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Letters to the Editor

Stable Coronary Artery Disease

TO THE EDITOR: Drs. Gutstein and Fuster¹ review the management of stable coronary artery disease by detailing the considerations behind the revascularization options of coronary artery bypass grafting and angioplasty. Modest attention is given to medical therapy, suggesting that these procedures have become standard and often preferred therapy for stable coronary artery disease.

In his accompanying editorial,² Dr. Grauer discusses the family physician's role in stable coronary artery disease; he emphasizes proper diagnosis and referral and assisting the patient in deciding about revascularization options. Dr. Grauer also mentions medical therapy and encourages family physicians to promote smoking cessation, estrogen replacement therapy and regular physical activity. Vitamin E and folic acid are mentioned as "controversial measures." A "healthy diet" is mentioned in the patient information handout that accompanies the article.

Something is seriously missing here. Ornish and colleagues³ demonstrated in the 1980s that coronary artery disease can be reversed with a low-fat diet and stress reduction. Dramatic results, such as the elimination of symptoms, can be achieved in 30 days. While Ornish's approach has been considered impractical by many, his books have become bestsellers, and the belief that individuals with coronary artery disease should follow a very-low­fat diet has become more widely accepted.^4,5

Family physicians should routinely offer a very-low­fat diet and stress reduction as alternate approaches to the management of coronary artery disease, especially stable disease. We are in an ideal position to educate and support the patient in making lifestyle changes. As Ornish states, "... it's actually easier to make big changes than small ones."⁵ This is especially true when one's life is on the line. With this approach, the potential benefits include not only reversing coronary disease, but also normalizing cholesterol, weight and blood pressure, all of which help our patients to achieve excellent health.

JOSEPH E. SCHERGER, M.D., M.P.H.
Department of Family Medicine
University of California, Irvine
Orange, CA 92868

REFERENCES

1. Gutstein DE, Fuster V. Management of stable coronary artery disease. Am Fam Physician 1997;56:99-106.
2. Grauer K. Stable coronary artery disease: the family physician's approach [Editorial]. Am Fam Physician 1997;56:31-7.
3. Ornish D, Scherwitz LW, Doody RS, Kesten D, McLanahan SM, Brown SE, et al. Effects of stress management training and dietary changes in treating ischemic heart disease. JAMA 1983;249: 54-9.
4. Ornish D. Stress, diet, and your heart. New York: New American Library (Signet), 1983.
5. Ornish D. Dr. Dean Ornish's program for reversing heart disease: the only system scientifically proven to reverse heart disease without drugs or surgery. New York: Ballantine Books, 1990:303.

IN REPLY: Dr. Scherger's point regarding aggressive dietary therapy for patients with coronary artery disease is well taken. Indeed, all patients with atherosclerosis should be educated and encouraged in all aspects of risk factor modification. This represents a mainstay of the physician's approach to coronary disease, not an "alternate" approach. We did not intend to de-emphasize dietary therapy in the treatment of coronary disease. Rather, as it states in the introduction, our review is intended as a guide to help the physician decide when to consider revascularization rather than medical therapy alone, and to identify the procedure that is most appropriate to prolong survival.

VALENTIN FUSTER, M.D., PH. D.
DAVID E. GUTSTEIN, M.D.
Cardiovascular Institute
Mount Sinai Medical Center
One Gustave L. Levy Pl.
New York, NY 10029-6574

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Primary Mediastinal Germ Cell Tumor in HIV Infection

TO THE EDITOR We describe here a case of mediastinal germ cell tumor in a patient with human immunodeficiency virus (HIV) infection. A 30-year-old man presented with a three-day history of dyspnea, cough and fever. He had had pneumonia six months prior. He used cocaine, tobacco and, occasionally, alcohol. Physical examination revealed the following findings: mild dyspnea; pulse, 110 per minute; blood pressure, 120/70 mm Hg; temperature, 38.3°C (101°F); respiration 20 per minute, with crepitations at the lung bases. The remaining physical examination was unremarkable.

