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 Leukemia
P.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(Drug information on doxorubicin), 150 mg/m2; high-dose methotrexate(Drug information on methotrexate); dexamethasone(Drug information on dexamethasone); cyclophosphamide(Drug information on cyclophosphamide); vincristine; thioguanine; mercaptopurine(Drug information on mercaptopurine); cytarabine(Drug information on 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(Drug information on 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(Drug information on 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.