Eric E. Prommer
I. SEXUAL FUNCTION IN PATIENTS WITH CANCER
A. Background. Sexuality is a complex and subjective concept that changes over time as a person ages and gains experience. Sexuality as a concept can include body image (how someone sees oneself physically and perceives one’s overall health and sexuality), sexual response (interest, function, and satisfaction), sexual roles, and relationships. Sexuality is a personal expression of one’s self and one’s relationship with others.
The effects of cancer and its treatment on sexuality are not usually included in assessments and plans of care for patients, nor are they often addressed in patient education. The disease and its treatments may cause patients to doubt their humanness and their passion for living; at the same time, their body image and their ability to express themselves sexually may become altered. Consequently, closeness, sharing, and other aspects of sexual expression may be avoided or neglected at a time in life when these experiences can be most beneficial. Factors affecting sexual function in cancer patients include the following:
1. Psychological factors. In the early stages of cancer diagnosis and treatment, patients may confront feelings of depression, fear of death or of treatment consequences, apprehension of functional loss, deterioration of self-esteem, or impairment of a long-lasting emotional and sexual balance with their spouse. Both patient and spouse may experience difficulties in discussing sexual relationship issues, feeling that it is not appropriate when confronting cancer. Libido is adversely affected from the initial steps of diagnosis and treatment planning, and sexually oriented thoughts and desire, if they exist, may result in feelings of guilt and further suppression of sexuality. Patients may experience fears—often unrealistic—of potential harm to themselves or their partner during sexual activity, especially when cancer treatment is ongoing. Patients must be evaluated and treated for depression.
2. Body-image alterations. Body-image changes for men and women are related to perceived losses and influences. The term influences relates to the quality of relationships before the diagnosis of cancer and the amount of control and information the patient had at the time of diagnosis. For women, losses include missing body parts (mastectomy), loss of menses, loss of sexual sensation, and, ultimately, loss of womanhood. For men, body-image changes as a result of treatment include loss of ejaculatory function, incontinence, penile deformities, and skin changes.
3. Physical symptoms. Uncontrolled symptoms impair all aspects of sexual function, including sexual interest and sexual desire. Fatigue, gastrointestinal symptoms (nausea, diarrhea), urinary tract symptoms, sleep disorders, and pain can alter sexual function. Surgical treatment, chemotherapy, radiation therapy, combined-modality treatment, and biologic and hormonal therapies may all exacerbate physical symptoms.
4. Drug effects. Chronic opioid consumption to control pain in cancer patients has been demonstrated to induce hypogonadism in men and further exacerbate depression, fatigue, and sexual ill health. In men, hypogonadism is also due to androgen-deprivation therapies or bilateral orchiectomy. Treatment of depression and anxiety in cancer patients with psychotropic drugs may further impair sexual function by adverse effects on libido, erection ejaculation, and orgasmic function. Selective serotonin-reuptake inhibitors (SSRIs) also have been reported to decrease libido in up to 40% of patients. SSRIs and tricyclic antidepressants (TCAs) have been shown to impair orgasmic function; indeed, they are used in clinical practice to treat premature ejaculation.
5. Impaired sexual response. Even before a diagnosis of cancer, women may have problems with sexual function. More than 40% of healthy women have been reported to have one or more sexual problems, such as vaginal dryness, lack of sexual interest, dyspareunia (pain with intercourse), difficulty reaching orgasm, or lack of pleasure with sexual activity. Cancer and its treatment can compound these difficulties.
6. Sexual roles and relationships. Research from cancer survivors suggests that survivors who had a good sexual relationship before therapy continued to have a satisfying relationship after surgery for breast cancer. Understanding and support from the partner were critical for the survivor to be able to obtain and maintain healthy sexual roles and relationships. The partner’s overall sexual health and function may also influence a survivor’s sexual roles.
7. Cultural differences. Research from breast cancer patients suggests that culture may affect body image. There are no data on cultural effects when it comes to male sexuality and cancer.
B. Sexual problems specific to women
1. Germ cell depletion is discussed in Section III. Indirect indicators of menopause are amenorrhea, increased serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, and symptoms of estrogen deficiency. Symptoms include hot flashes, loss of vaginal lubrication, atrophy of genital structures, and discomfort with intercourse.
