Wednesday, August 21, 2019

Late Effects of Treatment for Childhood Cancer (PDQ®) 8/11 –Health Professional Version - National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version

Late Effects of the Musculoskeletal System

The musculoskeletal system of growing children and adolescents is vulnerable to the cytotoxic effects of cancer therapies, including surgery, chemotherapy, and radiation therapy. Documented late effects include the following:
  • Bone and joint (abnormal bone and/or muscle growth) problems.
  • Deformity and functional loss associated with amputation/limb-sparing surgery, joint contracture, osteoporosis/fractures, and osteonecrosis.
  • Changes in body composition (obesity and loss of lean muscle mass).
While these late effects are discussed individually, it is important to remember that the components of the musculoskeletal system are interrelated. For example, hypoplasia to a muscle group can negatively affect the function of the long bones and the resultant dysfunction can subsequently lead to disuse and osteoporosis.
The major strength of the published literature documenting musculoskeletal late effects among children and adolescents treated for cancer is that most studies have clearly defined outcomes and exposures. However, many studies are observational and cross-sectional or retrospective in design. Single-institution studies are common, and for some outcomes, only small convenience cohorts have been described. Thus, it is possible that studies either excluded patients with the most severe musculoskeletal effects because of death or inability to participate in follow-up testing, or oversampled those with the most severe musculoskeletal late effects because these patients were accessible as they returned for complication-related follow-up. Additionally, some of the results reported in adult survivors of childhood cancer may not be relevant to patients currently being treated because the delivery of anticancer modalities, particularly radiation therapy, has changed over the years in response to documented toxicities.[1,2]

Abnormal Bone Growth

The effect of radiation on bone growth depends on the sites irradiated, as follows:

Radiation to the head and brain

In an age- and dose-dependent fashion, radiation can inhibit normal bone and muscle maturation and development. Radiation to the head (e.g., cranial, orbital, infratemporal, or nasopharyngeal radiation therapy) can cause craniofacial abnormalities, particularly in children treated before age 5 years who received radiation doses of 20 Gy or higher [3-8] or who were treated with concomitant chemotherapy.[9] Soft tissue sarcomas such as orbital rhabdomyosarcoma and retinoblastoma are two of the more common cancer types treated with these radiation fields. Often, in addition to the cosmetic impact of the craniofacial abnormalities, there can be related dental and sinus problems.
Cranial radiation therapy damages the hypothalamic-pituitary axis in an age- and dose-response fashion and can result in growth hormone deficiency.[10-13] If the growth hormone deficiency is not treated during the growing years and, sometimes, even with appropriate treatment, it leads to a substantially lower final height. Patients with a central nervous system (CNS) tumor [10,14] or acute lymphoblastic leukemia (ALL) [15-17] treated with 18 Gy or higher of cranial radiation therapy are at highest risk. Patients treated with total-body irradiation (TBI), particularly single-fraction TBI,[18-21] and those treated with cranial radiation for non-CNS solid tumors [22] are also at risk of growth hormone deficiency. If the spine is also irradiated (e.g., craniospinal radiation therapy for medulloblastoma or early ALL therapies in the 1960s), growth can be affected by two separate mechanisms—growth hormone deficiency and direct damage to the spine.

