4
Late Effects of Childhood Cancer

Childhood cancer survivors, though being “cured” of cancer, often experience late effects, both physical and psychological, secondary to their cancer or its treatment. Complications, disabilities, or adverse outcomes that are the result of the disease process, the treatment, or both, are generally referred to as “late effects.” Late effects may be easy to identify because of their visibility (e.g., amputation) or direct effects on function (e.g., severe cognitive impairment). Other late effects, however, can be subtle and apparent only to the trained observer (e.g., scoliosis or curvature of the spine) or not directly observable and identified only through screening or imaging tests (hypothyroidism, infertility). In addition to concerns about a recurrence of the cancer for which they were treated, cancer survivors are also at increased risk of developing a second type of cancer because of either their treatment for cancer (e.g., radiation), their genetic or other susceptibility, or some interaction between treatment and genetic susceptibility.

Some late effects of therapy are identified early in follow-up—during the childhood or adolescent years—and resolve without consequence. Others may persist, become chronic problems, and influence the progression of other diseases associated with aging. For example, renal dysfunction secondary to treatment with the chemotherapeutic agent ifosfamide may be accelerated if the survivor develops hypertension or diabetes mellitus, two common adult health problems (Prasad et al., 1996; Skinner et al., 2000).

Chemotherapy, radiation therapy, and surgery may all cause late effects involving any organ or system of the body. Effects of surgery with



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4 Late Effects of Childhood Cancer Childhood cancer survivors, though being “cured” of cancer, often experience late effects, both physical and psychological, secondary to their cancer or its treatment. Complications, disabilities, or adverse outcomes that are the result of the disease process, the treatment, or both, are generally referred to as “late effects.” Late effects may be easy to identify because of their visibility (e.g., amputation) or direct effects on function (e.g., severe cognitive impairment). Other late effects, however, can be subtle and apparent only to the trained observer (e.g., scoliosis or curvature of the spine) or not directly observable and identified only through screening or imaging tests (hypothyroidism, infertility). In addition to concerns about a recurrence of the cancer for which they were treated, cancer survivors are also at increased risk of developing a second type of cancer because of either their treatment for cancer (e.g., radiation), their genetic or other susceptibility, or some interaction between treatment and genetic susceptibility. Some late effects of therapy are identified early in follow-up—during the childhood or adolescent years—and resolve without consequence. Others may persist, become chronic problems, and influence the progression of other diseases associated with aging. For example, renal dysfunction secondary to treatment with the chemotherapeutic agent ifosfamide may be accelerated if the survivor develops hypertension or diabetes mellitus, two common adult health problems (Prasad et al., 1996; Skinner et al., 2000). Chemotherapy, radiation therapy, and surgery may all cause late effects involving any organ or system of the body. Effects of surgery with

