Medscape Hematology-Oncology
Journal Scan
Volume 3, Number 7
(Updated July 24, 2000)
Harold J. Burstein, MD, PhD
[Medscape, 2000. © 2000 Medscape, Inc.]
Can Herbs Cause Cancer?
Chinese-herb nephropathy is a form of end-stage renal disease associated
with ingestion of certain Chinese herbs (Stephania tetrandra and
Magnolia officinalis) that are sometimes consumed as weight-reducing
remedies. In a curious clinical report, investigators in Brussels, Belgium,
investigated this association when they began to follow up patients diagnosed
with end-stage renal disease following ingestion of Chinese herbs. In fact,
the herbal preparations did not contain S tetrandra or M officinalis,
but aristolochic acid, a derivative of the herb Aristolochia fangchi,
which had been substituted for S tetrandra in the proprietary herbal
extracts.
Aristolochic acids are known to be carcinogens in many murine
and bacterial models. Because of the possible cancer risk, 43 patients
with Chinese-herb nephropathy were prospectively evaluated with cystoscopy,
and patients were advised to have prophylactic surgery to remove their
nonfunctioning kidneys and ureters. The authors have reported in The
New England Journal of Medicine[1]
(Abstract only at: http://www.nejm.com/content/2000/0342/0023/1686.asp)
a remarkably high incidence of urothelial cancers among this patient population.
Eighteen cases of urothelial cancers were identified, including 1 bladder
cancer and 17 upper urinary tract tumors, among the 39 patients who underwent
cystoscopy and prophylactic nephrectomy. The prevalence of such tumors
was 46%. Dysplastic precancerous lesions were found in 19 of 21 patients
without tumors. A search for other risk factors for urothelial cancer disclosed
no significant use of analgesics, anti-inflammatory agents, or smoking
that would have accounted for a marked increase in risk.
Although this study does not prove that the herbs caused urothelial
cancer in addition to contributing to end-stage renal disease, it strongly
suggests an association. What are the lessons from such a finding? First,
it reminds clinicians to inquire about use of herbal medications as part
of the work up of renal failure and/or urothelial cancers. More significantly,
it is a powerful reminder of the potential toxic effects associated with
the use of unstudied herbal agents. While the incidence of such dramatic
toxicities may be rare, the safety for most such herbal products has not
been evaluated. In an accompanying editorial, Dr. David Kessler, former
director of the FDA, called on Congress to take notice of the cancers disclosed
in the NEJM article, and challenged Congress to "change the law
to ensure the safety and efficacy of dietary supplements before more people
are harmed."
Reference
-
Nortier JL, Martinez MCM, Schmeiser HH, et al. Urothelial carcinoma associated
with the use of a Chinese herb (Aristolochia fangchi). N Engl
J Med. 2000;342:1686-1692.
Combined Hormonal Therapy for Advanced Breast Cancer?
Endocrine therapy is an important part of the management for early- and
advanced-stage breast cancer. A variety of endocrine treatments is available,
including estrogen-receptor modulators (tamoxifen), ovarian ablation (either
surgical or medical), progestins, and, for postmenopausal women, aromatase
inhibitors. The standard practice for use of hormonal therapies for advanced
breast cancer remains the use of single-agent therapy, followed sequentially
by second- and sometimes third-line hormonal treatments.[1]
To date, there has been no compelling reason to begin ovarian ablation
therapy prior to tamoxifen. Tamoxifen is effective in premenopausal women,[2]
and randomized studies have shown that either treatment is effective as
first-line therapy for advanced breast cancer.[3]
There have been few studies that have evaluated use of tamoxifen and ovarian
ablation as treatment for advanced breast cancer. One small randomized
trial reported comparable survival among women treated with ovarian ablation
(surgical or with luteinizing hormone-releasing hormone [LHRH]-agonist
therapy) with or without tamoxifen, and found no survival advantage.[4]
Nonetheless, there has been ongoing interest in using combined
hormonal strategies for advanced breast cancer, particularly for women
who are premenopausal. The European Organization for Research Treatment
of Cancer (EORTC) has now concluded a larger randomized trial studying
combined hormonal therapy and reports a survival advantage for use of the
combination treatment[5] (Abstract only
at: http://jnci.oupjournals.org/cgi/content/abstract/92/11/903).During
a 7-year span from 1988 to 1995, 161 women with estrogen receptor (ER)-positive
or ER-unknown advanced breast cancer were enrolled into the study. Women
were required to be premenopausal, defined as having had a menstrual
period within 3 months of enrolling in the study. Patients with rapidly
progressive cancer or with life-threatening tumor burden such as extensive
hepatic disease were not eligible for the study nor were women who had
received prior hormonal or chemotherapy for metastatic disease. Patients
could have received adjuvant tamoxifen provided they had at least a 1-year
disease-free interval after finishing tamoxifen. In fact, only 2% of the
study population had received adjuvant tamoxifen. Women were randomized
to receive buserelin, a LHRH-agonist, tamoxifen, or both treatments.