Radiation to the spine and long bones

Radiation therapy can also directly affect the growth of the spine and long bones (and associated muscle groups) and can cause premature closure of the epiphyses, leading to the following:[23-31]
  • Short stature.
  • Asymmetric growth (scoliosis/kyphosis).
  • Limb-length discrepancy.
Orthovoltage radiation therapy, commonly used before 1970, delivered high doses of radiation to bone and was commonly associated with subsequent abnormalities in bone growth. However, even with contemporary radiation therapy, if a solid tumor is located near an epiphysis or the spine, alterations in normal bone development can be difficult to avoid.
The effects of radiation therapy administered to the spine on stature in survivors of Wilms tumor have been assessed.
Evidence (effect of radiation therapy on the spine and long bones):
  1. In the National Wilms Tumor Study (NWTS), studies 1 through 4, stature loss in 2,778 children was evaluated.[24] Repeated height measurements were collected during long-term follow-up. The effects of radiation dosage, age at treatment, and chemotherapy on stature were analyzed using statistical models that accounted for the normal variation in height with sex and advancing age. Predictions from the model were validated by descriptive analysis of heights measured at ages 17 to 18 years for 205 patients.
    • For those younger than 12 months at diagnosis who received more than 10 Gy of radiation therapy, the estimated adult-height deficit was 7.7 cm when compared with the nonradiation therapy group.
    • For those who received 10 Gy, the estimated trunk shortening was 2.8 cm or less.
    • Among those whose height measurements in the teenage years were available, patients who received more than 15 Gy of radiation therapy were 4 to 7 cm shorter on average than their nonirradiated counterparts, with a dose-response relationship evident.
    • Chemotherapy did not confer additional risk.
  2. The effect of radiation therapy on the development of scoliosis has also been re-evaluated. In a group of 42 children treated for Wilms tumor from 1968 to 1994, scoliosis was seen in 18 patients, with only one patient needing orthopedic intervention.[32]
    • Median time to development of scoliosis was 102 months (range, 16–146 months).
    • A clear dose-response relationship was seen; children treated with lower doses (<24 Gy) of radiation had a significantly lower incidence of scoliosis than those who received more than 24 Gy of radiation.
    • There was also a suggestion that the incidence was lower in patients who received 10 to 12 Gy, the dosages currently used for Wilms tumor, although the sample size was small.

Osteoporosis and Fractures

Although increased rates of fracture are not reported among long-term survivors of childhood cancer,[33] maximal peak bone mass is an important factor influencing the risk of osteoporosis and fracture among older patients. Treatment-related factors that affect bone mineral loss include the following:
  • Chemotherapy. Methotrexate has a cytotoxic effect on osteoblasts, resulting in a reduction of bone volume and formation of new bone.[34,35] This effect may be exacerbated by the chronic use of corticosteroids, another class of agents routinely used in the treatment of hematological malignancies and in supportive care for a variety of pediatric cancers.
  • Radiation therapy. Radiation-related endocrinopathies, such as growth hormone deficiency or hypogonadism, may contribute to ongoing bone mineral loss.[36-39]
  • Nutrition and activity. Suboptimal nutrition and physical inactivity may further predispose to deficits in bone mineral accretion.
Most of our knowledge about cancer and treatment effects on bone mineralization has been derived from studies of children with ALL.[34,40] In this group, the leukemic process, and possibly vitamin D deficiency, may play a role in the alterations in bone metabolism and bone mass observed at diagnosis.[41] Antileukemic therapy causes additional bone mineral density loss,[42] which has been reported to normalize over time [43,44] or to persist for many years after completion of therapy.[45,46] Clinical factors predicting higher risk of low bone mineral density include treatment with the following:[38,45,47-49]
  • High cumulative doses of methotrexate (>40 g/m2).
  • High cumulative doses of corticosteroids (>9 g/m2).
  • Cranial radiation therapy or craniospinal radiation therapy.
  • More potent glucocorticoids such as dexamethasone.
The development of osteonecrosis during treatment for ALL also predicts higher risk of low bone density.[50]
Clinical assessment of bone mineral density in adults treated for childhood ALL indicates that most bone mineral deficits normalize over time after discontinuing osteotoxic therapy.
Evidence (low bone mineral density):
  1. A cohort of 845 adult survivors of childhood ALL were evaluated at a median age of 31 years.[38]
    • Very low bone mineral density was relatively uncommon, with only 5.7% and 23.8% of patients demonstrating bone mineral density z-scores consistent with osteoporosis and osteopenia, respectively.
    • Cranial radiation dose of 24 Gy or higher, but not cumulative methotrexate or prednisone equivalent doses, was associated with a twofold elevated risk of bone mineral density z-scores of -1 or lower.
    • In a subset of 400 survivors with longitudinal bone mineral density evaluations, bone mineral density z-scores tended to improve from adolescence to young adulthood.
  2. Among 862 ALL survivors (median age, 31.3 years) evaluated by quantitative computed tomography of L1 through L2 vertebrae, 30% of survivors had low bone mineral density (z-score below -1) and 18.6% met criteria for frailty or prefrailty.[51]
    The prefrail phenotype is characterized by having two of five characteristics (low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness) and the frail phenotype is characterized by having three or more of these characteristics. Modifiable factors such as growth hormone deficiency, smoking, and alcohol consumption were significant predictors for these outcomes, with varying impact on the basis of sex. These data underscore the importance of lifestyle counseling and screening for hormonal deficits during long-term survivors' follow-up evaluations.
Bone mineral density deficits that are likely multifactorial in etiology have been reported in allogeneic hematopoietic stem cell transplantation (HSCT) recipients conditioned with TBI.[52,53] French investigators observed a significant risk of lower femoral bone mineral density among adult survivors of childhood leukemia treated with HSCT who had gonadal deficiency.[54] Hormonal therapy has been shown to enhance the bone mineral density of adolescent girls diagnosed with hypogonadism after HSCT.[55]
Despite disease-related and treatment-related risks of bone mineral density deficits, the prevalence of self-reported fractures among Childhood Cancer Survivor Study (CCSS) participants was lower than that reported by sibling controls. Predictors of increased prevalence of fracture by multivariable analyses included the following:[33]
  • Among female survivors, increasing age at follow-up, white race, methotrexate treatment, and balance difficulties.
  • Among male survivors, smoking history and white race.
Radiation-induced fractures can occur with doses of radiation of 50 Gy or higher, as is often used in the treatment of Ewing sarcoma of the extremity.[56,57]