2. Hormonal therapy for breast cancer. Tamoxifen, which is commonly used in women with breast cancer, may have a positive estrogenic effect on the vaginal mucosa or may contribute to vaginal atrophy and dyspareunia. Patients who are taking tamoxifen often experience hot flashes or vaginal discharge. Tamoxifen does appear to have a somewhat proestrogenic effect on serum lipids and bone density. Aromatase inhibitors may have a lower incidence of estrogen deficiency symptoms compared with tamoxifen, with an as yet unknown effect on general sexual function.
3. Chemotherapy may cause ovarian failure (see Section III.B). Emotional and physical changes can also adversely affect sexual function. The effect of chemotherapy on ovarian androgen output is unknown. Diminished androgen production affects libido.
4. Radiation therapy (RT). Effects of ionizing radiation on sexual function depend on age, field, and dose (see Section III.A). RT for cervical cancer leads to vaginal fibrosis, dyspareunia, and ovarian failure. Symptoms may not become apparent until 1 year after treatment.
5. Pelvic surgery
a. Cervical conization does not impair desire, arousal, or orgasm.
b. Radical hysterectomy has been shown to have no negative impact on sexual satisfaction after abdominal hysterectomy, whether subtotal or total. The only predictor of negative sexual experience of partners after hysterectomy was negative sexual experience before hysterectomy. Women may need to experiment with different positions to experience comfortable penetration.
c. Radical cystectomy can lead to decreased vaginal lubrication and dyspareunia. Newer techniques, such as quality-of-life (QOL) measurements, have shown that newer surgical procedures can maintain sexual function compared with traditional techniques. These newer approaches with cystectomy involve (1) bilateral nerve-sparing (NS) surgical technique, (2) preservation of the anterior vaginal wall (to enhance lubrication) and anterior vaginal tubularization (to preserve the depth of the vagina), and (3) avoidance of routine hysterectomy.
d. Abdominoperineal resection (APR). Sexual and bladder functions are quite often sacrificed when a conventional low anterior resection and APR with an extended lymph node dissection (LND) are performed in patients with advanced lower rectal carcinoma. These complications are due to injury of the pelvic plexus. APR commonly causes dyspareunia but orgasmic function is preserved.
The consensus is that the iatrogenic genitourinary dysfunctions are mostly caused by either a non–sphincter-sparing procedure or a non–nerve-sparing surgical approach. The practice of total mesorectal excision (TME) in rectal cancer treatment has substantially improved autonomous pelvic nerve preservation with reduction of sexual dysfunction rates.
e. Total pelvic exenteration with vaginal reconstruction results in loss of vaginal lubrication, loss of some erotic zones, dyspareunia, decreased intensity of orgasm, and the need to relearn how to achieve orgasm.
6. Mastectomy. There are consistent benefits of breast conservation or lumpectomy over mastectomy alone in preserving women’s body image and comfort with sexuality. It is clear that the type of primary surgery a woman receives for her breast cancer continues to play an important role in her body image and feelings of attractiveness, with women undergoing lumpectomy experiencing more positive outcomes than women undergoing mastectomy, with or without reconstruction. Women often feel less feminine and less physically attractive after mastectomy. About one-third experience significant anxiety or depression and are unable to enjoy or tolerate making love. A similar percentage of patients’ partners reported decreased sexual activity after mastectomy and fears of causing pain during intercourse. Men’s reactions to seeing their partner’s incision and chest wall area appear to have prognostic value: If the reaction is primarily empathic rather than negative, the prognosis for good sexual adjustment appears favorable. Women treated with lumpectomy and breast irradiation have improved self-image compared with those treated with mastectomy. Women who undergo breast reconstruction have a better body image than those who do not.
C. Sexual problems specific to men. Men treated for testicular cancer, prostate cancer, and Hodgkin lymphoma (HL) are particularly at risk for sexual dysfunction (see Section II.A). Twenty percent of surviving testicular cancer patients have reported that they have been sexually inactive; many have reported decreased sense of pleasure with orgasm, anxiety, and marital unhappiness.