Buserelin, tamoxifen, and combination therapy were associated
with response rates of 34%, 28%, and 48%, respectively, and with median
progression-free survival of 6.3, 5.6, and 9.7 months. Median overall survival
was greater for women treated initially with combination therapy (3.7 years
vs 2.9 years (tamoxifen) and 2.5 years (buserelin). The actuarial 5-year
survival for buserelin, tamoxifen, or combination treatment was 15%, 18%,
and 34%, respectively. The improved overall survival for combination treatment
was statistically significant (P = .01). Correlative endocrine studies
confirmed that women treated with buserelin had reduction in circulating
estrogen levels to postmenopausal levels.
These data suggest that for premenopausal women with hormonally
sensitive advanced breast cancer, use of ovarian ablation and tamoxifen
may be superior to single-modality therapy. However, as noted in the accompanying
editorial by Dr. Nancy Davidson, there are many reasons why this practice
may not become widespread.[6] First, most
women with ER-positive tumors will have received adjuvant tamoxifen, and
it is not clear how combination therapy would work in such women. Secondly,
many younger women with early-stage breast cancer will have received chemotherapy
that causes premature menopause. Thus, there are not likely to be many
of these patients, and, in fact, the study was stopped with less than half
of the projected number of patients because of slow accrual. Finally, the
results are based on only 50 or so women in each treatment group, a relatively
small number given the heterogeneous nature of outcomes for breast cancer.
Nonetheless, the trial is provocative and provides a rationale
for combination hormonal therapy in premenopausal women with advanced breast
cancer. Perhaps more significantly, it lends further impetus to evaluating
the role of ovarian ablation among women with early-stage breast cancer.
References
-
Goldhirsch A, Gelber RD. Endocrine therapies of breast cancer. Semin
Oncol. 1996;23:494.
-
Sunderland MC, Osborne CK. Tamoxifen in premenopausal patients with metastatic
breast cancer: a review. J Clin Oncol. 1991;9:1283-1297.
-
Ingle JN, Krook JE, Green SJ, et al. Randomized trial of bilateral oophorectomy
versus tamoxifen in premenopausal women with metastatic breast cancer.
J Clin Oncol. 1986;4:178-185.
-
Boccardo F, Rubagotti A, Perrotta A, et al. Ovarian ablation versus goserelin
with or without tamoxifen in pre-perimenopausal patients with advanced
breast cancer: results of a multicentric Italian study. Ann Oncol.
1994;5:337-342.
-
Klijn JGM, Beex LV, Mauriac L, et al. Combined treatment with buserelin
and tamoxifen in premenopausal metastatic breast cancer: a randomized study.
J Natl Cancer Inst. 2000;92:903-911.
-
Davidson NE. Combined endocrine therapy for breast cancer--new life for
an old idea? J Natl Cancer Inst. 2000;92:859-860.
Choosing Treatments for Prostate Cancer: It Matters Whom You Talk To
Of the 180,000 cases of prostate cancer diagnosed annually in the United
States, more than 80% reflect clinically localized cancers. The optimal
treatment for these men is not known. Choices include radical prostatectomy,
external beam radiotherapy, or surveillance. There are not enough data
to suggest which treatment affords optimal long-term survival, although
in the United States, most men receive some definitive therapy. In the
absence of clearly defined clinical recommendations, patients rely on expertise
from their physicians for selecting their treatment options. Historically,
it has been clear that specialists would choose their own treatments. In
a 1988 US survey, 79% of urologists said they would choose radical prostatectomy,
while 92% of radiation oncologists would choose external beam therapy,
if they had prostate cancer.[1] It is not
clear to what extent such professional bias affects recommendations clinicians
make to patients.
A study published this week in the Journal of the American
Medical Association suggests that recommendations for management of
localized prostate cancer are overwhelmingly affected by the type of therapy
delivered by the consultants[2] (Abstract
only at http://jama.ama-assn.org/issues/v283n24/abs/joc91742.html).
This finding has important implications for patients seeking advice on
managing their newly diagnosed prostate cancer.
In this study, investigators mailed questionnaires to radiation
oncologists (n = 559; 76% response rate) and urologists (n = 504; 64% response
rate). The radiation oncologists tended to be younger, were more likely
to be women, and were less likely to rely on fee-for-service as their source
of income. Clinicians were asked a variety of questions about their opinions
on the utility of prostate-specific antigen (PSA) screening and whether
local therapy afforded survival advantages. Not surprisingly, radiation
oncologists tended to believe more strongly that radiation therapies were
curative, and urologists tended to believe that surgery was more likely
to offer survival benefit.
