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It has been

reported after combination chemotherapy that involves topoisomerase inhibitors,

including etoposide and anthracyclines. These leukemias usually occur 1 to 3 years

after the completion of chemotherapy, and myelodysplasia does not usually occur

before the leukemia. Other characteristics include chromosomal abnormalities

involving chromosome 11q23.

265 This challenge is an important area for research

given the widespread use of these agents for many curable diseases such as Hodgkin

lymphoma, breast cancer, and testicular cancer.

Acute myeloid leukemia has also been reported in patients who have had previous

exposure to alkylating agents. It usually occurs 5 to 7 years after the patient finishes

chemotherapy. Myelodysplastic syndrome (preleukemia changes) commonly occurs

in 50% of patients before overt acute leukemia. Although all alkylating agents can

cause acute leukemia, melphalan appears to be the most potent leukemogenic agent in

this class; other classes of chemotherapy agents do not appear to carry as significant

a risk. Large doses, continuous daily dosing, prolonged treatment periods, age older

than 40 years, and concomitant radiation therapy may increase the risk of exhibiting

acute leukemia. Several additional factors may increase a patient’s risk of exhibiting

acute leukemia.

265

Evidence that cytotoxic agents can cause secondary lymphoid malignancies,

particularly non-Hodgkin lymphoma, is also strong. Immunosuppression from the

disease and its treatment rather than the particular agent may be the primary cause of

non-Hodgkin lymphoma. Other secondary malignancies can occur after anticancer

treatment as well. Solid tumors have been associated with superficial bladder cancer

in patients treated with daily oral cyclophosphamide, and bone sarcoma has occurred

after treatment with alkylating agents.

266,267 The secondary solid tumors in patients

treated with other cytotoxic agents are considered coincidental.

T.D.’s AML probably occurred secondary to her previous doxorubicin. The

chemotherapy agent, as well as the time course for her acute leukemia, is consistent

with topoisomerase-II agent-induced malignancies. The use of adjuvant AC has been

associated with an acute leukemia incidence of 0.2%. In addition, cytogenetic

abnormalities occur in more than 90% of those patients who have received

chemotherapy or radiation therapy and have subsequently experienced therapyrelated myelodysplastic syndrome or AML.

265 Abnormalities in chromosome 11q23

are involved in many of the cases with cytogenetic abnormalities from topoisomerase

inhibitors.

265 The chromosomal abnormalities of 11q23 in T.D. strongly support the

diagnosis of chemotherapy-associated acute leukemia rather than de novo leukemia.

CASE 94-12, QUESTION 2: Are the therapy and prognosis of T.D. with treatment-associated AML similar

to those of patients with de novo AML?

Therapy for patients with treatment-associated AML is much less effective than

that of patients with de novo leukemia. Complete remissions with standard cytarabine

and daunorubicin regimens are obtained in less than half of patients with treatment-

associated AMLcompared with a complete remission rate of 70% to 80% in patients

with de novo leukemia

265

(see Chapter 96, Adult Hematologic Malignancies).

The best “treatment” of therapy-associated AML is prevention. In patients such as

T.D. receiving adjuvant chemotherapy for a curable malignancy, avoiding the use of

agents that cause treatment-related AML should be discussed in conjunction with the

benefits of therapy. Use of alternative regimens is increasing as more is learned

about secondary leukemias.

Fertility and Teratogenicity

EFFECTS ON OOGENESIS

CASE 94-13

QUESTION 1: C.L., a 32-year-old woman with recently diagnosed stage II breast cancer, underwent a

lumpectomy and external beam radiation therapy and is scheduled to begin adjuvant chemotherapy with

doxorubicin and cyclophosphamide followed by paclitaxel (AC-T). C.L. was married 12 months before her

diagnosis and wishes to have children. What are C.L.’s prospects for fertility after adjuvant chemotherapy?

Cytotoxic chemotherapy is potentially gonadotoxic in humans. Ovarian biopsies

taken from women treated for cancer demonstrate loss of ova and follicular elements.

This injury is evident even in prepubertal female patients treated for cancer. Ova die

or become nonfunctional by direct injury to the ova or by indirect injury resulting

from loss of supporting follicular cells. If the damage to the follicular elements is

extensive and irreversible, fertility is impaired even if the ova are spared.

Agent-induced injury to ova and follicular elements reduces ovarian estrogen and

progesterone secretion in menstruating women. This causes the hypothalamus and

pituitary to secrete more follicle-stimulating hormone (FSH) and luteinizing hormone

(LH), which in turn increase follicular recruitment and the number of follicles

vulnerable to cytotoxic chemotherapy agents. If the gonadal toxicity is severe or

prolonged, permanent ovarian failure can occur secondary to depletion of ova and

follicles. Recovery of some of the affected follicles often occurs, however, and this

may be manifested by irregular menses or delayed recovery of menses. If the ova are

spared and follicular cells recover sufficiently, ovulation and pregnancy might occur,

but premature ovarian failure is inevitable in most women treated with large doses of

gonadotoxic agents given for long periods.

