EDITORIALS

PC-SPESA Lesson for Future Dietary

Supplement Research
Jeffrey White
In the past few years, the herbal mixture PC-SPES had be-
come one of the best prospects for an alternative medicine can-
cer treatment that would be able to stand up to the intense
scrutiny of biomedical research. Previously, the failure to per-
form adequately in well-designed clinical trials negated further
research on alternative medicine products such as laetrile and
hydrazine sulfate. Now, with the report by Sovak et al. in this
issue of the Journal (1), the fatal flaw with PC-SPES is in the
more fundamental issue of product integrity.
Although legally sold in the United States as a dietary supple-
ment for prostate health, PC-SPES was in fact an alternative
medicine treatment for prostate cancer (the PC in the name
stands for prostate cancer and spes is Latin for hope). After its
release in 1996, the product rapidly became known throughout
the prostate cancer patient community. Figures are lacking for
the exact rate of use of PC-SPES by patients with prostate can-
cer, but the results of a University of Virginia survey reported in
1999 showed that 13% of the respondents used an herbal medi-
cine (1a). A similar survey in a radiation oncology clinic in
Philadelphia found that 22% of survey respondents used an
herbal therapy (2). The University of Virginia study also asked
radiation oncologists and urologists to estimate the use of a
broad range of complementary and alternative medical therapies
by their patients. They guessed 4.4%, whereas the actual figure
was 37%. This discrepancy is not surprising given the data in-
dicating that approximately 70% of U.S. patients who use
complementary and alternative medical interventions do not re-
veal the use to their conventional health care practitioner (3).
Allegations that PC-SPES contained the synthetic estrogen
diethylstilbestrol (DES) began appearing on e-mail listservs of
prostate cancer patients and in on-line newsletters by the sum-
mer of 2001. One patient who was taking PC-SPES and his wife
apparently were concerned enough about this possibility to com-
mission their own analysis of samples from two separate lots in
June 2001 (4). Simultaneously, evidence was emerging that the
herbal mixture was causing abnormalities in clotting times in
some patients and severe bleeding episodes in others (57).
In this setting, the California Department of Health Services
decided to test lots of PC-SPES and found contamination with
both DES and warfarin (8). This finding has now been indepen-
dently verified and extended to include indomethacin by Sovak
et al. Uncovering the adulteration of PC-SPES with these syn-
thetic drugs initiated a cascade of effects. On February 8, 2002,
the California Department of Health Services released a warning
on the contamination of PC-SPES (8). Simultaneously, the Cali-
fornia-based manufacturer, BotanicLab, voluntarily recalled
PC-SPES nationwide. The Food and Drug Administration
(FDA) published a medical product safety alert (9). Canada and
Ireland also announced recalls of the product. A multicenter
clinical trial comparing PC-SPES and DES was stopped (10). On
June 5, 2002, the California Department of Health Services an-
nounced that several other herbal products sold by the same
company were contaminated with indomethacin, DES, or alpra-
zolam, either individually or in combination. BotanicLabs went
out of business on June 1, 2002, and PC-SPES is no longer
available (11). Lastly, the National Center for Complementary
and Alternative Medicine of the National Institutes of Health
placed all its funded grants using PC-SPES on hold pending
further review (12). Likely because of the successful market-
ing of PC-SPES, products with similar names (i.e., PC-Calm,
PC-Plus, and PC-Care) and herbal compositions are starting to
fill the void. None of these products, however, appears to have
any report of research in a search of MEDLINE (July 30, 2002).
Unlike most herbal medications, the potential anticancer ac-
tivities of PC-SPES have been extensively researched, resulting
in more than 45 MEDLINE-indexed research articles since the
product was released in 1996. PC-SPES was reportedly stan-
dardized via high-performance liquid chromatography profiling.
Each batch was evaluated for the presence of six specific peaks
(13). The main peak is baicalin, a flavone found in high con-
centration in Scutellaria baicalensis, one of the eight herbs re-
ported in the mixture (14,15). Baicalin is orally bioavailable in
rats (16) and is metabolized in the body to baicalein, a flavonoid
similar to genistein. (17). Baicalein inhibits 12-lipoxygenase and
5reductase (17) and also has aromatase inhibitor activity (18).
Aqueous and ethanol PC-SPES extracts have been shown to
induce apoptosis and to prolong the G
1
phase of the cell cycle in
a variety of cancer cell lines (13,1922). When added to the diet
of rats that had been subcutaneously inoculated with a rat pros-
tate cancer cell line, PC-SPES decreased the incidence and
growth rate of established tumors (22,23). Four uncontrolled,
clinical trial, or case series reports on PC-SPES have been pub-
lished, each indicating an impressive activity in both androgen-
dependent and androgen-independent prostate cancer (2427).
Prostate-specific antigen levels dropped by more than 50% in
most patients reported in these studies. One study that used the
FACTP (Functional Assessment of Cancer TherapyProstate)
questionnaire reported an improved quality of life (25). Objec-
tive improvements of bone scans and measurable disease on
radiographic imaging studies were noted in some patients
(25,27). The estrogen-like side effects of breast tenderness, de-
creased libido and potency, and thromboembolic events were
also frequently observed.
Herbal research is complicated enough without having to deal
with the added problem of potential product adulteration. Inher-
ent problems in studying herbal extracts arise from the variation
in the concentration of active ingredients in herbs caused by
Correspondence to: Jeffrey White, M.D., National Cancer Institute, National
Institutes of Health, Executive Plaza North, Rm. 102, 6130 Executive Blvd.,
Bethesda, MD 20892 (e-mail: jeffreyw@mail.nih.gov).
Journal of the National Cancer Institute, Vol. 94, No. 17, September 4, 2002 EDITORIALS 1261

