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Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Chapter Overview
Advances in therapies over the past four decades have improved overall survival for children and adolescents with cancer. Currently, 80% of patients diagnosed with cancer before the age of 20 years will survive beyond 5 years from diagnosis. Improved outcomes have resulted in a growing population of adult survivors of childhood cancer. Survival of childhood cancer comes at the price of lifelong chronic health issues in at least 62% of survivors. Radiation therapy, especially at a young age, carries the highest risk of late adverse outcomes. Radiation therapy has been associated with an increased risk for late premature mortality, subsequent neoplasms, obesity, and pulmonary, cardiac, and thyroid dysfunction, as well as an increased overall risk for chronic health conditions. Surgery and chemotherapy also increase the risk for chronic health conditions such as cardiomyopathy, osteoporosis, renal dysfunction, hearing loss, pulmonary dysfunction, and liver dysfunction. Although many survivors are satisfied with their quality of life, long-term follow-up for all adult survivors of childhood cancer is recommended to screen for second malignancies and late effects of therapy, make appropriate referrals for care of treatment-related health conditions, and provide psychosocial support and advice. This chapter will discuss the practices and recommendations for care of adult survivors in the Childhood Cancer Survivor Clinic at MD Anderson.
Introduction
Substantial improvements in treatment effectiveness for childhood cancers have resulted in cure or increased survival times for this population. Current estimates are that 80% of all patients diagnosed with cancer before the age of 20 years will be cured. As a consequence of both improved survival rates and increasing incidence of childhood cancer, the number of long-term survivors of childhood cancer in the United States is rapidly increasing. An estimated 320,000 or more childhood cancer survivors are living in the United States, and at least 75% of these survivors are now adults. Of these, 24% have survived more than 30 years (Mariotto et al. 2009).
These individuals are living long enough to demonstrate the human costs of cure (Diller et al. 2009). Short- and long-term side effects of treatment are common and have the potential to adversely affect the survivor’s future physical, cognitive, and psychosocial health. Some problems, such as cognitive deficits from cranial radiation therapy, are apparent within 3–5 years after completion of therapy. However, other problems occur after long latencies. For example, the risk for anthracycline-induced cardiomyopathy can continue for decades after the treatment. In an epidemiologic study of childhood cancer survivors treated between the 1960s and early 1990s, investigators found that 62% of adult survivors of childhood cancer had at least one chronic health condition and 27% had a severe condition (grade 3 or 4) related to the cancer or treatment. The most common severe and life-threatening (grade 3 and 4) chronic health conditions identified in the national Childhood Cancer Survivor Study were as follows, in decreasing order of incidence: major joint replacement, congestive heart failure, second malignant neoplasm, cognitive dysfunction, coronary artery disease, cerebrovascular accident, renal failure, hearing loss, legal blindness or loss of an eye, and ovarian failure (Oeffinger et al. 2006).
There is a growing need to screen for and, if possible, prevent or decrease late-occurring problems such as heart disease, thyroid dysfunction, osteoporosis, and second malignancies to promote and maximize the physical and psychosocial health of long-term cancer survivors and their families. With this in mind, the Children’s Oncology Group has developed evidence-based guidelines that recommend follow-up screening and care of childhood cancer survivors who are at risk for late effects (available at http://www.survivorshipguidelines.org). These guidelines for follow-up and surveillance for known late effects of cancer and cancer treatment are quite specific for the exact type of treatments and doses of chemotherapy and radiation that the patient received. They are primarily designed for use in specialized clinics for childhood cancer survivors. However, many adult survivors of childhood cancer, for various reasons, do not attend a specialized clinic for childhood cancer survivors, relying instead on their local physicians for care. This chapter will discuss the main principles of care of adult survivors of childhood cancer that are used in the Childhood Cancer Survivor Clinic at MD Anderson and highlight the most important issues for primary care physicians in the community.
Common Childhood Cancers
Childhood cancers comprise an extensive array of types of cancers, but most childhood cancers fall into categories of disease that are uncommon in adults. Carcinomas are rarely seen in children but can occur in adolescents. The most common types of childhood cancer are leukemia/lymphoma, embryonal cancers such as neuroblastoma, Ewing sarcoma, primitive neuroectodermal tumor/medulloblastoma, Wilms tumor of the kidney, rhabdomyosarcoma, and other central nervous system tumors. Among central nervous system tumors, the most common to appear in children include low-grade astrocytoma, medulloblastoma, and ependymoma; anaplastic astrocytoma and glioblastoma are more commonly seen in adults. Low-grade astrocytoma, medulloblastoma, and ependymoma have higher survival rates than other types of brain tumors; thus, the population of adult survivors of childhood brain tumors is increasing. Germ cell tumors also occur in children. The types of cancer associated with the highest numbers of current living survivors are brain tumors, acute lymphoblastic leukemia, germ cell tumors, and Hodgkin lymphoma. Among adult survivors of childhood cancer who were diagnosed before 1975, the most common sites of the original cancer are germ cells, soft tissue, kidneys, and bones (Mariotto et al. 2009).