1. Germ-cell depletion. Clinical indicators of germ-cell depletion include decreased testicular size, severe oligospermia or azoospermia, infertility with elevated serum LH and FSH levels, and decreased testosterone level.
2. Impotence. The reported incidence of impotence in the general population is about 10%: 8% at 50 years of age, 20% at 60 years of age, and 80% at 80 years of age. The incidence of impotence in men treated for cancer is increased, particularly for men with tumors involving the pelvis and genital tract. Often, men emotionally relate impotence to a loss of masculinity, with attendant fear, anxiety, depression, and feelings of diminished self-worth.
Temporary or permanent erectile impotence is the most common symptom of sexual dysfunction in men with cancer. Recovery of erectile function is more likely in men <60 years of age and may take months to years. Preexisting conditions, such as diabetes, cardiovascular disease, and antihypertensive medication, exacerbate the risk for erectile dysfunction. Ejaculatory dysfunction occurs less frequently and may be due to retrograde ejaculation or dry orgasm. The presence of nocturnal tumescence is helpful in differentiating nonorganic from organic causes of impotence.
3. Systemic therapy. Fatigue, nausea, alopecia, anxiety, and other general effects of chemotherapy interact to diminish libido during treatment.
a. Chemotherapy is thought to suppress Leydig cell function, resulting in decreased serum testosterone, increased serum LH levels, and resultant loss of desire and erectile function. Chemotherapeutic agents associated with neuropathy (e.g., vinca alkaloids) can cause dry orgasm with preservation of pleasurable sensation. The effect of chemotherapy on spermatogenesis is discussed in Section II.C.
b. Hormonal therapy for prostate cancer can impair all phases of the sexual response cycle. Gonadotropin-releasing hormone (GnRH) agonists (e.g., leuprolide, goserelin) reduce serum testosterone to prepubertal levels and lead to loss of libido, difficulty with arousal, and diminished intensity of orgasm. Hot flashes may occur. In addition, flutamide and similar agents can cause gynecomastia. There is evidence that patients getting intermittent androgen deprivation have improved quality of life.
4. RT
a. Prostate cancer. RT can result in loss of erectile function in 20% to 80% of patients treated for prostate cancer. Younger men with intact sexual function before RT are most likely to regain adequate erectile function. Semen volume is also reduced with RT, leading to little or no ejaculatory fluid.
b. Testicular cancer. Patients who receive radiation to the pelvis and retroperitoneum have an increased incidence of erectile dysfunction. The effects of RT on sperm count are discussed in Section II.B. Men treated for testicular cancer had a higher risk of having low sexual desire and erectile dysfunction 3 to 5 years after completion of therapy than comparators. These sexual dysfunctions were not significantly associated with treatment intensity or hypogonadism.
c. Testicular shielding should be used if the distance between the testes and the radiation field boundary is <30 cm. Radiation dose to the testes is reduced to <10% of the total dose if this method is used.
5. Surgery. After the recovery period from pelvic surgery itself, the desire phase generally remains intact. Orgasmic function may be normal or reduced.
a. Radical prostatectomy causes impotence or impaired erection in most patients, although partial recovery of erectile function is possible. Parasympathetic stimulation causes tumescence; sympathetic stimulation causes detumescence. One or both of these autonomic bundles are at risk during radical prostatectomy.
b. Nerve-sparing techniques during radical prostatectomy allow a greater percentage of men to recover erectile function (reportedly up to 85%). Closer analysis, however, has disclosed that many men do not have erections firm enough for vaginal penetration.
c. Radical cystectomy results in erectile dysfunction and dry orgasm. With nerve-sparing procedures, up to 67% may recover erectile function.
d. APR leads to problems with erection (55%) and dry orgasm as a result of nerve damage.
e. Total pelvic exenteration results in permanent impotence and dry orgasm.
f. Retroperitoneal lymph node dissection (RPLND) leads to retrograde ejaculation. With modified RPLND in clinical stage I nonseminomatous germ-cell tumor patients, ejaculatory function can be preserved in about 90% of cases.
D. Guidelines for treatment of sexual problems
1. Initial history should include information about the patient’s sexual function before diagnosis. Patients at particular risk for dysfunction include those in relationships characterized by conflict and poor emotional adjustment, younger patients, those who want more children, and those with a history of rape or incest.
