Chapter 57: Late Consequences of Cancer and Its Treatment

There are over 10 million American cancer survivors. The vast majority of these will bear some mark of their cancer and its treatment, and a large proportion will experience long-term consequences including medical problems, psychosocial dysfunction, economic hardship, sexual dysfunction, and discrimination regarding employment and insurance. Many of these problems are directly related to cancer treatment. As patients survive longer from more types of malignancies, we are increasingly recognizing the biologic toll our very imperfect therapies take in terms of morbidity and mortality. The human face of these consequences of therapy confronts the cancer specialist who treats them every day. Although long-term survivors of childhood leukemias, Hodgkin’s lymphoma, and testicular cancer, as examples, have taught us much about the consequences of cancer treatment, we keep learning more as patients survive longer with newer therapies. Newer “targeted” chemotherapy drugs have their own, often unique, long-term toxicities about which we remain in a learning process. Cancer “survivorship” clinics are increasing to expressly follow patients for long-term toxicities of cancer treatment.

The pace of developing therapies that mitigate treatment-related consequences has been slow, partly due to an understandable aversion to alter 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 with 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, and neurocognitive impairment, and may act as a direct carcinogen. Cancer chemotherapy can be a direct carcinogen and has a kaleidoscope of other toxicities discussed in this chapter. Table 57-1 lists the late effects of cancer 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

Cardiovascular toxicity of cancer chemotherapeutic agents includes dysrhythmias, cardiac ischemia, 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, 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 are often important in raising suspicion. Dose-dependent myocardial toxicity of anthracyclines with characteristic myofibrillar dropout is pathologically pathognomonic on endomyocardial biopsy. Anthracycline cardiotoxicity occurs through a root mechanism of chemical free radical damage. Fe³⁺-doxorubicin complexes damage DNA, nuclear and cytoplasmic membranes, and mitochondria. About 5% of patients receiving >450–550 mg/m² of 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. The risk of cardiac failure appears to be substantially lower when doxorubicin is administered by continuous infusion. Anthracycline-related CHF is difficult to reverse and has a mortality rate as high as 50%, making prevention crucial. Some anthracyclines such as mitoxantrone are associated with less cardiotoxicity, and continuous-infusion regimens and liposomally encapsulated doxorubicin are associated with less cardiotoxicity. Dexrazoxane, an intracellular iron chelator, may limit anthracycline toxicity, but the concern of limiting chemotherapeutic efficacy has somewhat limited its use. Monitoring patients for cardiac toxicity typically involves periodic gated nuclear cardiac blood pool ejection fraction testing (multigated acquisition scan [MUGA]) or cardiac ultrasonography. More recently, cardiac magnetic resonance imaging (MRI) has been used, but MRI is not standard or widespread. Testing is performed more frequently at higher cumulative doses, with additional risk factors, and certainly for any newly developing CHF or other symptoms of cardiac dysfunction.

After anthracyclines, trastuzumab is the next most frequent cardiotoxic drug currently in use. Trastuzumab is frequently used as adjuvant breast cancer therapy, sometimes in conjunction with anthracyclines, which is believed to result in additive or possibly synergistic toxicity. In contrast to anthracyclines, cardiotoxicity 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 typically routinely monitored every three to four doses using functional cardiac testing as mentioned earlier for anthracyclines.

Other cardiotoxic drugs include lapatinib, phosphoramide mustards (cyclophosphamide), ifosfamide, interleukin 2, ponatinib, 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 following radiation therapy. Cardiac valvular disease includes aortic insufficiency from fibrosis or papillary muscle dysfunction resulting 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.

TREATMENT

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. A nonproductive cough with or without fever may be an early sign. 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 is generally obtained for future comparison prior to bleomycin therapy. Additive or synergistic risk factors include age, prior lung disease, and concomitant use of other chemotherapy, 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 frequently used 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, and radiation volume and dose. The dose “threshold” is thought to be in the range of 5 to 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 even occasionally involve the contralateral unirradiated lung.

TREATMENT

CHEMOTHERAPEUTIC AGENTS

Chemotherapy- and radiation-induced neurologic dysfunction is unfortunately increasing in both incidence and severity as a result of improved supportive care leading to more aggressive regimens and longer cancer survivorship allowing the development of late toxicity. Direct effects on myelin, glial cells, and neurons have all 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 careful patient history and physical examination by experienced oncologists to decide when the drug must be stopped due to toxicity. Milder toxicity often slowly completely resolves. Vinca alkaloids may sometimes 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 and hearing loss, especially at doses >400 mg/m², requiring audiometry in patients with preexisting hearing compromise. Carboplatin is often substituted in such cases given its lesser effect on hearing.

Many of the agents that target kinase enzymes in tumor cells and 5-fluorouracil congeners produce dysesthesias and painful hands and feet known as hand-foot syndrome or palmar-plantar erythrodysesthesia. Symptoms usually abate when the agent is stopped.

