CHAPTER 55: LATE CONSEQUENCES OF CANCER AND ITS TREATMENT

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 55-1 lists the long-term effects of treatment.

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.

CHEMOTHERAPEUTIC AGENTS

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 magnetic resonance imaging (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 earlier for anthracyclines.

Other cardiotoxic drugs include lapatinib, phosphoramide mustards (cyclophosphamide), ifosfamide, interleukin 2, imatinib, and sunitinib.

RADIATION THERAPY

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 chemotherapy exposure. Symptoms of acute pericarditis, which peaks about 9 months after treatment, include dyspnea, chest pain, and fever. Chronic constrictive pericarditis may develop 5–10 years after radiation therapy. Cardiac valvular disease includes aortic insufficiency from fibrosis and papillary muscle dysfunction that results in mitral regurgitation. A threefold increased risk of fatal myocardial infarction is associated with mantle field radiation, with accelerated coronary artery disease. Carotid radiation similarly increases the risk of embolic stroke.

CHEMOTHERAPEUTIC AGENTS

Bleomycin generates activated free-radical oxygen species and causes pneumonitis associated with a radiographic or interstitial ground-glass appearance diffusely throughout both lungs, often worse in the lower lobes. This toxicity is dose-related and dose-limiting. The diffusion capacity of the lungs for carbon dioxide (DL^CO) is a sensitive measure of toxicity and recovery, and a baseline value generally is obtained for future comparison before bleomycin therapy. Additive or synergistic risk factors include age, prior lung disease, and concomitant use of other chemotherapy, along with lung irradiation and high concentrations of inspired oxygen. Other chemotherapeutic agents notable for pulmonary toxicity include mitomycin, nitrosoureas, doxorubicin with radiation, gemcitabine combined with weekly docetaxel, methotrexate, and fludarabine. High-dose alkylating agents, cyclophosphamide, ifosfamide, and melphalan are used frequently in the hematopoietic stem cell transplant setting, often with whole-body radiation. This therapy may result in severe pulmonary fibrosis and/or pulmonary venoocclusive disease.

RADIATION THERAPY

Risk factors for radiation pneumonitis include advanced age, poor performance status, preexisting compromised pulmonary function, radiation volume, and dose. The dose "threshold" for lung damage is thought to be in the range of 5–20 Gy. Hypoxemia and dyspnea on exertion are characteristic. Fine, high-pitched "Velcro rales" may be an accompanying physical finding, and fever, cough, and pleuritic chest pain are common symptoms. The DL^CO is the most sensitive measure of pulmonary functional impairment, and ground-glass infiltrates often correspond with relatively sharp edges to the irradiated volume, although the pneumonitis may progress beyond the field and occasionally involve the contralateral unirradiated lung.

CHEMOTHERAPEUTIC AGENTS

Chemotherapy-and radiation-induced neurologic dysfunction are increasing in both incidence and severity as a result of improved supportive care leading to more aggressive regimens and longer cancer survival allowing the development of late toxicity. Direct effects on myelin, glial cells, and neurons have been implicated, with alterations in cellular cytoskeleton, axonal transport, and cellular metabolism as mechanisms.

Vinca alkaloids produce a characteristic "stocking-glove" neuropathy, with numbness and tingling advancing to loss of motor function, which is highly dose-related. Distal sensorimotor polyneuropathy prominently involves loss of deep tendon reflexes with initially loss of pain and temperature sensation, followed by proprioceptive and vibratory loss. This requires a careful patient history and physical examination by experienced oncologists to decide when the drug must be stopped due to toxicity. Milder toxicity often slowly resolves completely. Vinca alkaloids may be associated with jaw claudication, autonomic neuropathy, ileus, cranial nerve palsies, and, in severe cases, encephalopathy, seizures, and coma.

Cisplatin is associated with sensorimotor neuropathy as well as hearing loss, especially at doses >400 mg/m², requiring audiometry in patients with preexisting hearing compromise. Carboplatin often is substituted in such cases because of its lesser effect on hearing.

Neurocognitive dysfunction has been well described in childhood survivors of acute lymphocytic leukemia (ALL) treatment, including intrathecal methotrexate or cytarabine in conjunction with prophylactic cranial irradiation. Methotrexate alone may cause acute leucoencephalopathy characterized by somnolence and confusion that is often reversible. Acute toxicity is dose-related, especially at doses >3 g/m², with younger patients being at greater risk. Subacute methotrexate toxicity occurs weeks after therapy and often is ameliorated with glucocorticoid therapy. Chronic methotrexate toxicity (leucoencephalopathy) develops months or years after treatment and is characterized clinically as progressive loss of cognitive function and focal neurologic signs that are irreversible, are promoted by synchronous or metachronous radiation therapy, and are more pronounced at a younger age.