268

Prepubertal girls have a greater reserve of primary follicles. Because their ovaries

are not producing estrogen and progesterone, increases in FSH and LH with resultant

recruitment of

p. 1997

p. 1998

follicular elements do not occur. For this reason, prepubertal girls can tolerate

large doses without apparent effects even if the pathology previously described

occurs. The gonadal effects of cytotoxic chemotherapy in women and girls have been

described in several reviews.

268–270

C.L. is going to receive one of the alkylating agents, which are the most potent

gonadotoxic agents. Cyclophosphamide is well known for producing infertility in

men and women and gonadal failure even in children. The effect is influenced

strongly by the total dose of cyclophosphamide and the patient’s age at the onset of

chemotherapy. Nearly 100% of women older than 20 years of age experience

amenorrhea when the mean total dose is 20 to 50 g. The same consequence can be

expected in women older than 35 years of age who receive greater than 6 to 10 g and

in women 40 years of age and older who receive more than 5 g.

271 Depending on the

exact dose of cyclophosphamide in the AC-T regimen planned, C.L. may or may not

fall into a dose range that would be expected to produce permanent amenorrhea.

The clinician also must consider that a synergistic gonadotoxic effect has been

reported when doxorubicin is combined with cyclophosphamide. Aside from the

alkylating agents, the only agents with strong evidence of gonadal toxicity include

vinblastine, etoposide, and cisplatin. Several resources discuss the doses of

chemotherapy agents, used both alone and in combination, and specific incidences of

associated gonadotoxicity, as well as the prevalence of temporary and permanent

amenorrhea.

269,271,272

C.L. most likely will experience amenorrhea along with the signs and symptoms of

menopause as both estrogen and progesterone production diminishes during cytotoxic

chemotherapy. C.L. may recover from chemotherapy-induced amenorrhea months to

years after completion of her therapy. Recovery may be manifested as amenorrhea

interspersed with normal menstrual periods.

Pregnancy is possible during periods of normal menstruation because ovulation

does occur in most instances. Premature menopause is inevitable, however. Because

the greatest risk of pregnancy exists early in the course of therapy, C.L. should be

counseled to practice birth control while receiving cytotoxic chemotherapy. Because

oral contraceptives are contraindicated in patients with breast cancer, barrier

methods (i.e., diaphragm, condoms, spermicide) should be advised.

EFFECTS ON SPERMATOGENESIS

CASE 94-14

QUESTION 1: J.K., a 25-year-old man with recently diagnosed testicular cancer, will receive systemic

chemotherapy with bleomycin, etoposide, and cisplatin. What effect does systemic chemotherapy have on male

gonadal function?

The primary gonadal toxic effect of cytotoxic chemotherapy agents in male patients

is a progressive dose-related depletion of the germinal epithelium lining the

seminiferous tubule. The clinical manifestations of germinal depletion include a

marked reduction in testicular volume and azoospermia. The Leydig cells

responsible for testosterone production remain morphologically intact, although mild

functional impairment occurs rarely. The major toxicity of chemotherapy in men is

loss of reproductive capacity. During treatment, libido and sexual activity may

decline, but most men report a return to pretreatment sexual function after

chemotherapy.

273

Of the cytotoxic chemotherapy agents, alkylating agents are associated most

commonly with azoospermia. Progressive dose-related oligospermia occurs in men

receiving chlorambucil,

274,275 cyclophosphamide,

276,277 melphalan, busulfan,

procarbazine, and nitrosoureas; procarbazine appears to be the most gonadotoxic

alkylating agent in men. Doxorubicin, vinblastine, cytarabine, and cisplatin also have

been associated with azoospermia,

278 and doxorubicin appears to have a synergistic

toxic effect in men when given with cyclophosphamide similar to that previously

described in women. Phase-specific agents, such as antimetabolites and vinca

alkaloids, seem unlikely to produce azoospermia when used alone, but may play a

minor role in combination chemotherapy regimens.