The radiation oncologists and urologists tended to agree on the
likely adverse effects of such procedures as prostatectomy, external beam
radiation, and brachytherapy. They also tended to agree that radiation
and surgery afforded survival advantage and shared attitudes on which patients
they would recommend for either watchful waiting or androgen ablation as
primary therapy. However, the different specialists disagreed substantially
on the value of their respective procedures. Physicians were asked "For
patients with clinically localized prostate cancer...how do you think treatment
1 and treatment 2 compare in terms of survival benefit they offer?" The
results are summarized in the Table.
| Scenario |
Radiation Oncologists, % |
Urologists, % |
Radical Prostatectomy Vs External Beam Radiation
(Estimated Life Expectancy < 10 Years) |
| X-ray therapy (XRT) better |
10 |
9 |
| Prostatectomy better |
2 |
17 |
| Both the same |
68 |
40 |
| Neither has survival benefit |
19 |
32 |
Radical Prostatectomy Vs External Beam Radiation
(Estimated Life Expectancy >10 Years) |
| XRT better |
3 |
0 |
| Prostatectomy better |
20 |
93 |
| Both the same |
72 |
6 |
| Neither has survival benefit |
3 |
0 |
The differences of opinion were significant (P < .001). Radiation
oncologists were more likely to believe in the equivalence of radiation
and surgery and were more skeptical that surgery alone could be beneficial.
Urologists strongly favored surgery, particularly for patients with greater
life expectancy and were less likely to believe that radiation therapy
was an equivalent option.
As noted in the accompanying editorial,[3]
there is no "right or wrong" answer here; the data are considered insufficient
by many clinical experts to recommend one treatment or another. Nonetheless,
these attitudes are likely to have dramatic effect on clinical recommendations
from specialists. For a patient weighing treatment choices for localized
prostate cancer, the optimal care would seem to include consultation with
both a urologist and a radiation oncologist. Without input from both types
of specialists, the available choices for patients may not be fully displayed.
References
-
Moore MJ, O'Sullivan BO, Tannock IF. How expert physicians would wish to
be treated if they had genitourinary cancer. J Clin Oncol. 1988;6:1736-1745.
-
Fowler FJ, Collings MM, Albertsen PC, et al. Comparison of recommendations
by urologists and radiation oncologists for treatment of clinically localized
prostate cancer. JAMA. 2000;283;3217-3222.
-
Wilt TJ. Uncertainty in prostate cancer care. JAMA. 2000;283;3258-3260.
Can Warfarin Prevent Cancer?
Patients who develop venous thromboembolism may be at greater risk for
subsequent diagnosis of cancer in the first year after their blood clot.[1,2]
There have been suggestions during the years that anticoagulants may have
antineoplastic properties; however, retrospective analyses among patients
taking anticoagulants for heart disease have not suggested a reduction
in the incidence of cancer through anticoagulation. To clarify the risk
of cancer following thromboembolic events and the role of anticoagulation
in reducing cancer risk, investigators conducted a review of a prospective,
randomized trial for management of deep venous thromboembolism (DVT). The
results are likely to reenergize the debate on the possible role of anticoagulation
in reducing cancer risk[3] (Abstract only
at: http://www.nejm.org/content/2000/0342/0026/1953.asp).
The study began as a randomized trial to evaluate the optimal duration
of therapy with either warfarin following a DVT in the leg or symptomatic
pulmonary embolism (PE). Between 1988 and 1991, 902 patients with DVT/PE
were randomized to receive either 6 weeks or 6 months of oral anticoagulation
with warfarin. Subsequently, patients enrolled in the study were followed
up for diagnosis of cancer, using records from the medical institutions
and from the Swedish Cancer Registry.
In the years following their episode of DVT/PE, 13% of study participants
were diagnosed with cancer (mean follow-up, 8.1 years). The likelihood
was greatest in the first year after DVT/PE but remained higher than the
standardized risk for population controls throughout the duration of follow-up.
The risk of cancer diagnosis was compared among the patients treated with
either 6 weeks or 6 months of warfarin. At 6 years, the actuarial risk
of cancer diagnosis was 9% among patients anticoagulated for 6 months vs
nearly 16% for those who received 6 weeks of anticoagulation. The investigators
examined the type of cancers encountered by those who received either 6
weeks or 6 months of anticoagulation. The only difference was in the risk
of urogenital cancers (this category included kidney, bladder, prostate,
ovary, and uterine cancers, but the difference was essentially limited
to prostate cancer). By contrast, there was no difference in the risk of
respiratory tract, gastrointestinal tract, hematologic, or skin cancers.
When the analyses were limited to cancers diagnosed at least 2 years after
the incident of DVT/PE episode, the differences were even more pronounced.
These are provocative results, suggesting that sustained anticoagulation
may reduce the risk of urogenital cancers, particularly prostate cancer.