2. Brief counseling can alleviate most problems. Physicians should include the sex partner in discussions and recognize and deal with feelings and fears. In addition, clinicians should specifically tell patients that it is all right to resume sexual activity and that cancer is not contagious.
3. Refer for expert assistance if needed: Occasionally, patients need the services of a sex therapist or marital counselor or a referral to a urologist. An invaluable resource is the pamphlet “Sexuality and Cancer” (separate pamphlets for women and men), available from the American Cancer Society; it can be downloaded from their Web site (www.cancer.org).
4. Control pain and treat depression.
5. For men with erectile dysfunction
a. Oral therapy with sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) is efficacious in half of patients or more regardless of the underlying cause. These drugs are contraindicated in patients taking nitrates. Efficacy improves when there is preservation of neurovascular bundles. Oral therapy is considered first-line therapy.
b. Second-line therapy involves intraurethral or intracavernosal administration of vasoactive agents such as alprostadil (Muse, Caverject).
c. Vacuum erection device (VED) provides a well-tolerated, cost-effective, noninvasive, nonmedical alternative to intracavernosal injection therapy in the population with erectile dysfunction following prostatectomy. Proper instruction and reinforcement in the use of the VED are crucial to its overall efficacy. Patient satisfaction with VED varies significantly compared with the placement of a penile prosthesis. Penile prosthetic devices include rod implants and inflatable cylinders (pump in scrotum). Implants are usually placed via coronal incision.
d. Small studies suggest combinations of the above may be helpful.
6. For men with testicular cancer
a. Depo-Testosterone, 200 to 300 mg IM every 3 weeks, for hypotestosteronism (check serum testosterone levels)
b. Imipramine, 25 to 50 mg daily PO, may induce antegrade ejaculation in those who have undergone RPLND.
7. For women with dyspareunia and vaginal fibrosis
a. Vaginal dilators of graduated sizes can help women learn to relax voluntary muscles progressively until penetration can be achieved without pain.
b. Water-based lubricants and vaginal moisturizers can be used.
8. For women with dyspareunia and vaginal dryness. Vaginal dryness is one of the most important predictors of sexual health. Vaginal moisturizers can be used on a regular basis to decrease dryness and subsequent associated irritation. Polycarbophil-based vaginal moisturizers (Replens, Hill Dermaceutical, Sanford, FL) can be used. For women whose symptoms are not controlled by nonhormonal preparations, using low-dose estrogen creams or tablets applied intravaginally are options. With these agents, systemic absorption is probably minimal. Conjugated estrogens, such as Premarin in the form of vaginal creams, can be used at a very small dose of 0.3 mg (one-eighth of the applicator dose) daily for 3 weeks, followed by maintenance with the same dose administered only twice weekly. This dose is associated with a low incidence of endometrial proliferation. Estradiol vaginal tablets (Vagifem, Novo Nordisk, Princeton, NJ) are also available and have been shown to have even less systemic absorption when compared with estrogen vaginal creams.
9. Vasomotor symptoms are traditionally treated with antidepressants. This treatment is justified due to increased monoamine oxidase activity and lower serum serotonin levels compared with premenopausal women. Estrogen enhances serotoninergic transmission by decreasing the levels of monoamine oxidase, increasing the availability of free tryptophan to the brain and enhancing serotonin transport. SSRIs, such as venlafaxine (Effexor) at 75 mg/d, are recommended. One concern associated with the use of SSRIs to treat hot flashes in women with breast cancer is the interaction of these drugs with tamoxifen (see Section I.D.10.c. below).
Hot flashes and vaginal dryness remain legitimate indications for hormone replacement therapy (HRT), which must be individualized and done with informed consent. The Women’s Health Initiative study showed increased rates of stroke, pulmonary embolism, and breast cancer in women taking HRT.
