which generated three submissions with one actual completed presentation;
to 120+ inquiries between September and May of this year. Additionally,
the time between inquiry and completion has shortened.
Dr. White
then announced a new position opening for a nurse consultant in research,
OCCAM, NCI. Applications are due by June 5. Dr. White stated that this
person would be involved mainly in data collection and the real nuts and
bolts of data assessment and coordination.
Dr. White
then discussed the status of Practice Outcomes Monitoring and Evaluation
projects involving insulin potentiation therapy; and the P Banerji Homeopathic
Research Foundation in Calcutta, India. Dr. Tripathy asked whether special
patient protocols were needed for this and other studies, and Dr. White
responded that they have them wherever necessary.
Dr. White
went on to discuss the status of three CAM cancer clinical trials: a randomized
trial of phase III lung cancer patients in a study of a liquid shark cartilage
product; a randomized trial of phase III breast and colorectal cancer
patients with a powdered shark cartilage product; and the Kelley/Gonzalez
Regimen study on pancreatic cancer at Columbia University. This study
is ongoing but no longer randomized and needs patients.
A long
discussion ensued about the Kelley/Gonzalez criteria and efficacy of study;
and the potential dampening effect of a failure of this study. Dr. White
noted that the eligibility criteria may be too strict. Although the study
has been highly publicized, only about 10% of referrals qualify. Possible
solutions were discussed without clear answers, since publicity has not
been the problem. Dr. Straus noted that in the future, with best case
series data, we can have other trials with easier recruitment of patients
and less stringent criteria. Dr. Tripathy said that there was no need
to throw out the whole process just because this case has been difficult.
Dr. Moss made a general observation that although vast numbers of people
use alternative medicine, many are unwilling to go through extensive,
arduous therapies. Dr. Hawkins noted that most alternative cancer centers
are vastly underused. Dr. Straus said, "Our ability to reach out and be
open-minded about alternative therapies is constantly impugned by traditional
medicine and others. We must press on, because this is groundbreaking
and important." Dr. Hawkins made these the final comments.
Top
VIII.
Public Comment
No public
comments were made.
IX.
Adjournment
The meeting
was adjourned at 2:30 pm.
Certification:
We hereby certify that, to the best of our knowledge, the foregoing minutes
are accurate and complete.
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