Laboratory evaluation showed a total white blood cell count of 12,400 per mm³ (12.4 3 10⁹ per L), with 74 percent (0.74) neutrophils, 12 percent (0.12) bands, 9 percent (0.09) lymphocytes, 4 percent (0.04) monocytes and 1 percent (0.01) basophils. Lactate dehydrogenase was 472 U per L. Chest radiographs and computed tomography (CT) scan of the chest showed a large anterior mediastinal mass and bilateral interstitial infiltrates. CT scan of the abdomen and pelvis did not reveal lymphadenopathy or mass. A limited anterior thoracotomy showed a 10 to 15 cm soft and rubbery mass in the anterior mediastinum. Biopsy of the mass confirmed the diagnosis of malignant germ cell tumor (see figure) comprising a combination of seminomatous and nonseminomatous elements in the form of embryonal carcinoma and choriocarcinoma.

Further laboratory investigations revealed positive HIV₁ antibodies with an absolute CD4⁺ cell count of 110 cells per mm³ (200 3 10⁶ per L). Alpha-fetoprotein was normal (5.5 ng per mL [5.5 µg per L]) but the human chorionic gonadotropin (hCG) level was very high (90,100 mIU per mL [90,000 IU per L]). Ultrasonogram of both testicles was normal.

The patient was offered chemotherapy and radiotherapy but elected to receive therapy at an institution closer to his home.

FIGURE. Biopsy of mediastinal germ cell tumor, showing both seminomatous and nonseminomatous elements of embryonal carcinoma and choriocarcinoma.

Primary mediastinal germ cell tumors are rare and not often reported in patients infected with HIV.¹ Patients may remain asymptomatic or may present with cough, dyspnea and chest pain.² Histologically, germ cell tumors are classified as seminomas or nonseminomas. Nonseminomas are further subclassified as embryonal cell tumors, choriocarcinomas or teratomas. Seminomas are radiosensitive, while nonseminomas are radioresistant. Alpha-fetoprotein and hCG are useful tumor markers. Serum alpha-fetoprotein is elevated in 85 percent of patients with nonseminomatous tumors. Pure seminomas do not produce it. Generally speaking, alpha-fetoprotein is produced by embryonal cell carcinoma and hCG by choriocarcinoma. A high lactate dehydrogenase level is also considered an independent prognostic predictor.

Treatment consists of surgery, radiotherapy and cisplatin-based combination chemotherapy. Mediastinal nonseminomas carry a poor prognosis. Approximately 50 percent of patients survive after cisplatin-based chemotherapy followed by aggressive resection. Mediastinal seminomas, on the other hand, have a five-year disease-free survival rate of over 80 percent.³

MONJUR AHMED, M.D.
BIPINCHANDRA BHAGAT, M.D.
JOSEPH ANIGBOGU, M.D.
MICHAEL KHINE, M.D.
Catholic Medical Center of Brooklyn & Queens, Inc.
Jamaica, NY 11432

REFERENCES

1. Chaisson RE, Volberding PA. Clinical manifestations of HIV infection. In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases. 3d ed. New York: Churchill Livingstone, 1990:1085.
2. Montresor E, Nifosi F, Lupi A, Gorla A, Iacono C, Modena S, et al. Primary germinal tumors of the mediastinum: our experience in 9 cases [Italian]. Chir Ital 1994;46:46-52.
3. Goss PE, Schwertfeger L, Blackstein ME, Iscoe NA, Ginsberg RJ, Simpson WJ, et al. Extragonadal germ cell tumors. A 14-year Toronto experience. Cancer 1994;73:1971-9.

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Famciclovir and Valacyclovir

TO THE EDITOR: We are writing in response to the article by Dr. Stott about famciclovir (Famvir).¹ Several comparisons of famciclovir and acyclovir (Zovirax) were made; however, there was no mention of valacyclovir (Valtrex).

It is worth noting the following: both famciclovir and valacyclovir were available in 1995; both drugs are dosed less frequently than acyclovir; both drugs have better bioavailability than acyclovir; both are prodrugs, and both may have effects on postherpetic neuralgia.

In addition to omitting information about valacyclovir, the article included several comments that were incorrect or were not clinically relevant.

The author implies that the intracellular pharmacokinetics of famciclovir may be responsible for its reduced dosing frequency and its effects on postherpetic neuralgia (compared with placebo) in patients with herpes zoster. Although valacyclovir has quite different intracellular pharmacokinetics, it still demonstrates an effect on postherpetic neuralgia, not only when compared with placebo, but also when compared with acyclovir. Moreover, a trial comparing famciclovir with acyclovir² in otherwise healthy patients (one not mentioned in the article) showed no difference between famciclovir and acyclovir in terms of efficacy for postherpetic neuralgia despite the high intracellular concentrations of drug. If intracellular pharmacokinetics of antivirals were indeed clinically relevant, one would expect an improvement in efficacy; however, no additional clinical benefit seems apparent.