279

In contrast to oogenesis, in which women are born with a full complement of ova,

spermatogenesis occurs in a continuous cycle of regeneration, differentiation, and

maturation beginning in the second month of embryogenesis and continuing through

old age. Although different cytotoxic chemotherapy agents appear to exert more

damage to germ cells in specific phases of spermatogenesis in animal models, in

humans, gonadotoxic agents generally are used in sufficiently large doses to affect

varying proportions of maturing sperm cells in any stage of development. This has

two realistic implications. The first is that because spermatogenesis must start at the

beginning after agent-induced azoospermia occurs, the length of recovery is

prolonged, usually lasting at least 2 to 3 years. The second is that the relationship of

age to the development of azoospermia is far less clear than the relationship of age to

ovarian suppression. Although conventional wisdom holds that prepubertal boys are

less likely to be affected by chemotherapy agents than adult men, the reserve of

primitive sperm cells in male children is far less than it is in adults. Therefore, the

spermatogenesis potential in prepubertal testes may make them more vulnerable to

cytotoxic damage than those of adults. A review of the literature regarding the effects

of cytotoxic chemotherapy administered to male children concluded that agents and

regimens known to be toxic in men should be considered toxic in young boys.

272,273

Short of a testicular biopsy, the damage cannot be detected until puberty.

The two diseases most likely to affect young men who are concerned with their

fertility are Hodgkin lymphoma and testicular cancer. The standard treatment for

advanced Hodgkin disease is ABVD. Azoospermia has been observed in 35% of

patients receiving ABVD and spermatogenesis nearly always recovered in these

patients.

278 A similar scenario exists in patients about to start on chemotherapy for

testicular cancer. Evidence to date suggests that therapy-induced azoospermia that

follows treatment with vinblastine, bleomycin, and cisplatin for nonseminomatous

testicular carcinoma is reversible within 2 to 3 years in approximately 50% of

patients treated and that those who recover spermatogenesis are capable of

impregnating their partners.

280,281

In this particular patient population, it is important

to recognize that retroperitoneal lymph node dissection, which results in retrograde

ejaculation, as well as cryptorchidism, which predisposes to infertility, may

contribute to the lack of full recovery of fertility potential.

CASE 94-14, QUESTION 2: Aside from the use of anticancer therapy agents with less gonadal toxicity, are

there means of circumventing infertility in young patients such as J.K. receiving therapy?

Sperm or gamete cryopreservation should be considered in males. A major

limitation of this approach has been the finding of diminished sperm counts, sperm

volume, and sperm motility in young men affected with Hodgkin lymphoma and

testicular cancer even before combination chemotherapy is initiated. Although

published studies suggest that the quantity and motility of sperm are important

determinants of successful artificial insemination, pregnancies have been reported.

Thus, sperm banking should be considered even in oligospermic men.

273,279 Oocyte

cryopreservation and embryo cryopreservation now are feasible options for young

women about to undergo cytotoxic chemotherapy. Even in the

p. 1998

p. 1999

face of cytotoxic chemotherapy-induced ovarian failure, in vitro fertilization of an

ovum and implantation into the endometrium with proper hormonal support can

successfully accommodate a term pregnancy. This may be an option for females.

270,282

In both sexes, it has been hypothesized that gonadal toxicity from cytotoxic

chemotherapy could be decreased by inhibiting spermatogenesis or follicular

development during therapy. Methods used to suppress gonadal function have

included administration of testosterone in men, oral contraceptives in women, and

gonadotropin-releasing hormone analogs in both men and women. Several reviews

describe these approaches in detail,

269,270,273 and ASCO provides recommendations

on preserving fertility in cancer patients.

282

TERATOGENICITY

CASE 94-14, QUESTION 3: If J.K. regains fertility after his planned combination chemotherapy regimens, is

he at risk for producing offspring with congenital abnormalities or an excess risk of cancer?

Most of the agents used to treat cancer are designed specifically to interfere with

DNA synthesis, cellular metabolism, and cell division. Thus, reason exists to suspect

that they may cause mutation of ova or spermatocytes exposed to these effects. The

actual outcomes of pregnancies in survivors of cancer are published as case reports,

small series, and retrospective case series. Nearly 1,600 children have been born to

1,078 patients previously treated for malignancy in childhood or as adults. A review

of the published information suggests no evidence that spontaneous abortion, genetic

disease, or congenital anomalies occur more frequently in the progeny of cancer

survivors. Similarly, there does not appear to be an increased risk of malignancy in

the offspring of patients treated for cancer.

272 The likely explanation for this is that

ova and sperm cells affected by cytotoxic chemotherapy usually are killed. The risk

of producing an abnormal offspring thus would be highest at the time of

chemotherapy. Men and women should be explicitly discouraged from conception

during chemotherapy. In general, adults surviving cancer should be advised to wait at

least 2 years after completion of therapy before attempting to parent a child; this

theoretically allows time for elimination of damaged germ cells. This also provides

time to assess the likelihood of the necessity for further treatment that would have

grave consequences on the fetus, particularly in the case of female patients.

KEY REFERENCES AND WEBSITES

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