A Risk-Based Approach to the Care of Survivors of Childhood Cancer: 3 Case Studies

Survivors of childhood cancer frequently present to primary care practitioners for a routine physical examination or for urgent care. Knowledge of the patient's cancer history and of the specifics of the treatment are essential to providing proper care and addressing his or her unique risks. The specific risks vary widely, depending on the type of cancer and the nature of treatment. Here we present the cases of 3 patients, each of whom had a history of a common pediatric cancer. The discussion and table that follow each vignette highlight the risks associated with the cancer in question and the most effective preventive and management strategies for survivors. Acute Lymphoblastic LeukemiaP.G. is a 14-year-old boy in whom high-risk acute lymphoblastic leukemia was diagnosed at the age of 9 years. He was treated with chemotherapy (daunorubicin, 125 mg/m2; doxorubicin, 150 mg/m2; high-dose methotrexate; dexamethasone; cyclophosphamide; vincristine; thioguanine; mercaptopurine; cytarabine; PEG-asparaginase; intrathecal methotrexate; and intrathecal cytarabine) and cranial radiation therapy (18 Gy) over the course of 36 months. He has been overweight since completing treatment and has been complaining of right hip pain for the past few months. Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood, accounting for almost one-quarter of all diagnoses in patients younger than 21 years, with a peak incidence between 2 and 5 years of age.1 Ongoing modifications in multidrug chemotherapy regimens, risk-stratified treatment, and prophylactic CNS-directed therapy have led to a 5-year survival rate in children that is approaching 90%.2 From the late 1960s to the early 1980s, the use of prophylactic cranial radiation therapy (CRT) at a standard dose of 24 Gy led to significant improvements in survival but with significant and frequent neurocognitive and neuroendocrine morbidities. Contemporary therapy is based on the risk of recurrence or CNS disease at diagnosis, with patients at low risk or standard risk treated over 30 months with induction, consolidation, and maintenance chemotherapy, including intrathecal methotrexate. Only the 5% to 15% of children with high-risk disease are treated with CRT in addition to chemotherapy-and then at a reduced dose of 18 Gy. CRT, neurocognitive problems, and endocrinopathy. In general, the risk of long-term complications in ALL survivors is related to whether CRT was required for cure; the risk is greatest in those treated with 24 Gy CRT, lowest in those treated with chemotherapy alone, and intermediate in those treated with 18 Gy CRT. Those treated with CRT may have mild to moderate neurocognitive problems that manifest primarily as learning difficulties in school. Rarely do ALL survivors have severe neurocognitive deficits such as those seen in brain tumor survivors, who were treated with much higher doses of CRT. An endocrinopathy (eg, growth hormone deficiency, hypothyroidism, insulin resistance, or diabetes), obesity, and physical inactivity may also develop in ALL survivors treated with CRT (Table 1, Table 1 continued); all of these contribute to an increased risk of premature cardiovascular disease. Girls, those treated at a younger age, and those who received higher-dose CRT (24 Gy vs 18 Gy) are at higher risk. Survivors treated with chemotherapy alone have a significantly lower risk of endocrinopathy, cognitive dysfunction, obesity, and physical inactivity. Risk of bone loss. Therapy for ALL is also associated with alterations in bone metabolism that can lead to osteopenia/osteoporosis or osteonecrosis. Studies have generally shown that children who are receiving therapy for ALL or who have recently completed it may have reduced bone mineral density (BMD). However, over time, most patients' BMD will return to normal or near-normal. The etiology of bone loss is multifactorial, with CRT, high-dose methotrexate, corticosteroids, growth hormone deficiency and/or gonadotropin deficiency, low calcium intake, and reduced physical exercise all contributing to risk. Osteonecrosis, or avascular necrosis, of the larger joints (eg, hip, knee, shoulder, or elbow) is an infrequent but debilitating sequela of high-dose corticosteroids. It is most commonly seen in children older than 10 years while they are receiving therapy. However, patients who have recently completed therapy can also