10. For women with breast cancer
a. The dictum that estrogen replacement therapy is contraindicated is being challenged. A decision for such replacement therapy must be individualized.
b. Early discussion of the option of breast reconstruction may alleviate feelings of loss and poor self-image. A prosthesis should be fitted as soon as feasible for a normal silhouette in clothing. The Reach to Recovery program of the American Cancer Society exposes the patient to women with breast cancer who have made successful adjustments.
c. Tamoxifen taken with SSRIs. A recent study raises concerns about the use of paroxetine (Paxil, an irreversible inhibitor of CYP2D6) concomitantly with tamoxifen. Of 2,430 women treated with tamoxifen and a single SSRI, 374 died of breast cancer during follow-up. After adjustment for age, duration of tamoxifen treatment, and other potential confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine were associated with 24%, 54%, and 91% increases in the risk of death from breast cancer, respectively (P < 0.05 for each comparison). The authors estimated that use of paroxetine for 40% of tamoxifen treatment would result in one additional breast cancer death within 5 years of cessation of tamoxifen for every 20 patients so treated. By contrast, no such risk was seen with other antidepressants.
II. REPRODUCTIVE FUNCTION IN MEN WITH CANCER
A. Pretreatment hypogonadism in cancer patients
1. Testicular cancer. More than 80% of men with disseminated germ-cell tumors are oligospermic or azoospermic before therapy, probably owing to effects of the disease itself and abnormalities of the malignancy-prone testis.
2. Hodgkin lymphoma (HL). More than half of the men with HL have low sperm counts and poor motility before treatment.
3. Metastatic cancer of any type may be associated with low levels of testosterone in up to two-thirds of male patients. Malnutrition is believed to play a significant role.
B. Effects of RT in men. The testes are exquisitely sensitive to radiation. Doses as low as 15 cGy result in transient suppression of spermatogenesis. The duration of azoospermia is proportional to the magnitude of the RT dose. At 200 to 300 cGy, recovery takes 3 years, and at 400 to 500 cGy, azoospermia can persist for 5 years. A dose of >600 cGy results in permanent sterility.
C. Effects of chemotherapy in men. Spermatogenesis is highly susceptible to toxic effects of certain chemotherapeutic agents, depending on age and total dose per m2, particularly when administered in combinations.
1. Alkylating agents cause germ-cell depletion in a dose-related fashion. Drugs reported to be definitely associated with azoospermia include chlorambucil (possibly reversible if total dose is <400 mg), cyclophosphamide (possibly reversible if total dose is <6 to 10 g), nitrogen mustard, busulfan, procarbazine, and nitrosoureas.
2. Other drugs probably associated with germ-cell depletion include doxorubicin, vinblastine, cytosine arabinoside, and cisplatin. Effects of methotrexate, 5-fluorouracil, 6-mercaptopurine, vincristine, and bleomycin are either unknown or unlikely to cause damage.
3. Combination regimens. Therapy with MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone) for HL leads to testicular atrophy in 80% of patients and 100% sterility. The ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine) is an alternative to MOPP, with a reported 35% occurrence of azoospermia during therapy but an eventual return of spermatogenesis in nearly 100% of cases; similar regimens based on mitoxantrone show similar results. About half of the patients treated with cisplatin, vinblastine, and bleomycin for nonseminomatous testicular cancer regain spermatogenesis within 2 to 3 years.
D. Measures to protect reproductive function in men
1. Sperm banking can be offered to men who are likely to suffer prolonged or permanent sterility. Between 50% and 80% of patients with HL or testicular cancer, however, have low sperm counts (<20 million/mL) with poor motility (<50%) before treatment. Sperm banking should be offered to all patients at risk for treatment-related infertility. Surveillance in lieu of chemotherapy or RT may be offered to men with good-prognosis testicular cancer, which optimizes fertility.
2. Artificial insemination may be tried in women whose partner’s posttreatment sperm quality is good despite low sperm count.
3. In vitro fertilization (IVF) techniques in men with very low sperm counts can result in successful production of an embryo with relatively few sperm. In addition, IVF can be carried out before cancer therapy with cryopreservation of embryos. Intracytoplasmic sperm injection enables even apparently azoospermic men to achieve fertilization. Only a single viable sperm is needed for micropipette insertion into an ovum. Consultation with fertility specialists should be considered due to the rapidly changing knowledge and practice in this field.
4. Nerve-sparing procedures for prostatectomy, modified RPLND to reduce retrograde ejaculation, and testicular shielding for RT are discussed in Sections I.C.4.c and I.C.5.b.