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1) known and unknown genetic and environmental factors (28
30); 2) inconsistent and inaccurate identification of plant species
(31,32); and 3) contamination by molds, mycotoxins (33), or
pesticides (34). Problems may also occur when there is insuffi-
cient regulatory oversight of the production facility. Although
the source of contamination of BotanicLabs herbal products has
not been determined, some have speculated that it originated at
the manufacturing plant in China (35). Other instances of herbal
products from China being adulterated with synthetic drugs have
been reported (36,37).
Preclinical and clinical trial research of promising herbal in-
terventions should continue. The fundamental questions raised
by herbal medicine, such as the synergistic therapeutic activity
of various components, need to be answered for the field to
progress. We need to know if there are sufficient reasons (sci-
entific, economic, or other) to continue to pursue research of a
product as an incompletely characterized and variable mixture
rather than follow the more mainstream drug development
model of isolating and purifying an active ingredient.
Regulatory challenges also exist. Clinical and, perhaps, pre-
clinical investigators should preferentially study products that at
least meet the FDAs newly developed botanic guidelines (38).
However, this requirement may not be enough to identify erratic
changes in production quality. Consequently, investigators
should consider regular quality control evaluations by indepen-
dent laboratories throughout the course of their research.
Much remains to be learned about the mechanism of action of
PC-SPES as a cancer therapy in humans. Despite some lots
having sufficient concentrations of DES to cause one to wonder
if it is responsible for some of the activity, there are intriguing
hints that there may be other, possibly novel drug activities
present. For example, in the study by Small et al. (27), more than
one endocrine manipulation had failed for many of the patients
included in the study, and yet some of these patients apparently
responded to PC-SPES. The trial comparing DES and PC-SPES
(10) was designed so that patients would cross over to the op-
posite arm after progression. It will be interesting to learn wheth-
er analysis of these data shows responses in any patients after the
crossover.
Perhaps the story of the demise of PC-SPES will serve as a
lesson to help future researchers uncover such confounding el-
ements earlier in their research. The story also tells how patient
interests and concerns can help push research investigations in
positive directions. The lesson must be well learned, because the
loss of a product that symbolized hope to some should not occur
without leading to an ultimate gain for all cancer patients.
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1262 EDITORIALS Journal of the National Cancer Institute, Vol. 94, No. 17, September 4, 2002

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Journal of the National Cancer Institute, Vol. 94, No. 17, September 4, 2002 EDITORIALS 1263

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