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implications for survivorship may include amputation, eye removal, disfigurement, or growth abnormalities. Exposure to therapeutic agents during the rapid and dramatic physiologic and psychologic changes occurring from infancy to early adulthood can result in specific tissue or organ damage, or alteration of normal patterns of growth and development. Long-term sequelae of chemotherapy and radiation are common, may be mild or severe, and may be asymptomatic for extended periods. As many as two-thirds of survivors will experience a late effect of chemotherapy or radiation, defined as any chronic or late occurring outcome—physical or psychosocial—that persists or develops beyond five years from the diagnosis of the cancer (Garre et al., 1994; Oeffinger et al., 2000; Stevens et al., 1998; Vonderweid et al., 1996). These late effects include cognitive impairment, fertility problems, alterations in growth and development, organ system damage, chronic hepatitis, and second malignant neoplasms (DeLaat and Lampkin, 1992; Donaldson, 1993; Dreyer et al., 2002; Friedman and Meadows, 2002; Marina, 1997; Meister and Meadows, 1993; Neglia and Nesbit, 1993; Schwartz, 1995). Survivors frequently have more than one late effect, with perhaps as many as a quarter of survivors experiencing one that is severe or life-threatening (Garre et al., 1994; Oeffinger et al., 2000; Stevens et al., 1998). The seriousness of the consequences of late effects is evident in studies of premature death following cancer treatment. In one study of late mortality among 20,227 5-year survivors of childhood cancer diagnosed with cancer from 1970 to 1986, there was a 10.8-fold excess in overall mortality (Mertens et al., 2001). Ten percent of these individuals had died by 1996. Figure 4.1 shows all-cause mortality in this cohort as compared to age-adjusted expected survival rates for the U.S. population. Survival is shown by original cancer diagnosis in Figures 4.2a and 4.2b. Among those for whom cause of death was ascertained, relapse of the primary cancer accounted for 67.4 percent of deaths and treatment-related consequences accounted for 21.3 percent of deaths. The remaining 11.3 percent of deaths were caused by non-treatment external causes (e.g., motor vehicle accidents) or medical conditions (e.g., HIV, pneumonia) (Table 4.1). The three most common treatment-related causes of death observed were (1) the development of a secondary or subsequent cancer, (2) cardiac toxicity, and (3) pulmonary complications. Among the Childhood Cancer Survivor Study (CCSS) cohort, the overall all-cause absolute excess risk was 8.8 deaths per 1,000 person-years. Within treatment-related cause-specific categories (i.e., excluding recurrences and non-treatment-related deaths), the absolute excess risk was 1.26, 0.27, and 0.015 deaths per 1,000 person-years for secondary and subsequent cancers, cardiac causes, and pulmonary causes, respectively. These treatment-related deaths account for 18 percent of the excess risk of death

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FIGURE 4.1 All-cause mortality, by sex (Childhood Cancer Survivor Study). US population: Age-adjusted expected survival rates. Cancer survivor: All-cause mortality experience from five years after inital canccer diagnosis. SOURCE: Mertens et al., 2001. Reprinted with permission of the American Society of Clinical Oncology. observed in this cohort. The risk was highest among females, those diagnosed with cancer before the age of 5, and those with an initial diagnosis of leukemia or central nervous system (CNS) tumor (Mertens et al., 2001; Moller et al., 2001). The cumulative cause-specific mortality was highest for cancer recurrence (7 percent at 25 years from diagnosis) (Figure 4.2). Death rates due to subsequent cancers and other causes increased more rapidly in the time period 15 to 25 years after diagnosis than from 5 to 15 years after diagnosis. Despite the relatively high prevalence of late effects, recent evidence suggests that survivors of childhood cancer view themselves as being in relatively good health. Only 11 percent of 9,434 members of the CCSS cohort reported that they were in fair or poor general health when recently surveyed (Kevin Oeffinger, personal communication to Maria Hewitt, August 16, 2002). This assessment may not necessarily indicate a lack of limitations or disability. People with serious chronic illness, recurring disease, or disability sometimes report being in good health because they

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FIGURE 4.2 Mortality, by cancer type (Childhood Cancer Survivor Study). NOTE: CNS = central nervous system; NHL = non-Hodgkin’s lymphoma. SOURCE: Mertens et al., 2001. Reprinted with permission of the American Society of Clinical Oncology.

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TABLE 4.1 Causes of Death in the Childhood Cancer Survivor Study Cohort Cause of death Number of deaths Percent of deaths Total 1,848 100.0 Recurrence 1,246 67.4 Treatment-related consequences 394 21.3 Subsequent neoplasm 235 12.7 Cardiac 83 4.5 Pulmonary 33 1.8 Other sequelae 43 2.3 Non-treatment related 208 11.3 External causes 94 5.1 Medical conditions 114 6.2   SOURCE: Adapted from Mertens et al., 2001. FIGURE 4.3 Cumulative cause-specific mortality (Childhood Cancer Survivor Study). NOTE: SMN = second malignant neoplasm. SOURCE: Mertens et al., 2001. Reprinted with permission of the American Society of Clinical Oncology.

