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Editorial Indian Pediatrics 1999;36: 975-980 |
Long-Term Complications Following Childhood Cancer |
Neurocognitive Complications Late neurocognitive sequelae of childhood cancer treatment most often occur as a result of radiation to the whole brain or as a consequence of therapy with high-dose or intrathecal metho-trexate. Risk factors include radiation dose, concomitant treatment with both cranial radia-tion and systemic or intrathecal methotrexate, young age at time of treatment, and female gender(1). Affected children may have diffi-culty attaining age-appropriate developmental milestones. Information processing deficits are commonly experienced and may result in academic difficulties including problems with receptive expressive language, visual and perceptual motor skills, attention span, reading, language, and mathematics(2). All children who have received therapy capable of causing neurocognitive deficits should be monitored closely for problems with school performance. If any deficits are noted, referral for neuropsychiatric evaluation should be undertaken. Appropriate adaptations should be made to foster attainment of the child's greatest educational potential, including curricular modifications and utilization of special services such as speech and language therapy(3). Auditory Complications Ototoxic agents commonly used in the treatment of childhood cancer include platinum-based chemotherapy, aminoglycoside, loop diuretics and radiotherapy; all are capable of causing sensorineural hearing loss. Children who received ototoxic agents during their cancer treatment should undergo periodic audiologic evaluations. Interventions for hearing loss associated with cancer treatment include hearing aids and assistive devices, special classroom seating, and for more severely affected children, placement in special educational environments for the hearing impaired. Referral to a pediatric audiologist or otologist for evaluation and ongoing management is indicated for all children experiencing hearing loss related to their cancer treatment(4). Ocular Complications Children who received total body irradiation or radiation to the brain, head, or orbit, as well as children treated with busulphan or long-term corticosteroids are at risk for cataract formation and dry eyes. Those children who received orbital radiation are at risk for retinitis, iritis, glaucoma, blepharitis, corneal ulceration, dry eyes, optic nerve damage, and orbital hypoplasia(5). Ocular sequelae of childhood cancer therapy should be managed collabora-tively with an ophthalmologist. Interventions may include various ophthalmic drops and ointments as well as surgical modalities including cataract extraction and photoco-agulation. Preservation of sight is the overall goal. Cardiovascular Complications The anthracyclines are well-known causes of cardiomyopathy. The onset of cardio-myopathy may be spontaneous or may coincide with exertion or pregnancy, and can occur many years after completion of therapy. The incidence of cardiomyopathy is dose-dependent. Risk factors known to be associated with anthracycline-induced cardiac toxicity include mediastinal radiation, underlying cardiac abnormalities, uncontrolled hyper-tension, exposure to other chemotherapeutic agents (particularly cyclophosphamide, dactino-mycin, DTIC, vincristine, bleomycin and methotrexate), female gender and younger age. The schedule of anthracycline administration also is important, with lesser toxicity for continuous infusions or weekly doxorubicin compared with every-3-week boluses(6,7). Chronic toxicity caused by radiation alone usually involves pericardial effusions or constrictive pericarditis. Because of the known long latency, a yearly history and physical examination is recommended in patients identified to be at high risk. In addition, an echocardiogram is recommended every 2 to 3 years for patients with a history of anthracycline therapy(8). Pulmonary Complications Radiation-induced restrictive lung disease may be seen in patients who received whole lung radiation. Children younger than 3 years of age at time of therapy appear to be more susceptible to chronic toxicity(9). Bleomycin is also associated with lung injury. The toxicity is dose-dependent and is exacerbated by con-current or previous radiation therapy, cyclophosphamide or subsequent oxygen therapy(10). Yearly follow-up should include evaluation for symptoms of pulmonary dysfunction, including chronic cough or dyspnea. Chest radiographs should be obtained every 2 to 5 years. Pulmonary function testing should be performed in symptomatic patients, or for those who require general anesthesia. In addition, all patients must be counseled regarding the risks of