present with symptoms. The frequency of osteonecrosis has increased since higher-potency glucocorticoids have become a mainstay of therapy. Outcome of this case. A history and examination guided by P.G.'s previous ALL therapy and his hip pain were performed. Of note, he had had recent difficulties in school and his grades had been slowly worsening. Otherwise, his history was unremarkable; it revealed no experimentation with illicit drugs, tobacco, or alcohol and no symptoms of depression. His height and Tanner stage were appropriate for his age. His body mass index was at the 90th percentile for his age and sex. Examination of his right hip revealed decreased range of motion and pain on weight bearing. Results of the examination were otherwise unremarkable. Based on P.G.'s ALL therapy, the following screening tests were recommended: • Fasting laboratory tests (lipid profile; complete blood cell count with differential; levels of glucose, blood urea nitrogen, creatinine, electrolytes, calcium, magnesium, phosphate, aspartate transaminase, alanine transaminase, total bilirubin, thyroid-stimulating hormone, and free thyroxine). • Urinalysis. • Echocardiogram. • ECG. • Dual-energy x-ray absorptiometry. He was referred for a formal neuropsychological evaluation and counseled regarding avoidance of tobacco, alcohol, and illicit drugs. He was also counseled regarding the benefits of a low-fat diet and adequate physical activity, a dental examination with cleaning every 6 months, and an evaluation for cataracts by an ophthalmologist every 3 years. To further evaluate his hip, an MRI scan of the right hip was ordered; this showed bone marrow edema, articular cartilage damage, and a joint effusion. P.G. was referred to an orthopedic surgeon for further evaluation and management of his osteonecrosis. REFERENCES: 1. Ries LAG, Melbert D, Krapcho M, et al; National Cancer Institute. SEER cancer statistics review, 1975-2004. http://seer.cancer.gov/csr/1975_2004/. Published 2007. Accessed March 27, 2008. 2. Pui CH, Relling MV, Sandlund JT, et al. Rationale and design of Total Therapy Study XV for newly diagnosed childhood acute lymphoblastic leukemia. Ann Hematol. 2004;83(suppl 1):S124-S126. 3. Children's Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. http://www.survivorshipguidelines.org. Published March 2006. Accessed January 30, 2008. Hodgkin LymphomaJ.S. is a 34-year-old woman who has just moved to town and presents for a routine physical examination. She had stage I Hodgkin lymphoma (HL) at age 14; she was treated with 44 Gy mantle radiation following a staging laparotomy and splenectomy. She has not seen an oncologist in over 15 years. Curing HL was one of the early success stories in the treatment of children with cancer. By the early 1980s, more than 80% of children with HL were living to become long-term survivors.1 The impressive rate of cure that began during that era was largely the result of the radiosensitive nature of HL. Pediatric patients with involvement of the mediastinal lymph nodes, the most common location of HL, received the standard treatment of about 40 Gy of radiation to the "mantle" field (this encompassed the primary lymph node regions of the neck and the supraclavicular, infraclavicular, axillary, and mediastinal areas). In the 1990s, when it was recognized that mantle radiation often led to second cancers and heart disease, multi-modal risk-adapted therapy evolved. The field and dose of radiation was reduced and radiation therapy was combined with chemotherapy. Now, fewer than 50% of children and adolescents with HL receive radiation therapy. Risk of second cancers. HL survivors whose cancer was treated with radiation have a significantly elevated risk of second (or subsequent) cancers, including thyroid, skin, lung, breast (in women), and other solid tumors in the ra-diation field (Table 2). The risk of breast cancer begins to increase 8 years after radiation therapy. In female HL survivors who received mantle radiation therapy before they were 21, breast cancer will have been diagnosed in 15% to 20% by the time they reach the age of 45 years. The cumulative risk of breast cancer in these young women is similar to that seen in women with a BRCA 1 or BRCA 2 mutation. Early detection of breast cancer in these women is imperative. First, an earlier stage of breast cancer at diagnosis is strongly associated with increased survival. In addition, the therapeutic options