Cardiac late effects are most closely associated with the anthracycline class of chemotherapeutic agents (doxorubicin, mitoxantrone, epirubicin). One of the mechanisms by which these drugs work is the creation of free radicals which damage the DNA of replicating cancer cells. However, free radicals also damage normal tissue. Cardiac muscle is particularly vulnerable because it lacks sufficient glutathione, which neutralizes free radicals. As a result, cardiac muscle accumulates progressive damage with increasing exposure to anthracycline drugs resulting in cardiomyopa-thy and congestive heart failure. This may also lead to arrhythmias. Consequently, the anthracycline class of chemotherapeutic agents each has limits above which exposure is not considered safe: for example, 450 mg/m2 for doxorubicin and 900 mg/m2 for epirubicin. Several drugs commonly combined with anthracyclines in breast cancer, such as cyclophosphamide, paclitaxel, and herceptin also have cardiac toxicity, thereby compounding the possibility of adverse cardiac effects. These latter drugs mostly contribute to acute toxicity, however. Cisplatin has also recently been recognized as having vascular toxicity in addition to contributing to dyslipidemia.51
Patient characteristics associated with cardiac long-term and late effects are older age and preexisting cardiac disease. Premature menopause from cancer therapy can adversely affect lipid profiles and accelerate atherosclerosis, as can the effects of some hormonal treatments. Cancer patients can also be at increase risk of venous thromboses because of hormonal effects on coagulability and vascular irritation from chemotherapy and implanted devices. Cardiovascular adverse effects can remain subclinical for many years before causing overt symptoms, often making the link with prior cancer therapy nonobvious.
Chemotherapy, particularly alkylating agents like cyclophosphamide, can induce infertility and, in women, premature menopause, with its attendant problems of hot flashes, mood swings, vaginal dryness, and urinary incontinence. Cyclophosphamide is commonly used in breast cancer, but management of the menopausal symptoms is complicated by the fact that hormone replacement therapy is considered contraindi-cated in patients with a history of breast cancer. Consequently, other treatments must be used for hot flashes, such as antidepressants.52 This example illustrates the importance of both recognizing the symptoms related to ovarian failure in a cancer patient in which it would be otherwise unexpected, and having knowledge of the oncologic considerations of the therapies being chosen.
In general, the younger a patient is, the more likely they are to have their fertility preserved after chemotherapy.53 However, breast cancer patients are usually advised to delay childbearing for at least 2 years after diagnosis because of their relatively high risk of early relapse. Moreover, the effects of adjuvant hormonal therapies on pregnancy are unclear and so patients are advised not to conceive while taking them. These delays can by themselves impair chances of conception. Although there is controversy, there is not clear evidence that pregnancy increases the risk of relapse, or that there is increased risk of birth defects in cancer survivors.54 Technologies for assisted reproduction for women, like cryopreserving ovaries, are not yet as successful as sperm banking is for men.
Alkylators also affect male fertility, but fertility usually recovers within 2-3 years. Studies have shown that more than half of testicular cancer patients have impaired spermatogenesis even before they develop their cancer. As a result, it has been difficult to evaluate the contribution of drugs like cisplatin to fertility problems in males.42,55
Among breast cancer survivors, sexual dysfunction appears to be more closely related to receipt of chemotherapy56,57 than the body image concerns resultant from mastectomy58 or tamoxifen effects,59 although all may play a role.60 Many of these symptoms improve with prolonged (i.e., >5 years) follow-up.61
Bone health can be impaired in many ways. Premature menopause induced in women by any of the mechanisms related to surgery, radiation, or systemic therapy predisposes to osteopenia and osteoporosis. Steroids, whether given as part of primary treatment or as adjunctive therapy with analgesics or antinauseants also weaken bone. They are also associated with avascular necrosis. Lastly, hormonal treatments for breast and prostate cancer accelerate bone loss, osteoporosis, and fractures.62 The endocrinology is complex, however. Tamoxifen can preserve bone mineral density in post-menopausal women but is associated with bone loss in younger women.63 Aromatase inhibitors adversely affect bone density in all ages.64 Consequently, ASCO
recommends regular monitoring of bone mineral density with dual energy x-ray absorptiometry, dietary intake of calcium and vitamin D, weight-bearing exercise, and smoking cessation.65 Bisphosphonates can be useful for the treatment of osteoporosis.
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