This finding may increase the number of future trials specifically designed
to evaluate the possible role of anticoagulation in preventing cancer.
The mechanisms that might contribute to such reduced risk are not clearly
known. Angiogenic factors are 1 possibility, although other mediators of
inflammation may also affect cancer incidence. It is notable that this
study did not include data on the use of aspirin or other medications that
might also affect cancer risk.
References
-
Baron JA, Gridley G, Weiderpass E, et al. Venous thromboembolism and cancer.
Lancet. 1998;351:1077-1088.
-
Sorenson HT, Mellemkjaer L, Steffensen FH, et al. The risk of a diagnosis
of cancer after primary deep venous thrombosis or pulmonary embolism. N
Engl J Med. 1998;338:1169-1173.
-
Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin
against recurrent venous thromboembolism. N Engl J Med. 2000;342:1953-1958.
COX-2 Inhibitors Prevent Colon Polyps
Epidemiological studies suggest that nonsteroidal anti-inflammatory drugs
(NSAIDs) reduce the incidence of colorectal cancers, and randomized trials
have shown that sulindac can reduce the size of polyps in patients with
familial adenomatous polyposis (FAP). NSAIDs work by inhibiting the enzyme
cyclooxygenase, which includes several isoforms. The next generations of
NSAIDs are selective for cyclooxygenase-2 (COX-2), the isoform that may
be most intimately associated with mediating inflammation and neoplasia.
A randomized trial has now evaluated the COX-2 inhibitor celecoxib as an
agent for reducing the incidence of colon polyps in FAP[1]
(Abstract only at: http://www.nejm.org/content/2000/0342/0026/1946.asp).
G. D. Searle, the manufacturer of celecoxib, provided the study medication
and support for the study, and several study authors serve as consultants
for the company.
Patients with FAP were followed up at M. D. Anderson Cancer Center
or St. Marks Hospital, London, England. Between 1996 and 1998, eligible
patients were evaluated with colonoscopy. Of the 108 patients screened,
29 had too few polyps for inclusion in the study and 2 required colectomy.
A total of 75 patients, who were randomized to receive either placebo,
or celecoxib at 1 of 2 doses (100 mg twice daily or 400 mg twice daily)
remained; 2 additional patients were added after 2 previous patients withdrew
from the study on account of noncompliance. The endpoint of the study was
regression in the number of colon polyps at 6 months. Patients received
baseline colonoscopy and were screened again with endoscopy after 6 months
of study medication. A predefined area of the colon was surveyed for polyp
counts. Videos of the endoscopy were also scored for polyp status. Endoscopists
were blinded to the patient's treatment group.
The use of celecoxib at 400 mg twice daily reduced the colorectal
polyp burden in the FAP patients (see Table).
Changes in Polyp Burden
| Treatment |
Patients, No. |
% Change in No. of Colorectal Polyps |
% Change in No. of Rectal Polyps |
| Placebo |
15 |
-4.5 |
+3.1 |
| Celecoxib, 100 mg twice daily |
32 |
-11.9 (P = .33) |
-3.4 (P = .52) |
| Celecoxib, 400 mg twice daily |
30 |
-28.0 (P = .003) |
-22.5 (P = .01) |
In addition to reducing the number of polyps, the higher dose of celecoxib
also reduced the measurement of cumulative diameter of polyps. A reduction
in the number of polyps was seen in the rectum, as well as the ascending
colon/cecum and the transverse/descending/sigmoid colon. Celecoxib seemed
to be well-tolerated, with no difference in the incidence of gastrointestinal
symptoms between patients taking celecoxib and placebo.
This trial demonstrates that the COX-2 selective inhibitor, celecoxib,
can reduce the number of adenomatous polyps in patients with FAP. The trial
was too small to answer whether such drugs reduce the incidence of colon
cancer among FAP patients, and the trial did not attempt to ask questions
about survival or survival without colectomy for these individuals. There
is a growing body of literature on chemoprevention for colon cancer.[2]
Randomized trials have shown that sulindac and celecoxib reduce polyps
in patients at high risk on account of genetic mutations. In the general
population, randomized trials have shown that aspirin and calcium can reduce
the incidence of colon cancer and adenomas, respectively. Population studies
suggest that folate and estrogens may also reduce the risk of colon cancer.
It remains to be seen how useful celecoxib and like drugs are
at preventing cancers, in reducing the risk of polyps, and in improving
survival for the general public. However, there are a growing number of
agents that may dramatically alter the future incidence of colon and rectal
cancer.
References
-
Steinbach G, Lynch PM, Phillips RKS, et al. The effect of celecoxib, a
cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl
J Med. 2000;342;1946-1952.
-
Janne PA, Mayer RJ. Chemoprevention of colorectal cancer. N Engl J Med.
2000;342:1960-1968.
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