CANCER D I A G N O S I S A N D M A N A G E M E N T M A U R I E M A R K M A N , M D , ED ITOR

M A U R I E M A R K M A N , MD Chairman of the Department of Hematology/Medical Oncology at the Cleveland Clinic, head of the Cleveland Clinic Cancer Center, and an associate editor of the Cleveland Clinic Journal of Medicine.

Assessing and minimizing reproductive risks of cancer chemotherapy

An important

concern about

chemotherapy

in young

patients is the

risk of sterility

or birth defects

O W T H A T M O R E A N D M O R E C H I L D R E N

and young adults are surviving malig-nant diseases such as acute leukemia, osteogenic sarcoma, Hodgkin's disease, non-Hodgkin's lymphomas, and germ cell tumors, a new problem is arising: the often-intensive chemotherapy necessary to cure the disease can also affect the patients' ability to have children, and sometimes causes birth defects in the children the patients do have.

• EFFECTS OF CHEMOTHERAPY ON MALE GONADAL FUNCTION

Most male patients who receive alkylating agents such as nitrogen mustard or cyclophos-phamide develop testicular atrophy and azoospermia, even when these drugs are used alone, but spermatogenesis commonly returns several years after therapy is completed if only one alkylating agent was used. For example, in one series of 26 men who developed azoosper-mia after receiving cyclophosphamide, normal sperm production eventually returned in 12 (46%).

With combination chemotherapy regi-mens, it is hard to predict the effect on reproductive function of any of the individ-ual drugs used. However, knowing the potential effects of the individual drugs used in treating Hodgkin's disease, researchers predicted that one commonly used regimen, ABVD (doxorubicin, bleomycin, vinblas-tine, dacarbazine), should cause less gonadal dysfunction than another standard regimen,

MOPP (nitrogen mustard, vincristine, pro-carbazine, prednisone). Subsequent clinical data confirmed this hypothesis. In fact, there is relatively strong evidence that the gonadal damage that the MOPP regimen causes is frequently irreversible. The less-toxic effect of the ABVD regimen is one of several fac-tors that should be considered when select-ing a chemotherapy regimen in Hodgkin's disease.

Similar data are available in male germ cell tumors, in which one common regimen (cisplatin, etoposide, bleomycin) produces a high incidence of azoospermia. However, most men treated with this regimen gradual-ly recover gonadal function over several years.

Of interest and clinical relevance, the testes appear to be more resistant to cytotox-ic chemotherapy before puberty than after-ward. Although the intensive chemotherapy often given for diseases such as acute leukemia that occur in prepubescent males can damage the testes, most boys appear to develop normally and few require hormone replacement therapy.

• EFFECT OF CHEMOTHERAPY ON FEMALE GONADAL FUNCTION

Like the testes, the ovaries are particularly sensitive to alkylating agents, and are more resistant before puberty than afterward.

Combination chemotherapy regimens cause a high rate of amenorrhea, which in

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Decreased

spermato-

genesis and

amenorrhea

are common

but frequently

reversible,

particularly in

adolescents

C H E M O T H E R A P Y A N D R E P R O D U C T I V E F U N C T I O N M A R K M A N

younger patients appears to be temporary. However, for women older than 25 years, the incidence of permanent amenorrhea and premature menopause (with symptoms of hot flashes and vaginal dryness) is consider-ably higher. In contrast, prepubertal girls appear to be protected from the effects of cytotoxic chemotherapy (as observed with boys).

• TERATOGENIC POTENTIAL OF CHEMOTHERAPY

Experiments in animals and experience in humans have demonstrated that certain chemotherapeutic agents can cause defects in the fetus. Unfortunately, experiments in ani-mals do not always predict the risk of terato-genesis in humans, because animals and humans are different in their susceptibility to the various toxic effects of cancer chemother-apeutic agents.

The risks to the fetus include: • Spontaneous abortions. • Severe developmental abnormalities. • Premature birth. • Damage to the cells of the developing

liver, lungs, heart, and kidneys. • Sterility. • Delayed physical and mental develop-

ment. • Mutagenic events leading to cancer

later in life. • Teratogenic events leading to malfor-

mations in a subsequent generation. Granted, most of these concerns are

entirely theoretical. However, even if a baby appears normal at birth, considerable time must pass before one can feel comfortable in stating that chemotherapy has not resulted in major clinical problems.

Drugs wi th teratogenic potential Alkylating agents (eg, busulfan, chlo-

rambucil, cyclophosphamide) produce a high rate of gonadal dysfunction, but are probably less teratogenic than the folic acid antago-nists.