III. REPRODUCTIVE FUNCTION IN WOMEN WITH CANCER
A. Effects of RT in women. The effects of radiation on fertility are strongly influenced by age as well as by RT field and total dose. Cessation of menses for variable periods of time occurs at doses >150 cGy. A dose of 500 to 600 cGy to the ovaries usually results in permanent ovarian failure. After total nodal irradiation, 70% of women <20 years of age resume normal menses, whereas 80% of women >30 years of age do not.
Oophoropexy, or sequestering the ovaries surgically in midline behind the uterus, reduces the risk for infertility in half of women undergoing inverted-Y field irradiation. Sparing one ovary in women <40 years of age prevents premature menopause.
B. Effects of chemotherapy in women. The likelihood of permanent ovarian failure after chemotherapy increases with age. Menses rarely return after age 35 to 40 years. Use of GnRH agonists before and during chemotherapy may prove useful in preventing premature ovarian failure.
1. Alkylating agents. Cyclophosphamide, nitrogen mustard, Alkeran, busulfan, and procarbazine are clearly associated with ovarian failure.
2. Other drugs. Methotrexate, 5-fluorouracil, and 6-mercaptopurine are unlikely to cause ovarian dysfunction. Agents with unknown effects on the ovary include doxorubicin, bleomycin, vinca alkaloids, cisplatin, nitrosoureas, cytosine arabinoside, etoposide, vinorelbine, paclitaxel, and interferon.
3. Combination regimens. MOPP leads to ovarian dysfunction in 40% to 50% of women treated for HL. Nearly all patients <25 years of age experience a return of normal menses, but these patients may experience very early menopause (before 30 years of age). ABVD is associated with a much lower incidence of infertility than is MOPP.
Ten years after receiving combination regimens for malignant ovarian germ-cell tumors (with drugs including cisplatin, vincristine, doxorubicin, etoposide, dactinomycin, bleomycin, methotrexate, and cyclophosphamide), two-thirds of women aged 14 to 40 years had regular menses, whereas about 10% had amenorrhea or premature ovarian failure.
IV. PREGNANCY AND CANCER
A. Background
1. Incidence. Cervical cancer is the most common malignancy complicating pregnancy, occurring in 1 in 1,000 pregnancies, followed by breast cancer (1 in 3,000), melanoma and ovarian cancer (1 in 10,000), and colon cancer, leukemia, and lymphoma (1 in 50,000 to 1 in 100,000).
2. Natural history. The incidence of malignancy is not increased in pregnancy. Pregnancy neither alters the biologic behavior or prognosis of cancer nor reactivates cancer in remission. Metastasis to the placenta or fetus is very rare but can occur with malignant melanoma.
3. Teratogenesis. The definition of teratogenesis has been broadened to encompass not merely morphologic abnormalities readily apparent at birth but also other types of malformation, growth retardation, fetal death, and developmental disability. The incidence of major malformations apparent at birth in the general population is about 3% to 4%. Damage from chemotherapeutic agents in the first trimester is more likely to cause morphologic abnormalities and spontaneous abortion. Exposure during the second and third trimesters is more likely to cause intrauterine growth retardation, microcephaly, and developmental delay with attendant risks for mental retardation and learning problems.
B. Diagnostic studies during pregnancy
1. Biopsies under local anesthesia carry essentially no risk to the fetus. Biopsy procedures using general anesthesia present minimal risk to the fetus.
2. Studies to avoid: radionuclide scans, contrast studies of the gastrointestinal and urinary tracts, abdominal and chest CT scans, and pelvic and lumbosacral spine films. Studies should only be done if results would have a significant effect on treatment decisions.
3. Mammograms lack sensitivity in pregnancy because of breast engorgement and histologic changes. Up to half of pregnant women with a breast mass have a negative mammogram.
4. Chest radiographs can be done safely with proper abdominal shielding. The dose of ionizing radiation to the fetus is about 0.008 cGy.
5. Bone scans are relatively contraindicated in pregnancy. The fetus receives a dose of about 0.1 cGy. Because of low yield, bone scans are not justified in asymptomatic stage I and II breast cancer patients and can be deferred until postpartum. MRI is preferred in place of bone scans.