smoking. Endocrine Complications Hypothyroidism is almost always related to radiation of the neck, occurring most commonly between 1.5 and 6 years following therapy. Thyroid cancers, thyroid nodularity and exophthalmos have been reported in some patients. Patients who have received neck radiation should be routinely screened for thyroid abnormalities by physical examination and by biochemical measures on an annual basis for at least six years after radiation. Evaluation and treatment by an endocrinologist are recommended if any abnormalities are detected. Decreased linear growth is a common problem during therapy in children with cancer. Although catch-up growth may occur, in some instances short stature is permanent or even progressive. Whole-brain irradiation has been identified as the principal cause of short stature for patients treated for acute lymphoblastic leukemia. The effects of cranial irradiation appear to be age-related, with children less than five years at time of therapy being more susceptible to the radiation effect(11). Monitoring long-term survivors for growth relies on the use of standardized curves. For children with abnormal growth patterns, collaborative evaluation and management with an endocrinologist is recommended. Germ cell depletion and abnormalities of gonadal endocrine function are observed in male survivors of cancer secondary to radiation, chemotherapy or surgery, with the effects of therapy varying with age at treatment. Patients should be routinely screened for gonadal dysfunction, with specific attention to problems with libido, impotence or fertility, and examina-tion for gynecomastia and Tanner staging. Hormonal evaluation, including measurement of serum LH, FSH and testosterone levels, should be obtained in pubertal boys and in boys with delayed puberty. When abnormalities are detected, close collaboration with an endocri-nologist is essential in planning hormonal replacement therapy. The effects of radiation on the ovary are both age-and dose-dependent. Ovarian failure has been observed after chemotherapy, particularly with alkylating agents, and also commonly occurs following radiation involving the ovaries. The diagnostic evaluation includes menstrual history, examination of the Tanner stage, and serum gonadotropin and estradiol levels. Because of increased risk of premature menopause, follow-up should be life-long. Gastrointestinal Complications Late effects of childhood cancer treatment on the gastrointestinal (GI) tract are most often related to surgery and radiation therapy. The most common late GI toxicities include adhesions, stricture formations, fibrosis and malabsorption(12). Children most likely to be affected are those who have undergone abdominal surgery for tumor resection or radiation with fields involving the GI tract. Appropriate surveillance includes careful history and physical examination and yearly complete blood count (CBC) to detect microcytic anemia associated with GI bleeding or macrocytic anemia associated with mal-absorption. In addition, serum protein and albumin levels should be monitored every 3 to 5 years in those patients at high risk for enteritis. Renal Complications Cisplatin and ifosfamide are the primary chemotherapeutic agents responsible for long-term renal damage in children treated for cancer. Cisplatin damages the glomerulus as well as the distal renal tubules and can result in persistently decreased glomerular filtration rate (GFR) and electrolyte loss in the urine, especially of magnesium, calcium, potassium and sodium(13). Ifosfamide causes damage to the proximal renal tubule, which may result in the Fanconi's renal syndrome of glucosuria, proteinuria, renal tubular acidosis, hypokalemia, hypophosphatemia and rickets(14). Although many children experience improvement in GFR over time, hypomagnesemia associated with cisplatin therapy and electrolyte wasting associated with ifosfamide therapy appear to persist in some children(15). Surveillance should include urinalysis, blood pressure measurement, and monitoring of serum creatinine, blood urea nitrogen and serum chemistries. Ongoing management includes electrolyte replacement, treatment of hypertension, and avoidance of further nephro-toxic agents. Patients with a history of nephrec-tomy should be counseled regarding the importance of avoiding contact sports, reducing sodium intake, avoiding potentially nephrotoxic agents, maintaining normal weight and obtain-ing early intervention for urinary tract infections in order to protect the remaining single kidney. Musculoskeletal Complications Osteoporosis may occur as a consequence of childhood cancer treatment, resulting in fractures of long bones and compression fractures of the vertebrae. The occurrence of osteoporosis may be