Neurocognitive dysfunction has been well described in childhood survivors of acute lymphoblastic leukemia (ALL) treatment, including intrathecal methotrexate or cytosine arabinoside in conjunction with prophylactic cranial irradiation. Methotrexate alone may cause acute leukoencephalopathy 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 is often ameliorated with glucocorticoid therapy. Chronic methotrexate toxicity (leukoencephalopathy) develops months or years after treatment and is characterized clinically as progressive loss of cognitive function and focal neurologic signs, which are irreversible, promoted by synchronous or metachronous radiation therapy, and more pronounced at a younger age.

Neurocognitive decline following 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. There is no clear mechanistic explanation for its cause and no clearly effective therapy. This entity is justifiably attracting more attention and clearly needs to be studied to develop effective therapy or prophylaxis.

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

RADIATION THERAPY

Acute radiation central nervous system (CNS) toxicity occurs within weeks; is characterized by nausea, drowsiness, hypersomnia, and ataxia; and is most often associated with recovery. Early delayed toxicity occurring weeks to 3 months following therapy is associated with similar symptoms as acute toxicity and is pathologically associated with reversible demyelination. Chronic, late radiation injury occurs 9 months to up to 10 years following 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 (CT) 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 may also be associated with an array of endocrine abnormalities with disruption of normal pituitary/hypothalamic axis function, and 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, for example, 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, there is venous congestion, epithelial cell proliferation, and hepatocyte atrophy progressing to frank fibrosis. Frequent monitoring of liver function tests during any chemotherapy is necessary to avoid both idiosyncratic and expected toxicities.

Certain nucleoside drugs have been associated with hepatic dysfunction; however, this complication is rare in oncology.

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 may also produce severe irreversible toxicity in the presence of renal disease and may predispose to accentuated damage with subsequent renal insults. Cyclophosphamide and ifosfamide, 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 MESNA (mercaptoethane sulfonate), which is required for ifosfamide administration. Hemorrhagic cystitis caused by these agents may predispose 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 azoospermia during lower intensity alkylator chemotherapy, and long-term infertility is associated with 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. Gonadotropin-releasing hormone (GnRH) analogs remain experimental to preserve ovarian function. Assisted reproductive technologies can be helpful to couples with chemotherapy-induced infertility.

RADIATION THERAPY

Testicles and ovaries in prepubertal patients are less sensitive to radiation damage; spermatogenesis is affected by low doses of radiation, and complete azoospermia occurs at 600–700 cGy. Leydig cell dysfunction, in contrast, occurs at <2000 cGy, and 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 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 is often 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, and bone mass should be monitored using bone density determinations. Paroxetine, clonidine, pregabalin, and other drugs may be useful in symptomatically controlling hot flashes.

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 (e.g., in Hodgkin’s lymphoma) may lead to hypothyroidism, Graves’ disease, thyroiditis, and thyroid malignancies. Thyroid-stimulating hormone (TSH) is followed routinely in such patients to prevent hypothyroidism, and to suppress persistently elevated levels of TSH which may cause or drive thyroid cancer.

Cataracts may be caused by glucocorticoids, depending on 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 as a result of an unknown mechanism.

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, gender, 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 breast cancer in the opposite breast. Patients with Hodgkin’s lymphoma are at risk for non-Hodgkin’s lymphomas. Genetic cancer syndromes (e.g., multiple endocrine neoplasia or Li-Fraumeni, Lynch’s, Cowden’s, 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-telangiectasia. Importantly, the risk of treatment-related second malignancies is at least additive and often synergistic with combined chemotherapy and radiation therapy, and hence for such combined-therapy treatment approaches, it is important to establish the necessity of each in the treatment program. All of 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 chromosome 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 of <1%, and generally occurs 1.5–3 years after treatment. Both of these acute myeloid leukemias are refractory to treatment and have a high mortality. The development of myelodysplastic syndromes is increased following chemotherapy, and these are often associated with leukemic progression and a dismal prognosis.

RADIATION THERAPY

Patients receiving radiation have an increasing and lifelong risk of second malignancies that is 1–2% in the second decade following 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 in women under age 30 but increases about 20-fold over baseline in women over 30. 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.

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 to the benefit of tamoxifen as adjuvant therapy for breast cancer.

IMMUNOSUPPRESSIVE THERAPY

Immunosuppressive therapy, as used in allogeneic bone marrow transplantation, particularly with T cell depletion 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%. Discontinuing immunosuppressive therapy, if possible, is often associated with complete disease regression.

All former cancer patients should be followed indefinitely. This is most often done 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 (e.g., 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 encompassing 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, to include cytogenetics, flow cytometry, or fluorescence in situ hybridization (FISH) studies as appropriate.

As the population of cancer survivors lives longer and grows, cancer survivorship has become an increasingly recognized subject, and the Institute of Medicine and National Research Council have published a monograph entitled From Cancer Patient to Cancer Survivor: Lost in Transition. The monograph proposes a plan that would inform clinicians caring for cancer survivors in complete detail of their previous treatments, complications thereof, signs and symptoms of late effects, and recommended screening and follow-up procedures. Table 57-2 lists 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 but less easily accomplished. As treatment becomes more effective in new patient populations (ovarian, bladder, anal, and laryngeal cancers, for example), we will expect to discover new populations at risk for late effects. These populations will need to be followed carefully, so that such effects are recognized and treated. Cancer survivors represent an underused resource for prevention studies. Childhood cancer survivors, especially, suffer 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.