6. Ultrasonography does not involve ionizing radiation and is safe.
7. Other permissible radiologic studies. Brain CT scans and radiographs of the cervical spine or long bones are probably associated with radiation doses to the fetus of <0.5 cGy if the abdomen and uterus are properly shielded.
8. MRI. Although no risks to the fetus from MRI have been demonstrated, first-trimester use should be avoided if possible. MRI has proven useful in pregnancy as an alternative to ionizing radiation in many instances, including studies of the brain, liver, and skeleton, and in staging cervical cancer.
9. Sentinel node imaging can safely be performed as the 99mTc dose to the fetus is negligible.
C. Principles of cancer therapy during pregnancy
1. Pregnancy prevention should be emphasized in all women of childbearing age with cancer and in the context of the patient’s personal goals. All options, including pregnancy termination, should be discussed.
2. Accurate determination of gestational age should be made before commencing diagnostic studies or therapy.
3. When maternal cure is possible and delay would compromise this goal, therapy should be instituted as soon as possible. If feasible, chemotherapy should be delayed until the second or third trimester or after delivery.
4. Therapeutic abortion (TAB) may be performed up to the 24th week of gestation. TAB should be offered to the patient if her fetus has received a dose of ionizing radiation in excess of 10 cGy during the first trimester.
5. Breast-feeding is usually contraindicated because chemotherapeutic agents are excreted into human milk and have caused neutropenia in infants.
D. Surgery during pregnancy. Surgical treatment is far less likely to affect pregnancy adversely than is chemotherapy or RT. General anesthesia is an uncommon cause of teratogenesis. The fetus is exquisitely sensitive to hypoxia; the anesthesiologist and surgeon must take special precautions to ensure adequate oxygenation.
E. RT during pregnancy
1. A dose of 10 cGy to the fetus during the first trimester carries a substantial risk for fetal damage. No increase in the incidence of spontaneous abortion, growth retardation, or congenital malformations has been noted when the dose of radiation is <5 cGy at any time during pregnancy.
2. Defects most commonly seen with radiation damage include microcephaly, growth retardation, and ocular abnormalities. Late effects of radiation in early pregnancy include an increased incidence of thyroid cancer and leukemia.
F. Chemotherapy during pregnancy
1. Pharmacokinetics. Absorption, distribution, and metabolism of chemotherapeutic agents are undoubtedly altered by the multiplicity of physiologic changes accompanying pregnancy. Because the effects of pregnancy on pharmacokinetics are unknown, standard drug dosages are used. It can be assumed that most antineoplastic drugs cross the placenta.
2. First-trimester exposure. When folic acid antagonists and concomitant RT are excluded, single agents lead to congenital defects in 6% of infants exposed in the first trimester.
a. Antimetabolites. Folic acid antagonists are the agents most frequently associated with teratogenesis and should not be used in the first trimester. Methotrexate is an abortifacient and is teratogenic. Methotrexate has caused facial anomalies, bone and limb deformities, and variable intellectual impairment (aminopterin syndrome). Although other antimetabolites, including cytarabine and 5-fluorouracil, have been associated with fetal malformation, 6-mercaptopurine has not.
b. Alkylating agents are less frequently associated with fetal malformation than are antimetabolites. A 14% overall occurrence rate has been reported in one series; cyclophosphamide was associated with congenital defects in three of seven exposed infants.
c. Vinca alkaloids. Vinblastine resulted in malformation in 1 of 14 exposed infants. No data are available for vincristine.
d. Others. Procarbazine is associated with fetal malformation. Diethylstilbestrol (DES) has been linked to clear-cell vaginal cancer in offspring.
e. Combination chemotherapy regimens are associated with a 25% rate of fetal malformation. MOPP was linked to congenital defects in four of seven exposed infants.
3. Second- and third-trimester exposure. Forty percent of fetuses exposed to a variety of antineoplastic agents in the second and third trimesters have exhibited low birth weight, with its attendant risk for developmental delay. Other potential adverse effects include prematurity, spontaneous abortion, and major organ toxicity.