related to renal toxicities of childhood cancer treatment and their resultant electrolyte wasting, especially of calcium and phosphorus. Other risk factors include therapy with corticosteroids, high-dose methotrexate, cranial irradiation, and premature menopause(15). Preventive measures and inter-ventions for asymptomatic osteoporosis include calcium supplementation, weight-bearing exer-cise, and hormone replacement if indicated. For those with more advanced bone demineraliza-tion, orthopedic and/or endocrine consultation and management should be obtained. Other musculoskeletal sequelae commonly seen in childhood cancer survivors include gait disturbances and weakness, avascular necrosis, scoliosis, kyphosis, and growth deficits secondary to radiation effects on bones, soft tissues and blood vessels. Radiation may cause physeal growth injury to the bones in growing children, resulting in arm and leg length discrepancies and spinal abnormalities. Children at greatest risk are those undergoing rapid growth, such as during infancy, early childhood and adolescence. Other risk factors include higher radiation doses, asymmetrical treatment fields, and large tissue treatment volumes(16). Second Malignant Neoplasms Survivors of childhood cancer are estimated to have a 10 to 20 times the lifetime risk of second cancers as compared to the general population(17). The incidence and type of second malignancy differs with the primary diagnosis, type of therapy received, and presence of genetic conditions. Patients at particularly high risk include those with Hodgkin's disease, retinoblastoma, the genetic form of Wilms' tumor, neurofibromatosis, xeroderma pigmen-tosum, Klinefelter's syn-drome, immunodeficiency, and patients who received high doses of radiation therapy or alkylating agents. Secondary myelodysplasia and myeloid leukemia are associated with alkylating agents in a dose-dependent fashion. Epipodophyllo-toxins and nitrosoureas have also been associated with secondary leukemia(18). Non-hematologic tumors are classically associated with radiation therapy, with the majority developing within the radiation port(19). These tumors include bone and soft tissue sarcomas and skin and thyroid carcinomas and breast cancers. An increased incidence of radiation-associated brain tumors also have been reported, occurring primarily in children treated for CNS leukemia when less than 5 years(20). Surveillance/Health Promotion Strategies Follow-up of the sequelae of childhood cancer treatment is complex and best done in a clinic familiar with current and past treatment of pediatric oncology patients. Ideally, the follow-up should involve a multidisciplinary team approach. Frequency of required follow-up visits depends on the disease, intensity of therapy, and treatment sequelae. At a minimum, all patients should receive a detailed yearly history and physical examination including evaluation of sexual maturation, height, weight, and blood pressure measurements, vision and hearing screening, complete blood count and urinalysis. Evaluation of cognitive and social functioning should be completed as well. Additional investigations, evaluations, and interventions depend on diagnosis, treatment, and results of the history and physical examination. As survivors of childhood cancer become young adults, they should be made aware of the importance of understanding their diagnosis and treatment history, and of providing this information to healthcare personnel who may be unfamiliar with their medical history. In addition, patients should be provided with a written summary of their cancer treatment and health status. Childhood cancer survivors should also receive information regarding health-promotion strategies aimed at cancer risk reduction. Counselling should include advice regarding smoking cessation or avoidance, the risks of sun exposure, and information regarding proper nutrition and exercise. In addition, patients should be taught cancer detection methods, including self-breast or testicular and skin examinations. Routine cancer screening exa-minations, such as mammograms and stool testing for occult blood, should be conducted as indicated based on age, gender and risk related to the child's specific diagnosis and treatment. Conclusion Follow-up care for patients with a history of cancer in childhood should be tailored according to primary disease and therapy received, and a multidisciplinary approach should be employed for the surveillance and management of long-term complications. In order to optimize quality of life for childhood cancer survivors, emphasis should be placed on health promotion strategies as well as prevention and early detection of treatment-related sequelae. 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