for women with breast cancer who received radiation therapy for HL as children or teens are limited because of their previous mantle radiation. Thus, the Children's Oncology Group (and other similar groups) recommends an annual mammogram and breast MRI starting at age 25 years or 8 years after the radiation, whichever occurs last. Risk of heart disease. Men and women who received mantle radiation for HL have a significantly increased risk of cardiovascular disease, including ischemic coronary artery disease, valvular heart disease, arrhythmias, and left ventricular dysfunction. By 20 years after mantle radiation, ischemic coronary artery disease will have been diagnosed in 20%; by 30 years, 13% will have sustained a myocardial infarction. Clinically significant valvular heart disease occurs in about 5% to 10% of these patients, with the aortic and mitral valves being most commonly affected. Vulnerability to infection. Before the advent of CT scans and the use of systemic chemotherapy, most patients with HL were evaluated for stage of disease by laparotomy, lymph node biopsy, and splenectomy. Thus, many HL survivors treated in the 1960s through the 1980s are asplenic. Because of poor defenses against encapsulated organisms, these patients have a 2% to 4% lifetime risk of overwhelming sepsis, with a 1% to 2% mortality rate. Proper education regarding this risk, appropriate re-immunization, and prompt medical evaluation during febrile episodes can substantially reduce the risk. Thyroid, lung, and muscle problems. Mantle radiation is also associated with other health problems. By 25 years after radiation therapy, over two-thirds of HL survivors will have hypothyroidism, many will have thyroid nodules, and fewer than 5% will have hyperthyroidism. Mantle radiation unaccompanied by chemotherapy that is toxic to the lungs (eg, bleomycin) generally does not cause severe pulmonary disease; however, it may result in mild to moderate obstructive or restrictive lung disease or a reduction in the diffusion capacity. Also, moderate- to higher-dose mantle radiation (35 to 55 Gy) is associated with radiation fibrosis and atrophy of the posterior cervical, supraspinatus, infraspinatus, trapezius, and rhomboid muscles, resulting in pain and loss of function. Outcome of this case. A history and physical examination guided by J.S.'s previous Hodgkin therapy were performed. Results were generally unremarkable. J.S. is a lawyer and in good health. No thyroid nodules were palpated, no carotid artery bruits were auscultated, her brachial and radial artery pulses were not diminished, findings from her breast examination were unremarkable, and there were no atypical skin lesions within the radiation field. A murmur consistent with mitral regurgitation was heard. Based on her previous mantle radiation, the following screening tests were recommended: • Fasting laboratory tests (lipid profile; levels of glucose, thyroid-stimulating hormone, and free thyroxine). • Mammogram and breast MRI scan. • Echocardiogram. • ECG. • Pulmonary function tests with carbon monoxide-diffusing capacity. • Baseline chest radiograph. J.S. was congratulated on her active lifestyle, low-fat diet, and avoidance of smoking. She was taught how to perform breast self-examination. A dental examination with cleaning every 6 months was recommended. Finally, she was counseled regarding her infection risk, a result of her asplenic condition. Because she had not received a polyvalent pneumococcal vaccine booster since her re-immunization after splenectomy, she was given pneumococcal, meningococcal, and Haemophilus influenzae vaccinations. REFERENCES: 1. Ries LAG, Melbert D, Krapcho M, et al; National Cancer Institute. SEER cancer statistics review, 1975-2004. http://seer.cancer.gov/csr/1975_2004/. Published 2007. Accessed March 27, 2008. 