Over 10 million Americans are cancer survivors. The vast majority of these people will bear some mark of their cancer and/or its treatment, and a large proportion will experience long-term consequences that include medical problems, psychosocial dysfunction, economic hardship, sexual dysfunction, and discrimination in employment and insurance. Many of these problems are directly related to cancer treatment. As patients with more types of malignancies survive longer, the biologic toll that very imperfect therapies take in terms of morbidity and mortality rates is being recognized increasingly. These consequences of therapy confront the patients and the cancer specialists and general internists who manage them every day. Although long-term survivors of childhood leukemias, Hodgkin's lymphoma, and testicular cancer have increased knowledge about the consequences of cancer treatment, researchers and physicians keep learning more as patients survive longer with newer therapies. The pace of the development of therapies that mitigate treatment-related consequences has been slow, partly due to an understandable aversion to altering regimens that work and partly due to a lack of new, effective, less toxic therapeutic agents with less "collateral damage" to replace known agents with known toxicities. The types of damage from cancer treatment vary. Often, a final common pathway is irreparable damage to DNA. Surgery can create dysfunction, including blind gut loops that lead to absorption problems and loss of function of removed body parts. Radiation may damage end-organ function, for example, loss of potency in prostate cancer patients, pulmonary fibrosis, neurocognitive impairment, acceleration of atherosclerosis, and second cancers. Cancer chemotherapy may act as a carcinogen and has a kaleidoscope of other toxicities, as discussed in this chapter. Table 102–1 lists the long-term effects of treatment.
Table 102–1 Late Effects of Cancer Therapy
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Table 102–1 Late Effects of Cancer Therapy
|Lymph node dissection||Risk of lymphedema|
|Splenectomy||Risk of sepsis|
|Adhesions||Risk of obstruction|
|Bowel anastomoses||Malabsorption syndromes|
|Bone||Premature termination of growth, osteonecrosis|
|Soft tissues||Atrophy, fibrosis|
|Brain||Neuropsychiatric deficits, cognitive dysfunction|
|Thyroid||Hypothyroidism, Graves' disease, cancer|
|Salivary glands||Dry mouth, caries, dysgeusia|
|Heart||Pericarditis, myocarditis, coronary artery disease|
|Kidney||Decreased function, hypertension|
|Gonads||Infertility, premature menopause|
|Bone||Glucocorticoids||Osteoporosis, avascular necrosis|
|Brain||Methotrexate, cytarabine (Ara-C), others||Neuropsychiatric deficits, cognitive decline?|
|Peripheral nerves||Vincristine, platinum, taxanes||Neuropathy, hearing loss|
|Kidney||Platinum, others||Decreased function, hypomagnesemia|
|Gonads||Alkylating agents, others||Infertility, premature menopause|
|Bone marrow||Various||Aplasia, myelodysplasia, secondary leukemia|
The first goal of therapy is to eradicate or control the malignancy. Late treatment consequences are, indeed, testimony to the increasing success of such treatment. Their occurrence sharply underlines the necessity to develop more effective therapies with less long-term morbidity and mortality. At the same time, a sense of perspective and relative risk is necessary; fear of long-term complications should not prevent the application of effective (particularly curative) cancer treatment.
The cardiovascular toxicity of cancer chemotherapeutic agents includes dysrhythmias, cardiomyopathic congestive heart failure (CHF), pericardial disease, and peripheral vascular disease. Because these cardiac toxicities are difficult to distinguish from disease that is not associated with cancer treatment, determining the clear etiologic implication of cancer chemotherapeutic agents may be difficult. Cardiovascular complications occurring in an unexpected clinical setting in patients who have undergone cancer therapy is often important in raising suspicion. Dose-dependent myocardial toxicity of anthracyclines with characteristic myofibrillar dropout is pathologically pathagnomonic on endomyocardial biopsy. Anthracycline cardiotoxity occurs through a root mechanism of chemical free-radical damage. Fe(III)-doxorubicin complexes damage DNA, nuclear and cytoplasmic membranes, and mitochondria. About 5% of patients receiving >450–550 mg/m2 doxorubicin will develop CHF. Cardiotoxicity in relation to the dose of anthracycline is clearly not a step function but rather a continuous function, and occasional patients are seen with CHF at substantially lower doses. Advanced age, other concomitant cardiac disease, hypertension, diabetes, and thoracic radiation therapy are all important cofactors in promoting anthracycline-associated CHF. Anthracycline-related CHF is difficult to reverse; the mortality rate is as high as 50%, making prevention crucial. Some anthracyclines, such as mitoxantrone, are associated with less cardiotoxicity, and continuous infusion regimens or doxorubicin encapsulated in liposomes are associated with less cardiotoxicity. Dexrazoxane, an intracellular iron chelator, may limit anthracycline toxicity, but concern about limiting chemotherapeutic efficacy has limited its use. Monitoring patients for cardiac toxicity typically involves periodic gated nuclear cardiac blood pool ejection fraction testing [multi-gated acquisition scan (MUGA)] or cardiac ultrasonography. Cardiac MRI has been used but is not standard or widespread. Testing is performed more frequently at higher cumulative doses, with additional risk factors, certainly for any newly developing CHF or other symptoms of cardiac dysfunction.
Trastuzumab after anthracyclines is currently the next most commonly used cardiotoxic drug. Trastuzumab is commonly used in adjuvant therapy or for advanced HER2-positive breast cancer, sometimes in conjunction with anthracyclines, and is believed to result in additive or possibly synergistic toxicity. In contrast to anthracyclines, cardiotoxicity from trastuzumab is not dose-related, is usually reversible, is not associated with pathologic changes of anthracyclines on cardiac myofibrils, and has a different biochemical mechanism inhibiting intrinsic cardiac repair mechanisms. Toxicity is monitored routinely every three to four doses with functional cardiac testing as described above for anthracyclines.
Other cardiotoxic drugs include lapatinib, phosphoramide mustards (cyclophosphamide), ifosfamide, interleukin 2, imatinib, and sunitinib.
Radiation therapy that includes the heart can cause interstitial myocardial fibrosis, acute and chronic pericarditis, valvular disease, and accelerated premature atherosclerotic coronary artery disease. Repeated or high (>6000 cGy) radiation doses are associated with greater risk, as is concomitant or distant cardiotoxic cancer ...