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experience benefits from their illness, for example, becoming closer to family, discovery of self and life priorities, and renewed spirituality (Justice, 1999; Kornblith et al., 1998). Researchers examined several health-related domains—general health, mental health, functional impairment, activity limitations, and pain or anxiety as a result of the cancer or its treatment— and found that 45 percent of the cohort members reported moderate to severe adverse outcomes in at least one of the domains (Kevin Oeffinger, personal communication to Maria Hewitt, August 16, 2002). Table 4.2 summarizes some of the late effects associated with the more common childhood cancers. The next section describes how specific treatments can contribute to physical and psychosocial damage. Chapter 5 describes approaches to monitor late effects. The most common late effects of childhood cancer include those that are neurocognitive and psychological, cardiopulmonary, endocrine (e.g., those affecting growth and fertility), musculoskeletal, and those related to second malignancies. The emergence of late effects depends on many factors, including age, exposures to chemotherapy and radiation during treatment (doses and parts of body exposed), and the severity of disease. The following section briefly reviews some of the late effects that occur following primary treatment. For a more complete discussion, see the background papers prepared for the Board (www.iom.edu/ncpb) and refer to comprehensive reviews that are available for both consumers (Keene et al., 2000; http://www.candlelighters.org) and providers (Dreyer et al., 2002; Friedman and Meadows, 2002; Schwartz, 1995, 1999; Schwartz et al., 1994; Ward, 2000). NEUROCOGNITIVE LATE EFFECTS Cognitive impairment is one of the most debilitating late effects among children whose cancer (or its treatment) involved the central nervous system. Learning problems, social difficulties, behavioral adjustment problems, and long-term education and vocational difficulties may be experienced. There are five primary groups of children that may experience CNS-related cognitive impairments: Children with tumors of the CNS Children with leukemia or non-Hodgkin’s lymphoma who receive CNS prophylaxis involving chemotherapy and/or radiation therapy Children with tumors of the face, eye, or skull that require localized, external beam radiation therapy Children treated with whole body radiation and myeloablative che-

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TABLE 4.2 Selected Physical Late Effects Associated with Childhood Cancer Cancer Potential Late Effects   Leukemias • Cognitive effects (e.g., learning disabilities) • Abnormal growth and maturation • Heart problems • Second cancers • Hepatitis C (effects of blood transfusion) • Weakness, fatigue • Obesity • Avascular necrosis of bone • Osteoporosis • Dental problems Brain cancer • Neurologic and cognitive effects (e.g., learning disabilities) • Abnormal growth and maturation • Hearing loss • Kidney damage • Hepatitis C • Infertility • Vision problems • Second cancers Hodgkin’s disease • Adhesions and intestinal obstruction (if spleen removed) • Decreased resistance to infection (potential for life-threatening sepsis) • Abnormal growth and maturation • Hypothyroidism (effects of neck radiation) • Salivary gland malfunctioning (effect of jawbone irradiation) • Lung damage • Heart problems • Infertility • Hepatitis C • Second cancers (e.g., breast cancer in females) Non-Hodgkin’s lymphoma • Heart problems • Hepatitis C • Cognitive effects • Infertility • Osteopenia/osteoporosis Bone tumor • Amputation/disfigurement • Functional, activity limitations • Damage to soft tissues and underlying bones (radiation may cause scarring, swelling, or inhibit growth) • Hearing loss • Heart problems • Kidney damage • Second cancers • Hepatitis C • Fertility problems Wilm’s tumor • Heart problems • Kidney damage • Damage to soft tissues and underlying bones (radiation may cause scarring, swelling, or inhibit growth) • Second cancers • Fertility problems • Scoliosis