2. Children's Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. http://www.survivorshipguidelines.org. Published March, 2006. Accessed January 30, 2008. OsteosarcomaS.B. is a 24-year-old woman in whom nonmetastatic osteosarcoma of the left distal femur was diagnosed when she was 14 years old. She was treated with chemotherapy (including doxorubicin [cumulative dose of 450 mg/m2], cisplatin, and high-dose methotrexate) and a limb-sparing surgery. For the past few weeks, she has experienced shortness of breath with minimal exertion. Osteosarcoma is the third most frequent neoplasm in adolescents and young adults, with the peak incidence in the second decade of life, during the adolescent growth spurt. Up until the past few decades, the majority of these patients died, even with aggressive surgery. With the development of effective adjuvant chemotherapy, the cure rates for nonmetastatic disease have risen to about 70%.1 Standard treatment now includes adjuvant chemotherapy with doxorubicin, cisplatin, and methotrexate. In addition, local control of the tumor is often achieved with surgery. Amputation is the traditional surgical approach, which permits removal of all gross and microscopic tumor with clean margins. However, because of improvements in adjuvant therapy, most patients are currently offered limb-sparing procedures, including allografts, endoprostheses, and metallic prostheses. Limb-sparing procedures and amputation each have advantages and disadvantages with respect to late functional outcomes, and numerous studies have shown little or no difference in quality of life. Anthracycline therapy and congestive heart failure. Anthracycline therapy (eg, treatment with doxorubicin, daunorubicin, or idarubicin) leads to the release of free radicals that damage cardiac myocytes; it may result in late-occurring left ventricular dysfunction and congestive heart failure (Table 3, Table 3 continued). The prevalence of subclinical cardiotoxicity in patients who received more than 300 mg/m2 of anthracycline ranges from 19% to 52%, depending on the study. By 20 years after anthracycline therapy of 300 mg/m2 or more, clinical heart failure develops in about 10% of patients.2,3 In addition to higher cumulative dosing, risk factors for late-onset cardiomyopathy and left ventricular dysfunction include female sex, early age at treatment, previous chest or mantle radiation, and longer time since treatment. Other chemotherapy-related risks. Cisplatin is associated with irreversible high-frequency hearing loss, especially in higher cumulative doses (400 mg/m2). Clinically significant hearing loss will develop in about one-third of patients. Dose-related nephrotoxicity is also observed following therapy with cisplatin; it may present as azotemia or tubular injury with electrolyte wasting. Both of these problems are generally apparent during therapy or soon thereafter. High-dose methotrexate is an important component of osteosarcoma therapy. As described in the case of the 14-year-old boy with leukemia, methotrexate is associated with bone loss both during and after therapy. Outcome of this case. A history and physical examination were performed, guided by S.B.'s previous osteosarcoma therapy and the recent development of dyspnea with exertion. She denied any orthopnea or paroxysmal nocturnal dyspnea, chest pain, or anginal equivalent. For the past 2 months, she has felt more fatigued in general. She walks with a mild limp but is fairly active. Her history was otherwise unremarkable. Physical examination revealed a hyperdynamic precordium and a soft S3 heart sound. No rales were audible on auscultation, and no jugular venous distention was evident. A well-healed scar was visible on her left leg. The remainder of the physical findings were normal. To further evaluate her dyspnea on exertion and S3 heart sound, an echocardiogram and ECG were ordered and she was referred to a cardiologist. In addition, in light of her osteosarcoma therapy, the following screening tests were recommended: • Fasting laboratory tests (lipid profile; complete blood cell count with differential; levels of blood urea nitrogen, creatinine, electrolytes, calcium, magnesium, phosphate, aspartate transaminase, alanine transaminase, and total bilirubin). • Urinalysis. • Audiogram. • Dual-energy x-ray absorptiometry. S.B. continues to be followed up by her orthopedic surgeon. REFERENCES: 1. Ries LAG, Melbert D, Krapcho M, et al; National Cancer Institute. SEER cancer statistics review, 1975-2004. http://seer.cancer.gov/csr/1975_2004/. Published 2007. Accessed March 27, 2008. 2. Kremer LC, van Dalen EC, Offringa M, Voute PA. Frequency and risk factors of anthracycline-induced clinical heart failure in children: a systematic review. Ann Oncol. 2002;13:503-512. 3. Kremer LC, van der Pal HJ, Offringa M, et al. Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review. Ann Oncol. 2002;13:819-829. 4. Children's Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. http://www.survivorshipguidelines.org. Published March 2006. Accessed January 30, 2008.