Neurocognitive decline after chemotherapy alone occurs notably in breast cancer patients receiving adjuvant chemotherapy; this has been referred to as "chemo brain." It is clinically associated with impaired memory, learning, attention, and speed of information processing. The magnitude of the problem has been difficult to assess in light of the fact that cognitive decline is a normal feature of aging. It is not entirely clear that women receiving adjuvant therapy for breast cancer have a more rapid cognitive decline than do age-matched control participants. Furthermore, its causes are unexplained given the poor penetrance of chemotherapy agents into the central nervous system (CNS). No prevention or therapy has been developed. This entity is attracting the attention of investigators.

Many cancer patients experience intrusive or debilitating concerns about cancer recurrence after successful therapy. In addition, these patients may experience job, insurance, stress, relationship, financial, and sexual difficulties. Physicians need to ask about and address these issues explicitly with cancer survivors, with referral to the appropriate counseling or support systems. Suicidal ideation and suicide have an increased incidence in cancer patients and survivors.

RADIATION THERAPY

Acute radiation CNS toxicity occurs within weeks and is characterized by nausea, drowsiness, hypersomnia, and ataxia, symptoms that most often abate with time. Early-delayed toxicity occurring weeks to 3 months after therapy is associated with symptoms similar to those of acute toxicity and is pathologically associated with reversible demyelination. Chronic, late radiation injury occurs 9 months to up to 10 years after therapy. Focal necrosis is a common pathologic finding, and glucocorticoid therapy may be helpful. Diffuse radiation injury is associated with global CNS neurologic dysfunction and diffuse white matter changes on computed tomography or MRI. Pathologically, small vessel changes are prominent. Glucocorticoids may be symptomatically useful but do not alter the course. Necrotizing encephalopathy is the most severe form of radiation injury and almost always is associated with chemotherapy, notably methotrexate.

Cranial radiation also may be associated with an array of endocrine abnormalities with disruption of normal pituitary–hypothalamic axis function. A high index of suspicion needs to be maintained to identify and treat this toxicity.

Radiation-associated spinal cord injury (myelopathy) is highly dose-dependent and rarely occurs with modern radiation therapy. An early, self-limited form involving electric sensations down the spine on neck flexion (Lhermitte's sign) is seen 6–12 weeks after treatment and generally resolves over weeks. Peripheral nerve toxicity is quite rare owing to relative radiation resistance.

CHEMOTHERAPEUTIC AGENTS

Long-term hepatic damage from standard chemotherapy regimens is rare. Long-term methotrexate or high-dose chemotherapy alone or with radiation therapy—e.g., in preparative regimens for bone marrow transplantation—may result in venoocclusive disease of the liver. This potentially lethal complication classically presents with anicteric ascites, elevated alkaline phosphatase, and hepatosplenomegaly. Pathologically, venous congestion, epithelial cell proliferation, and hepatocyte atrophy progressing to frank fibrosis are noted. Frequent monitoring of liver function tests during any type of chemotherapy is necessary to avoid both idiosyncratic and expected toxicities. Ursodiol may prevent cholestasis in the setting of high-dose therapy before bone marrow transplant.

RADIATION THERAPY

Hepatic radiation damage depends on dose, volume, fractionation, preexisting liver disease, and synchronous or metachronous chemotherapy. In general, radiation doses to the liver >1500 cGy can produce hepatic dysfunction with a steep dose-injury curve. Radiation-induced liver disease closely mimics hepatic venoocclusive disease.

Cisplatin produces reversible decrements in renal function but also may produce severe irreversible toxicity in the presence of renal disease and may predispose to accentuated damage with subsequent renal insults. Magnesium wasting with hypomagnesemia may be seen. Cyclophosphamide and ifosphamide, as prodrugs primarily activated in the liver, have cleavage products (acrolein) that can produce hemorrhagic cystitis. This can be prevented with the free-radical scavenger 2-mercaptoethane sulfonate (MESNA), which is required for ifosfamide administration. Hemorrhagic cystitis caused by these agents may predispose these patients to bladder cancer.