Other drugs known for their teratogenic potential include other antimetabolites (eg, cytarabine, 5-fluorouracil), vinblastine, and procarbazine.

Recommendations In general, cytotoxic chemotherapy should be avoided if possible during the first trimester of pregnancy, when the developing fetus is most vulnerable. Particularly to be avoided during this time are folic acid antagonists such as methotrexate. During the second and third trimesters the risk of a major developmental abnormality is significantly less.

m OPTIMIZING THE CHANCES FOR CHILDBEARING

Sperm cryopreservation is a very reason-able strategy for male patients who will be undergoing chemotherapy. Unfortunately, many cancer patients have low sperm counts or poor sperm motility, making their sperm inadequate for cryopreservation.

The likely reason for the poor sperm qual-ity is that any chronic illness tends to suppress spermatogenesis. Another explanation is that the cancer itself either directly or indirectly inhibits spermatogenesis. For men with poor sperm motility, a reasonable option is in vitro fertilization.

Oral contraceptives have been given to young women during chemotherapy in an effort to prevent gonadal failure by suppressing ovarian function, making the ovaries less sus-ceptible to the effects of the cytotoxic agents. While this is an interesting and reasonable strategy, its effectiveness has not been clearly established.

Gonadotropin-releasing hormones also suppress ovarian function, and might there-fore be used to protect the ovaries during chemotherapy. In experiments in animals, these agents prevented ovarian failure dur-ing treatment with alkylating agents. As with oral contraceptives, the clinical utility of this approach remains to be critically defined.

Embryo cryopreservation and ovarian cryopreservation may be considered in care-fully selected patients scheduled to receive cytotoxic chemotherapy. Again, in this clini-cal setting, the effectiveness of these interven-tions is uncertain.

Counseling is critically important for patients and their families. Topics that should be discussed include:

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• The relative risks of infertility associat-ed with treatment of the cancer.

• Options for alternative therapeutic strategies (eg, drugs with lower theoretical risk of causing sterility).

• Potential methods to preserve fertility. El

• SUGGESTED READING

A v e r e t t e HE, Boike G M , Jarrell M A . Effects of cancer chemotherapy on gonadal function and reproductive capacity. CA Cancer] Clin 1990; 40:199-209.

Doll DC, R i n g e n b e r g QS, Y a r b r o JW. Antineoplastic agents and pregnancy. Semin Oncol 1989; 16:337-346.

D r a s g a RE, E i n h o r n LH, W i l l i a m s SD, Patel SN, S t e v e n s EE. Fertility after chemotherapy for testicular cancer. ] Clin Oncol 1983; 1:179-183.

G a r b e r JE. Long-term follow-up of children exposed in utero to antineoplastic agents. Semin Oncol 1989; 16:437—444-

G r a d i s h a r W J , Sch i l sky RL. Ovarian function following radi-ation and chemotherapy for cancer. Semin Oncol 1989; 16:425-436.

H e i k e n s J, B e h r e n d t H, A d r i a a n s e R, B e r g h o u t A . Irreversible gonadal damage in male survivors of pediatric Hodgkin's disease. Cancer 1996; 78:2020-2024.

Meistr ich ML, C h a w l a SP, D a C u n h a MF, et al. Recovery of sperm production after chemotherapy for osteosarcoma. Cancer 1989;63:2115-2123.

Ort in TT, S h o s t a k C A , D o n a l d s o n SS. Gonadal status and reproductive function following treatment for Hodgkin's dis-ease in childhood: the Stanford experience. Int J Radiat Oncol Biol Phys 1990; 19:873-880.

R e d m a n JR, B a j o r u n a s DR, G o l d s t e i n MC, et al. Semen cryopreservation and artificial insemination for Hodgkin's dis-ease. J Clin Oncol 1987; 5:233-238.

R i v k e e s SA, C r a w f o r d JD. The relationship of gonadal activity and chemotherapy-induced gonadal damage. JAMA 1988; 259:2123-2125.

Sch i l sky RL, S h e r i n s RJ, H u b b a r d S M , W e s l e y MN, Y o u n g RC, D e V i t a VT. Long-term follow-up of ovarian func-tion in women treated with MOPP chemotherapy for Hodgkin's disease. Am J Med 1981; 71:552-556.

ADDRESS: Maurie Markman, MD, Department of Hematology/Medical Oncology, T40, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail markmam@cesmtp.ccf.org.

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