In addition, the author states that famciclovir has been compared with placebo in two clinical trials in immunocompromised patients with herpes zoster. To our knowledge, the trials to which the author refers were conducted in immunocompetent patients and formed the basis for the current use of famciclovir in immunocompetent patients.

LINDA J. DAWSON, PHARM. D.
DONNA K. MORGAN, M.D.
Medical Services Department
Glaxo Wellcome, Inc.
5 Moore Dr.
Research Triangle Park, NC 27709

REFERENCE

1. Stott GA. Famciclovir: a new systemic antiviral agent for herpesvirus infections. Am Fam Physician 1997;55:2501-4.
2. Package insert. Famciclovir. Philadelphia: SmithKline Beecham, 1997.

EDITOR'S NOTE: This letter was sent to the author of "Famciclovir: A New Systemic Antiviral Agent for Herpesvirus Infections," who declined to reply.

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Benefits of Screening for Colorectal Cancer

TO THE EDITOR: In their editorial, Drs. Woolf and Ganiats¹ state that there is "compelling evidence" and consensus among professional groups that all persons 50 years of age and older should be offered colorectal cancer screening. They also state that "a failure to offer such testing to our patients is to deny them a preventive measure of proven benefit." I must respectfully disagree that the evidence is compelling. I also submit that the benefit is uncertain.

In each of the three randomized controlled trials of colorectal cancer screening,^2-4 colorectal cancer mortality rates were reduced only modestly. The absolute reduction in risk of colorectal cancer death ranged from 0.10 per 1,000 person-years (95 percent confidence interval 0.18 to 0.01) in the Hardcastle study, to 0.22 per 1,000 person-years in the annually screened group in the Mandel study (95 percent confidence interval 0.34 to 0.09). The number needed to screen for eight to 13 years to prevent one colorectal cancer death would be near 700. The upper band of the 95 percent confidence interval would be several thousand. Thus, the chance that an individual who is screened for colorectal cancer will be spared death from colorectal cancer is small--quite possibly less than one in 1,000.

All-Cause Mortality Rates: A Summary of Data from Three Randomized Trials of Colorectal Cancer Screening Screening Number of patients Number of deaths Deaths per 1,000 patients Screened Unscreened 137,377 121,348 25,609 22,158 186.41 182.60 Information taken from references 2,3 and 4.

I also believe that the benefit from colorectal cancer screening is uncertain. In none of the randomized trials of colorectal cancer screening has all-cause mortality been reduced. Welch and Black⁵ have reviewed the importance of considering all-cause mortality when evaluating randomized trials of screening. "To consider whether a reduction in disease-specific mortality is somehow offset by an increase in mortality from other causes, all-cause mortality must be examined."⁵ To that end, I have combined the total deaths from the three randomized trials (see table).

If the biennially-screened group from the Mandel study is excluded, the all-cause mortality rate in the screened subjects still does not differ significantly from that in the unscreened subjects (182.39 deaths per 1,000 subjects). The evidence indicates that colorectal cancer screening using fecal occult blood testing fails to reduce all-cause mortality. In fact, since colorectal cancer mortality is reduced, it would appear that colorectal cancer screening increases non-colorectal cancer mortality slightly--countering the small benefit of reduced colorectal cancer mortality. Hence, it has not been proven that colorectal cancer screening is truly beneficial. Indeed, Mulcahy and colleagues⁶ have concluded that there are insufficient data to advocate a colorectal cancer screening program.

I believe that our patients will best be served if we use caution in offering colorectal cancer screening. I suggest that physicians discuss the limited benefit of colorectal cancer screening with their patients, and let them decide if the minimal reduction of risk of colorectal cancer death--and no proven reduction in risk of death itself--is worth the effort, cost and risk of harm from false-positive tests. I recommend informed consent before proceeding with screening.