CHEMOTHERAPEUTIC AGENTS

Alkylating agents are associated with the highest rates of male and female infertility, which is directly dependent on age, dose, and duration of treatment. The age at treatment is an important determinant of fertility outcome, with prepubertal patients having the highest tolerance. Ovarian failure is age-related, and females who resume menses after treatment are still at increased risk for premature menopause. Males generally have reversible azospermia during lower-intensity alkylator chemotherapy, and long-term infertility is associated with total doses of cyclophosphamide >9 g/m² and with high-intensity therapy such as that used in hematopoietic stem cell transplantation. Males undergoing potentially sterilizing chemotherapy should be offered sperm banking. However, some cancers are associated with defective spermatogenesis. Gonadotropin-releasing hormone (GnRH) analogues to preserve ovarian function remain experimental. Assisted reproductive technologies may be helpful to couples with chemotherapy-induced infertility.

RADIATION THERAPY

The testicles and ovaries of prepubertal patients are less sensitive to radiation damage; spermatogenesis is affected by low doses of radiation, and complete azospermia occurs at 600–700 cGy. Leydig cell dysfunction, in contrast, occurs at <2000 cGy; hence, endocrine function is lost at much higher radiation doses than spermatogenesis. Erectile dysfunction occurs in up to 80% of men treated with external-beam radiation therapy for prostate cancer. Sildenafil (and congeners) may be useful in reversing erectile dysfunction. Ovarian function damage with radiation is age-related and occurs at doses of 150–500 cGY. Premature induction of menopause can have serious medical and psychological sequelae. Hormone replacement therapy often is contraindicated, as in estrogen receptor–positive breast cancer. Attention must be paid to maintenance of bone mass with calcium and vitamin D supplements and oral bisphosphonates; this is monitored by bone density determinations. Paroxetine, clonidine, pregabalin, and other drugs may be useful in symptomatically controlling hot flashes. In those without contraindications, estrogen may be used for periods <5 years at the lowest dose that relieves symptoms.

Long–term survivors of childhood cancer (e.g., ALL) who have received cranial radiation may have altered leptin biology and growth hormone deficiency, leading to obesity and reduced strength, exercise tolerance, and bone density.

Radiation therapy to the neck, for example, in Hodgkin's lymphoma, may lead to hypothyroidism, Graves' disease, thyroiditis, and thyroid malignancies. Thyroid-stimulating hormone (TSH) is followed routinely in these patients and suppressed with synthroid when elevated to prevent hypothyroidism and suppress the TSH drive, which may cause thyroid cancer.

Cataracts may be caused by glucocorticoids, depending on the duration and dose; radiation therapy; and, uncommonly, tamoxifen. Orbital radiation therapy may cause blindness.

Radiation therapy can produce xerostomia (dry mouth) with an attendant increase in caries and poor dentition. Taste and appetite may be suppressed. Bisphosphonate use may result in osteonecrosis of the jaw.

Up to 40% of patients treated with bleomycin may develop Raynaud's phenomenon. The mechanism is unknown.

Second malignancies in patients cured of cancer are a major cause of death, and treated cancer patients must be monitored for their occurrence. The induction of second malignancies is governed by the complex interplay of a number of factors, including age, sex, environmental exposures, genetic susceptibility, and cancer treatment itself. In a number of settings, the events leading to the primary cancer themselves increase the risk of second malignancies. Patients with lung cancer are at increased risk of esophageal and head and neck cancers, and vice versa, due to shared risk factors, including alcohol and tobacco abuse. Indeed, the risk of developing a second primary head and neck, esophageal, or lung cancer is also increased in these patients. Patients with breast cancer are at increased risk of cancer in the opposite breast. Patients with Hodgkin's lymphoma are at risk for non-Hodgkin's lymphomas. Genetic cancer syndromes, for example, multiple endocrine neoplasia and Li-Fraumeni, Lynch, Cowden, and Gardner's syndromes, are examples of genetically based second malignancies of specific types. Cancer treatment itself does not appear to be responsible for the risk of these secondary malignancies. Deficient DNA repair can greatly increase the risk of cancers from DNA-damaging agents, as in ataxia-telangectasia. Importantly, the risk of treatment-related second malignancies is at least additive and often is synergistic with combined chemotherapy and radiation therapy; hence, for such combined therapy treatment approaches, it is important to establish the necessity of each modality in the treatment program. All these patients require special surveillance or in some cases prophylactic surgery as part of appropriate treatment and follow-up.