G. Recommendations concerning therapeutic abortion (TAB)
1. TAB not recommended
a. Treatment does not jeopardize the pregnancy (e.g., surgery for breast cancer).
b. Refractory malignancies for which treatment has no significant impact
2. TAB considered, but not strongly recommended
a. Treatment may be delayed with reasonable safety until fetal maturity allows delivery.
b. Treatment may be delayed into the second or third trimester, when the fetus is relatively resistant to the effects of chemotherapy (e.g., acute leukemia) or RT.
3. TAB strongly recommended
a. Cancers in which curative therapy cannot be delayed or accomplished during pregnancy (e.g., most gynecologic malignancies)
b. Treatment that is likely to cause abortion or fetal malformation is required in the first trimester (e.g., MOPP, methotrexate, pelvic RT).
V. MANAGEMENT OF SPECIFIC CANCERS AND PREGNANCY
A. Cervical cancer
1. Screening. Papanicolaou (Pap) smears should be done on all prenatal patients.
2. Evaluation of cervical dysplasia. Colposcopy can be done. Endocervical curettage biopsy is contraindicated. In the absence of invasive disease, there is no urgency to treat cervical dysplasia during pregnancy. Cervical conization should be avoided, but it may need to be done to exclude invasive disease. In pregnancy, conization is associated with cervical hemorrhage and a high incidence of incomplete resection.
3. Staging and treatment. The extent of invasive disease is often underestimated because of limitations of physical examination and diagnostic procedures. Treatment of invasive cervical cancer, using either surgery or RT, is incompatible with fetal survival. Consideration may be given to expectant management of early-stage cervical cancer (stage IA with <3 mm invasion) until delivery. Radical trachelectomy may be considered for early-stage cervical cancer to preserve future reproductive function.
B. Breast cancer
1. Screening. A delay in diagnosis of 5 months or more has been observed in gravid patients with breast cancer, resulting in node-positive disease in 74% of patients, as compared with 37% in nonpregnant patients. Physiologic changes in the breasts during pregnancy hamper adequate physical examination. Serial breast examinations should be done throughout pregnancy, and masses should be investigated promptly. Clinicians have tended to observe breast masses 2 months longer in pregnant than in nonpregnant patients.
2. Diagnosis. Mammograms are not helpful during pregnancy. Fine-needle aspiration may be inaccurate, and excisional biopsy is the procedure of choice. Estrogen and progesterone receptor studies may be falsely negative or difficult to interpret.
3. Treatment. Modified radical mastectomy is the procedure of choice. Lumpectomy with radiation results in unacceptable radiation exposure to the fetus. Tamoxifen is contraindicated during gestation. Adjuvant chemotherapy should be delayed until at least the second or third trimester or, if possible, until after delivery.
C. Hodgkin lymphoma
1. Limit staging procedures that may expose the fetus to radiation.
2. If the disease is diagnosed during the first trimester, either perform a TAB and proceed as usual or delay chemotherapy or RT until later in the pregnancy.
3. If the disease is diagnosed during the second or third trimester:
a. Try to delay therapy until delivery if the mother’s outcome will not be adversely affected.
b. If therapy is necessary, proceed with proper counseling regarding possible growth and developmental abnormalities.
c. Very-limited-field RT has been largely successful. Internal scatter from standard mantle field RT can result in fetal exposure of 50 to 250 cGy.
D. Non-Hodgkin lymphoma is generally a more virulent disease and poses a greater risk to the mother and secondarily to the fetus than does HL. Therapeutic recommendations parallel HL, except for the possibility of protracted delay of treatment with indolent lymphomas.
E. Genetic counseling. Retrospective studies and case reports of patients who were treated for malignancy in childhood or adolescence and bore children later show a 4% rate of major malformations in offspring. This rate is similar to the risk borne by the general population. The late effects of cancer treatment on infants exposed in utero are unknown. Female survivors of cancer who later become pregnant, particularly those who have had abdominal radiation, have an increased rate of preterm delivery and low–birth-weight infants.
Suggested Reading
Boice JD, Miller RW. Childhood and adult cancer after intrauterine exposure to ionizing radiation. Teratology 1999;59:227.
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Web Sites
Fertile Hope: Fertility resources for cancer patients. www.fertilehope.org
Lance Armstrong Foundation. www.laf.org