BRIAN BUDENHOLZER, M.D.
Group Health Northwest
P.O. Box 204
Spokane, WA 99210-0204

REFERENCES

1. Woolf SH, Ganiats TG. Judging the guidelines for colorectal cancer screening [Editorial]. Am Fam Physician 1997;55:2595-600.
2. Hardcastle JD, Chamberlain JO, Robinson MH, Moss SM, Amar SS, Balfour TW, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996;348:1472-7.
3. Kronborg O, Fenger C, Olsen J, Jorgensen OD, Sondergaard O. Randomised study of screening for colorectal cancer with faecal-occult-blood test. Lancet 1996;348:1467-71.
4. Mandel JS, Bond JH, Church TR, Snover DC, Bradley GM, Schuman LM, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993;328:1365-71 [Published erratum appears in N Engl J Med 1993;329:672].
5. Welch HG, Black WC. Evaluating randomized trials of screening. J Gen Intern Med 1997;12:118-24.
6. Mulcahy HE, Farthing MJ, O'Donoghue DP. Screening for asymptomatic colorectal cancer. BMJ 1997;314:285-91 [Published erratum appears in BMJ 1997;314:497].

IN REPLY: We agree with Dr. Budenholzer that the probability of benefiting from colorectal cancer screening is relatively small. We are puzzled, however, by his opposition to our statements that everyone 50 years of age and older should be offered colorectal cancer screening and that failure to offer such testing is to deny our patients a preventive measure of proven benefit. Not offering screening and the accompanying information denies patients the opportunity to decide whether the tradeoff is worthwhile.

We do not overstate the evidence (from three large clinical trials) to say that fecal occult blood testing, likely the least effective of the available screening tests,¹ is of proven benefit in reducing colorectal cancer mortality. The absolute risk reduction from fecal occult blood testing is relatively small, but this is because the baseline probability of dying from the disease is low. The chance that a healthy person will eventually die of a specific type of cancer is relatively small. For this reason, although annual fecal occult blood testing lowers the relative risk of dying from colorectal cancer screening by 30 percent, the absolute risk reduction is much smaller.

The same is true for the prevention of most chronic diseases. Those who advocate mammography screening for women aged 40 to 49 do so despite evidence that the probability of preventing a death from breast cancer in 10 years is only about one in 1,500 to 2,500. Other common screening tests (e.g., cholesterol, phenylketonuria, Papanicolaou smears) provide a chance of benefit that is even smaller than that calculated by Dr. Budenholzer for colorectal screening (one in 700 to 1,000).

Dr. Budenholzer also worries that colorectal cancer screening has not been shown to lower all-cause mortality. The same concern has been raised about other preventive measures, such as lowering high blood cholesterol. Are we simply replacing one cause of death with another? We must remember, however, that the trials cited by Dr. Budenholzer were not designed to answer this question. It took over a decade and the participation of over 100,000 patients to amass current evidence that screening lowers colorectal cancer mortality. Detecting an effect on overall mortality would require a much larger sample size and a longer follow-up period. Whether devoting scarce research dollars to the investigation of this hypothesis and not others (e.g., whether prostate-specific antigen screening lowers prostate cancer mortality) represents good public policy is debatable. In the meantime, however, it violates the rules of scientific inference to assert from existing data that screening does not lower overall mortality, or, even worse, to suggest that screening causes non-colorectal cancer deaths.

Whether the modest benefit from mammography or colorectal cancer screening is worth the risk, discomfort and cost is a matter of personal preference. We continue to urge the patient's participation in this judgment.

STEVEN H. WOOLF, M.D., M.P.H.
Medical College of Virginia

THEODORE G. GANIATS, M.D.
Division of Family Medicine
University of California-San Diego School of Medicine
9500 Gilman Dr.
La Jolla, CA 92093-0807

REFERENCE

1. Winawer SJ, Fletcher RH, Miller L, Godlee F, Stolar MH, Mulrow CD, et al. Colorectal cancer screening and surveillance: clinical guidelines, evidence and rationale. Gastroenterology 1997;112:594-642.

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SSRIs and St. John's Wort: Possible Toxicity?

TO THE EDITOR: I would like to report a case of a complication that occurred when an herb was taken along with the standard medication it was supposed to replace.