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Cancer Potential Late Effects   Neuroblastoma • Heart problems • Damage to soft tissues and underlying bones (radiation may cause scarring, swelling, or inhibit growth) • Neurocognitive effects • Hearing loss • Hepatitis C • Second cancers • Kidney damage Soft tissue sarcoma • Amputation/disfigurement • Functional, activity limitations • Heart problems • Damage to soft tissues and underlying bones (radiation may cause scarring, swelling, or inhibit growth) • Second cancers • Hepatitis C • Kidney damage • Cataracts • Infertility • Neurocognitive effects motherapy as part of a preparation regimen for allogeneic bone marrow transplantation (marrow is received from another person) Children with solid tumors or leukemia who are treated during critical developmental periods and who require prolonged and repeated hospitalizations that interfere with the acquisition of normal developmental skills. Since leukemias and lymphomas account for nearly 40 percent of childhood cancer diagnosed in the United States and tumors of the CNS account for nearly 20 percent, a total of about 50 to 60 percent of children treated for cancer will have at last some risk of neurocognitive impairment resulting from the cancer and/or its treatment. A number of factors can contribute to neurocognitive deficits: tumor characteristics (e.g., the location and extent of the tumor), surgery (e.g., bleeding or rarely, infection), radiation therapy (e.g., dose, volume, age at administration), and chemotherapy. Not all children with CNS exposure to radiation and chemotherapy will experience neurocognitive effects, and there is no certain way to predict which children will experience them. Factors associated with higher risk for cognitive impairment include younger age at the time of treatment, the intensity of treatment, the duration of time between treatment and evaluation, and the age of the child at the time he or she is evaluated. Absences from school during treatment can also contribute to impaired academic performance. For children with CNS tumors or acute lymphocytic leukemia (ALL), the severity of cognitive impairment following radiation therapy has been associated with the dose of radiation that is administered. Higher doses of radiation (e.g., above 24 Gy) are associated with more significant impair-

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ment, and these are the doses that are most frequently used in the treatment of children with CNS tumors. Studies of survivors of childhood CNS tumors have consistently shown substantial decreases in global IQ scores in the years following treatment, with declines of 20 to 50 full-scale IQ points noted. Lower doses of radiation (e.g., 18 Gy or less) are associated with less severe cognitive impairment. These doses are most frequently used in the treatment of children with CNS leukemia or as preparatory regimens for children treated with bone marrow transplantation. The addition of certain chemotherapeutic agents administered in high doses or injected into the spinal canal (e.g., methotrexate) significantly increases the risk for cognitive impairment. Females with ALL who received intrathecal methotrexate and cranial radiation as CNS prophylaxis have been shown to have lower levels of cognitive functioning than males. Preliminary reports suggest that cognitive dysfunction may also be more common when treatment for ALL includes dexamethasone instead of prednisone as the steroid (Waber et al., 2000). Deficits in neurocognitive function may not be apparent in the immediate period following treatment. In one study, for example, there were no differences in the results on 16 standardized memory measures between patients randomized to receive CNS prophylaxis with either 18 Gy cranial irradiation or high-dose intravenous methotrexate (Mulhern et al., 1988). Subsequent periodic evaluation of these patients, however, showed declines in scores in both treatment groups (Ochs et al., 1991). Studies of cognitive late effects in children treated for ALL and CNS tumors suggest that nonverbal abilities are most impaired, including short-term memory, processing speed, visual-motor integration, sequencing ability, and attention and concentration. These effects are common to other types of acquired brain injury. Such impairments can affect school performance, learning, and social function. Children may have difficulty completing work in the classroom, and may spend substantially more time completing homework assignments. There may also be difficulties with handwriting, organizing material on a page, lining up columns for arithmetic problems, and accurately responding to standardized testing forms that require shading responses on a computerized record. Problems with inattention may contribute to difficulties in completing tasks or following conversations. This complex of cognitive late effects contributes to educational difficulties with reading, language development, and complex mathematics (e.g., multiplication and division). Special education services are often required to overcome recognized learning difficulties. A large retrospective cohort study of 593 adult survivors of childhood ALL and 409 sibling controls demonstrated that ALL survivors have a greater likelihood of being placed in special education or learning disabled programs than their siblings, but that most are able to compensate and