Surveillance for Recurrence of Primary Cancer
Children and young adults are eligible for referral to the Childhood Cancer Survivor Clinic at MD Anderson when they are in remission or free of progressive cancer and 2 years have passed since treatment was completed. For most types of childhood cancer, disease surveillance tests are performed until 5 years have passed since treatment was completed. Each type of childhood cancer has specific recommendations for disease surveillance that are based on tumor location, most common site of metastatic disease, and natural history of the primary cancer. Any childhood cancer survivor referred back to the primary physician for continued surveillance should have detailed recommendations from the pediatric oncologist. If recommendations are not provided, it is appropriate to request this information. All patients in our Childhood Cancer Survivor Clinic who are transferred to the community are given a “Passport for Care” (Horowitz et al. 2009) that includes recommendations for both surveillance and monitoring for late effects of therapy. It is beyond the scope of this chapter to provide detailed recommendations for every type of childhood cancer. However, most survivor clinics do not recommend continued disease surveillance for more than 5 years after treatment completion because the risk of recurrence is low.
Some exceptions exist, however. For example, patients who had central nervous system tumors and patients who have already had one recurrence are at increased risk of recurrence beyond 5 years. In our clinic, patients with central nervous system tumors usually undergo routine magnetic resonance imaging of the brain for 10 years after treatment completion and then follow-up imaging for any symptoms or physical findings on a neurologic examination. This recommendation is based on a study of long-term follow-up of childhood brain tumor survivors who had survived for more than 5 years. In these patients, the risk of recurrence or death from the primary tumor continued for up to 30 years. Cumulative all-cause mortality rates were 13.5% at 15 years, 17.1% at 20 years, 21.5% at 25 years, and 25.8% at 30 years. Progression of primary disease was the cause of death in 61% of patients, followed by medical causes, including second neoplasm, in 9% (Armstrong et al. 2009).
Treatment-Related Late Effects
A complete list of late effects of treatment for childhood cancers is available at http://www.survivorshipguidelines.org and in an excellent publication (Dickerman 2007). The following treatment-related late effects are the most common ones that we encounter in the Childhood Cancer Survivor Clinic at MD Anderson.
Surgery
The late effects of cancer surgery are primarily related to the type of surgery and age of the patient at the time of the procedure. The following sections provide brief summaries of the most common surgery-related problems that we see in our adult survivors of childhood cancer.
Neurosurgery
The removal of a brain tumor can sometimes be curative. However, the consequences of neurological deficits that sometimes occur as a consequence of central nervous system surgery can be life-long. The seriousness of the deficit is related to the tumor location in the brain. Childhood brain tumors are most commonly found in the cerebellum and midline of the brain. Cerebellar surgery about 10% of the time can result in transient cerebellar mutism. The mutism usually resolves within 6 months, but patients often have learning and speech problems that are permanent. In addition, cranial nerve deficits caused by surgery can be permanent, resulting in such problems as hearing loss, visual deficit or field cut, or facial weakness. Tumors located in the region of the hypothalamus, such as juvenile pilocytic astrocytoma, germ cell tumors, and craniopharyngioma, are a particular problem. Both the tumor itself and the surgery can result in panhypopituitarism with hormonal deficiencies that can lead to life-threatening long-tern problems, even if hormone replacement therapy is available. For these patients, care by an endocrinologist is essential.
After a craniotomy, patients are also at risk for seizures or headaches. Both can be concerning as a sign of a recurrent or secondary tumor. However, more commonly the seizures are related to the scarring and gliosis at the site of the original surgery. Tumors in the cerebral hemispheres, especially the temporal and frontal lobes, are most often associated with seizures that can begin years after the surgery and other treatments are completed.
Orthopedic Surgery
Bone tumors such as osteosarcoma and Ewing sarcoma most commonly affect the long bones. Patients are treated with either amputation or limb-salvage surgery. Some patients who have undergone amputation and have a well-fitting prosthetic limb can function very well with little limitation to activity. Others experience chronic pain and even phantom pain for decades after the procedure. Limb-salvage surgery, although it spares the limb and is psychologically appealing to patients, requires follow-up by the orthopedic surgeon for years to ensure the integrity of internal hardware and reconstruction. For prepubescent children who have undergone laminectomy to remove a primary spinal cord tumor, kyphosis and scoliosis can occur when the children reach the adolescent growth spurt. Sometimes the curvature is severe enough that orthopedic intervention is necessary during the adolescent or young adult years.