CHEMOTHERAPEUTIC AGENTS

Chemotherapy is significantly associated with two fatal second malignancies: acute leukemia and myelodysplastic syndromes. Two types of leukemia have been described. In patients treated with alkylating agents, acute myeloid leukemia is associated with deletions in chromosomes 5 or 7. The lifetime risk is about 1–5%, is increased by radiation therapy, and increases with age. The incidence of these leukemias peaks at 4–6 years, with risk returning close to baseline at 10 years. The other type of acute myeloid leukemia is related to therapy with topoisomerase inhibitors, is associated with chromosome 10q23 translocations, has an incidence <1%, and generally occurs 1.5–3 years after treatment. Both of these acute leukemias are refractory to treatment and have a high mortality rate. The development of myelodysplastic syndromes is increased after chemotherapy, particularly chronic alkylating agent therapy, and these syndromes often are associated with leukemic progression with a dismal prognosis.

RADIATION THERAPY

Patients receiving radiation have an increasing and lifelong risk of second malignancies that is 1–2% per year in the second decade after treatment but increases to >25% after 25 years. These malignancies include cancers of the thyroid and breast, sarcomas, and CNS cancers, which often tend to be aggressive and have a poor prognosis. An example of organ-, age-, and sex-dependent radiation-induced secondary malignancy is breast cancer, in which the risk is small with radiation age 30 but increases about twentyfold over baseline in women >30 years. A 25-year-old woman treated with mantle radiation for Hodgkin's lymphoma has a 29% actuarial risk of developing breast cancer by age 55 years.

HORMONAL THERAPY

Treatment of breast cancer with tamoxifen for 5 years or longer is associated with a 1–2% risk of endometrial cancer. Surveillance is generally effective at finding these cancers at an early stage. The risk of mortality from tamoxifen-induced endometrial cancer is low compared with the benefit of tamoxifen as adjuvant therapy for breast cancer.

IMMUNOSUPRESSIVE THERAPY

Immunosupressive therapy, as used in allogeneic bone marrow transplantation, particularly with T cell depletion and using antithymocyte globulin or other means, increases the risk of Epstein Barr virus–associated B cell lymphoproliferative disorder. The incidence at 10 years after T cell depletion is 9–12%. Discontinuation of immunosuppressive therapy, if possible, often is associated with complete disease regression.

All former cancer patients should be followed indefinitely. This is done most often by oncologists, but demographic changes suggest that more primary care physicians will need to be trained in the follow-up of treated cancer patients in remission. Cancer patients need to be educated about signs and symptoms of recurrence and potentially adverse effects related to therapy. Localized pain or palpable abnormality in a previously radiated field should prompt radiographic evaluation. Screening tests, when available and validated, should be used on a routine and regular basis, for example, mammography and Pap smear, particularly in patients receiving radiation to specific organs. Annual mammography should start no later than 10 years after breast radiation. Patients receiving radiation fields that encompass thyroid tissue should have regular thyroid exams and TSH testing. Patients treated with alkylating agents or topoisomerase inhibitors should have a complete blood count every 6–12 months, and cytopenias, abnormal cells on peripheral smear, or macrocytosis should be evaluated with bone marrow biopsy and aspirate, along with cytogenetics, flow cytometry, or fluorescence in situ hybridization (FISH) studies as appropriate.

Cancer survival, as the population lives longer and expands, has become an increasingly recognized subject. The Institute of Medicine and the National Research Council of the National Academy of Sciences have published a monograph titled From Cancer Patient to Cancer Survivor: Lost in Transition. It proposes a plan to inform clinicians caring for cancer survivors in complete detail about their previous treatments, the complications of those treatments, signs and symptoms of late effects, and recommended screening and follow-up procedures. Table 55-2 describes long-term treatment effects by cancer type.

Clearly, the challenge for the future is to combine chemotherapy, targeted agents, biologic therapies, radiation, and surgery to produce better outcomes with less toxicity, including late effects of therapy. This is easily said and less easily accomplished. As treatment becomes more effective in new patient populations (ovarian, bladder, anal, and laryngeal cancers, for example), one can expect to discover new populations at risk for late effects. These populations will have to be followed carefully so that such effects are recognized and treated. Cancer survivors represent an underutilized resource for prevention studies. Childhood cancer survivors especially have multiple chronic health impairments. The incidence of these late treatment consequences appears to have no plateau with age, throwing in stark relief the necessity of close monitoring and therapies with fewer late consequences of treatment.