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adapt to overcome these problems (Challinor and Karl, 1995; Haupt et al., 1994, 1995). On average, ALL survivors had lower grades, higher enrollment rates in special education or learning disability programs (four times greater than their siblings), and when enrolled, spent a longer time in these programs than did their siblings (Table 4.3). Cancer survivors were also at higher risk of missing school for long periods and repeating a year of school. Most ALL survivors had rates of high school graduation, college entry, and college graduation that were similar to those of their brothers and sisters, suggesting that remediation was successful. Only survivors treated with 24 Gy or more of cranial radiation and those diagnosed at a preschool age were at higher risk for poor educational performance; this group was identified by investigators as in need of targeting for remediation. Participants in this study had to be at least 18 years old by 1990, to have been treated for ALL before age 20, to have survived at least 2 years after diagnosis, to be in remission, and to be receiving no leukemic therapy at follow-up. Nearly one-quarter (24 percent) of the sample had been diagnosed under age 6. Survivors were old enough to have finished high school and many had finished college. The educational outcomes of children currently treated on some of the intensive chemotherapy protocols in the 1990s are not yet available (D. Armstrong, University of Miami School of Medicine, personal communication to Maria Hewitt, March 28, 2002). Some small single-institution studies have found relatively high rates of use of special education. In one study, 12 of 24 survivors of childhood ALL treated with 18 Gy of craniospinal irradiation and intrathecal chemotherapy (methotrexate) had received some type of special education service when assessed 4 to 5 years from the time of their diagnosis (Rubenstein et al., 1990). Another study conducted in The Netherlands found that 7 of 28 children treated for ALL with chemotherapy and radiation and assessed 10 years later had received special education services, a rate much higher than for their siblings (4 percent). There were no differences in special education placements between children treated with chemotherapy without radiation and their siblings. However, they had significant deficits in auditory memory and fine-motor functioning (Kingma et al., 2001). Some estimate that as many as 70 to 80 percent of high-risk children (e.g., those with CNS tumors treated with high-dose, whole-brain radiation under age 4) may need special education services (Armstrong et al., 1999; Packer et al., 1987). As discussed above, neurocognitive deficits may not be evident in the period immediately following treatment. Studies of children with CNS tumors show that they generally do not lose abilities that had been acquired prior to treatment. Instead, the children appear to improve their skills in some areas, but at a substantially slower rate than healthy children. Other skills, which would be expected to emerge in a predictable developmental sequence in normal children, may not emerge because the underlying brain

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structures fail to develop. Learning disabilities are defined in terms of recognized discrepancies between intellectual functioning and academic achievement. A discrepancy may not be observed shortly following treatment, but may become evident at a later time. Because the kinds of impairments experienced by children with cancer emerge over time, neurocognitive evaluations need to be conducted on a schedule that anticipates areas of deficit (Iuvone et al., 2002). Assessment tools used in these evaluations should focus on the specific areas of potential deficits that are associated with the type of brain injury resulting from cancer treatment. This may require neuropsychological testing that is typically not provided by the educational system and the use of tests that fall outside the scope of those routinely used in educational planning. The evidence regarding neurocognitive deficits associated with cancer treatment is being used to moderate treatments to reduce these effects. The results of ongoing studies to maintain and improve survival while minimizing cognitive impairment, however, will not be available for another 5 to 10 years. Preliminary results of assessments of interventions to remediate treatment-related cognitive effects using a psychologically based outpatient rehabilitation program appear promising (Butler et al., 2002). Educational programs of relevance to cancer survivors are discussed in Chapter 6. PSYCHOSOCIAL AND BEHAVIORAL LATE EFFECTS “The experience of completing cancer treatment has two faces—one of celebration and hope, one of uncertainty and fear” (Haase and Rostad, 1994, p. 1490). Cancer may have psychological, social, and spiritual or existential effects secondary to worry about many aspects of survivorship, including the risk of relapses, dying, more treatments, potential problems with sexuality and fertility, body image, school and work performance, and social and family relationships (Gray et al., 1992; Rait et al., 1992; Roberts et al., 1998; Weigers et al., 1998). “Quality of life” studies assess the frequency of untoward consequences of disease and factors associated with them. Despite periods of intense stress, most survivors achieve normal levels of psychological and social functioning, and families adapt well. All survivors, however, even those apparently doing quite well, experience at least occasional problems in social adjustment and continue to be concerned about their medical and social futures. There is a small but significant minority of survivors who remain seriously troubled and are impaired by their psychological problems. The size of this group, and the nature and extent of their problems are not fully known (Fritz et al., 1988; Gray et al., 1992; Greenberg et al., 1989; Hobbie et al., 2000; Kazak and Meadows, 1989; Koocher and O’Malley, 1981; Kupst et al., 1995; Moore et al., 1987;

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