Thoracic and Abdominal Surgery
In patients who undergo abdominal surgery, the risk of bowel obstruction caused by adhesions lasts for as long as 20 years or more after the surgery. Surgical intervention may also be responsible for surgical menopause or sterility. Secondary problems related to oophorectomy and the resulting premature menopause include bone loss, osteopenia and osteoporosis, and loss of fertility. In our clinic, screening for osteoporosis begins during adolescence for patients who have premature menopause.
Patients who have undergone splenectomy or spleen ablative therapy are at particular risk for infections. These patients should be placed on a prophylactic antibiotic, usually penicillin or erythromycin, during childhood. However, regardless of age, anyone who has undergone splenectomy should receive prompt medical attention and antibiotics for suspected bacterial febrile illnesses. Pneumococcal vaccine to prevent pneumococcal pneumonia should also be given routinely: the generally accepted immunization schedule for pneumococcal vaccine is every 5 years. Patients who do not have a functioning spleen should also be vaccinated against hepatitis B.
Chemotherapy
Long-term and late effects of chemotherapy include potential injury to the heart, liver, lungs, gonads, kidneys, and bone marrow. Some of these late effects are increased in prepubescent children who are still growing. Issues specific to this population are discussed here.
Heart
Cardiotoxicity is one of the most serious chronic complications of treatment for cancer, and children are particularly vulnerable. Thirty-year survivors of childhood cancer have been shown to have a 15 times higher rate of heart failure, a 10 times higher rate of other cardiovascular diseases, and a 9 times higher risk of stroke than age-matched sibling controls. Cardiotoxicity may manifest as cardiomyopathy, pericarditis, congestive heart failure, valvular heart disease, or premature coronary artery disease. The most common causes of cardiotoxicity are anthracycline-based chemotherapy and radiation therapy to the neck and mediastinum (Shankar et al. 2008). Anthracyclines are a class of antineoplastic agents that are highly efficacious in the treatment of pediatric and adult hematologic cancers, including acute myeloid leukemia, acute lymphoblastic leukemia, Hodgkin disease, and non-Hodgkin lymphoma, as well as solid tumors, sarcomas, and ovarian cancer. Among children in the United States who are survivors of childhood cancer, approximately 50% have received anthracyclines. Cumulative dose-related cardiac adverse effects may become apparent at the time that the first dose is administered, and clinical data suggest that deterioration of cardiac function is sustained throughout treatment and may continue for many years after treatment is completed. As patients age, other risk factors for cardiovascular disease, such as hypertension, hyperlipidemia, diabetes, and obesity, may contribute to the clinical progression of cardiac damage in adulthood.
Known risk factors for anthracycline-induced cardiac adverse effects include high cumulative doses of anthracycline, high anthracycline dose intensity, female sex, age younger than 5 years at diagnosis, radiation therapy, and combining anthracyclines with other cardiotoxic chemotherapy. Patients who were treated for lymphoma, Hodgkin lymphoma, sarcomas, or myeloid leukemia generally have the highest risk of cardiotoxicity because of the high doses of anthracyclines they usually receive, often accompanied by radiation. Higher than expected occurrences of cardiac adverse effects are observed in patients who receive anthracyclines in combination with new targeted drugs, such as the human epidermal growth factor receptor-2 antibody trastuzumab. These risk factors provide helpful monitoring guidelines, although they do not predict the risk of cardiac adverse effects for all patients.
Both early- and late-onset cardiac adverse effects are characterized by symptomatic or asymptomatic progressive decrease in left ventricular function, often resulting in congestive heart failure. This progressive cardiomyopathy can appear anywhere from 1 to 30 years or more after treatment is completed. The incidence of congestive heart failure has been shown to range from 10% to 26% in cancer patients treated with anthracyclines at doses below the current recommended limits. The incidence of subclinical cardiac adverse effects ranges from 0 to 57%, depending on how cardiac adverse effects are defined and the dose of anthracyclines used (Gianni et al. 2008; Shankar et al. 2008). Overt congestive heart failure can occur in asymptomatic patients who undergo stress such as childbirth.
In 2003, the Children’s Oncology Group released risk-based, exposure-related guidelines for children treated with anthracyclines. These guidelines include recommendations for echocardiograms every 1–5 years depending on exposure (see Table 4.1). These recommendations differ substantially from those given for patients treated for cancer during adulthood and should be followed carefully.
Table 4.1
Recommended schedule for echocardiograms or multiple-gated acquisition scans in children treated with anthracyclines
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