The patient is a 50-year-old woman with asthma and chronic depression. She does not drink alcohol and was not using any tranquilizers. On the day before her symptoms started, she had a regularly scheduled office visit. She had no complaints, and her physical and mental examinations were normal. She reported that 10 days prior she had stopped taking paroxetine (Paxil) 40 mg per day, which she had been taking for eight months, and had started St. John's wort in powdered form, in a dosage of 600 mg per day. She experienced no adverse effects from switching preparations. The night after seeing me she slept poorly, feeling tired but not sad or depressed. Thinking it would help her return to sleep, she took 20 mg of paroxetine. At about noon her sister visited and found her to be arousable but incoherent, groggy, slow-moving and almost unable to get out of bed.

When I saw her at 2 p.m. she was groggy and lethargic but able to respond appropriately. She complained of nausea, weakness and fatigue but denied feeling sad or depressed. Her vital signs and physical examination were normal, except for slow response time and limp muscle tone. Her Mini Mental Status Examination was normal. Her chemistry panel and complete blood count were unremarkable. She was sent home, and reported the next day that she had slept all night. She was more spontaneously verbal and physically active. Her vital signs, physical, neurologic and mental examinations were normal. When seen the following day she was cheerful, alert and back to her baseline status.

St. John's wort (Hypericum perforatum) is an herbal remedy long used to treat melancholy. It has been widely used in Europe and is becoming more well-known in the United States, especially after a recent review of scientifically designed studies of its efficacy¹ and its' popularization in the book Hypericum and Depression.² St. John's wort is a monoaminoxidase inhibitor (MAOI).³ Concomitant administration of MAOIs and selective serotonin reuptake inhibitors (SSRIs) is generally contraindicated. Because additive effects may produce a "serotonin syndrome,"^4,5 i.e., sweating, tremor, flushing, confusion and agitation, people are often warned not to mix St. John's wort with other psychoactive pharmaceuticals. After taking St. John's wort and paroxetine together, this patient presented with a clinical syndrome resembling a sedative/hypnotic (e.g., benzodiazepine) intoxication. While the patient appears to have experienced no adverse effects on stopping the SSRI and immediately starting the herb, she experienced decided adverse effects when she took the SSRI after the herbal effect had reached a steady state. St. John's wort may have additional, as yet uncharacterized, neuropharmacologic actions.

Patients using St. John's wort should be advised to wait for a washout period of two weeks before restarting SSRI prescriptions. Physicians should be on the lookout for toxic interactions between prescribed psychoactive medications and herbal preparations (often covertly taken) which may have potent neuropharmaceutic effects.

JEOFFRY B. GORDON, M.D., M.P.H.
FPA Medical Group
Pacific Beach Family Care Center
4747 Mission Blvd., Ste. 7
San Diego, CA 92109

REFERENCES

1. Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D. St. John's wort for depression--an overview and meta-analysis of randomised clinical trials. BMJ 1996;313:253-8.
2. Bloomfield HH. Hypericum & depression: can depression be successfully treated with a safe, inexpensive, medically proven herb available without a prescription? Los Angeles: Prelude Press, 1996.
3. Bladt S, Wagner H. Inhibition of MAO by fractions and constituents of hypericum extract. J Geriatr Psychiatry Neurol 1994;(Suppl 1):S57-9.
4. Mills KC. Serotonin syndrome. Am Fam Physician 1995;52:1475-82.
5. Reynolds RD. Serotonin syndrome: what family physicians need to know [Editorial]. Am Fam Physician 1995;52:1263-71.

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Correction

The patient information handout "Preventing Overuse Injuries from Running" that accompanied the article "Common Overuse Running Injuries: Diagnosis and Management" (May 15, 1997) contained a printing error. Page two and page three of the handout were printed in reverse order.

The editors of AFP welcome input concerning topics of current medical interest and feedback in response to articles and other material published in AFP. Send letters to Jay Siwek, M.D., Editor, American Family Physician, 8880 Ward Pkwy., Kansas City, MO 64114; fax: 816-333-0303; e-mail: afplet@aafp.org. Please include your complete address, telephone number and fax number. Letters should be double-spaced, fewer than 500 words and limited to one table or figure and six references. Letters submitted for publication in AFP must not be submitted to any other publication. Letters pertaining to AFP subject matter must be received within two months of publication. Any financial associations or other possible conflicts of interest must be disclosed at time of submission. Submission of a letter constitutes transfer of copyright to the American Academy of Family Physicians. The editors reserve the right to edit correspondence to meet style and space requirements.

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