Osteonecrosis

Osteonecrosis (also known as aseptic or avascular necrosis) is a rare, but well-recognized skeletal complication observed predominantly in survivors of pediatric hematological malignancies treated with corticosteroids.[58-60] The prevalence of osteonecrosis has varied from 1% to 22% based on the study population, treatment protocol, method of evaluation, and time from treatment.[60-66]
The condition is characterized by death of one or more segments of bone that most often affects weight-bearing joints, especially the hips and knees. Longitudinal cohort studies have identified a spectrum of clinical manifestations of osteonecrosis, ranging from asymptomatic, spontaneously-resolving imaging changes to painful progressive articular collapse requiring joint replacement.[67,68] Symptomatic osteonecrosis characterized by pain, joint swelling, and reduced mobility typically presents during the first 2 years of therapy, particularly in patients with ALL. These symptoms may improve over time, persist, or progress in the years after completion of therapy.[69] In one series, 60% of patients continued to have symptoms at a median follow-up of 4.9 years after diagnosis of osteonecrosis.[70] Surgical procedures, including core decompression, osteotomy, and joint replacements, are sometimes performed in those with persistently severe symptoms.[70]
Factors that increase the risk of osteonecrosis include the following:
  • Exposure to corticosteroids and, possibly, methotrexate and concurrent asparaginase. The most important treatment factor associated with the development of osteonecrosis is prolonged exposure to corticosteroids, which is typical in treatment regimens used for ALL, non-Hodgkin lymphoma, and HSCT.[63,66,71,72]
    Osteonecrosis risk may be related to type of corticosteroid, with some studies in patients with ALL indicating increased risk with the use of dexamethasone compared with prednisone.[73,74]
    Corticosteroid dosing schedule also appears to impact the risk of developing osteonecrosis. In the Children’s Oncology Group (COG) 1961 trial for newly diagnosed high-risk ALL, patients were randomly assigned to receive either continuous (daily) dexamethasone or an alternate-week schedule of dexamethasone during the delayed intensification phase; the alternate-week schedule was associated with a lower incidence of osteonecrosis.[60]
    In addition to corticosteroids, exposure to methotrexate and concurrent asparaginase may contribute to the development of osteonecrosis.[75,76]
  • Development of thromboembolism during antileukemic therapy. In a retrospective review of 208 children treated for ALL, investigators at McMaster University reported a 5.21-fold (95% CI, 1.82–14.91) increased odds of osteonecrosis among children who experienced thromboembolism during antileukemic therapy than among those who did not have a thromboembolism, even after accounting for age and asparaginase exposure.[76]
  • HSCT conditioning and course. In a large case-control study that evaluated risk factors for osteonecrosis using data from the Center for International Blood and Marrow Transplant Research, lower risks of osteonecrosis were seen in patients with nonmalignant diseases and in those who had received reduced-intensity conditioning regimens for malignant diseases than were seen in patients receiving myeloablative regimens for malignant diseases.[77] Several studies have reported an increased risk of osteonecrosis in association with chronic graft-versus-host disease (GVHD).[64,71,77]
  • Age at time of diagnosis or transplant. Several studies have demonstrated that age at diagnosis (or at time of transplant) is a significant independent predictor of osteonecrosis.[60,61,66,70,71,73,77] Osteonecrosis is significantly more common in older children and adolescents than in younger children. In the COG-1961 trial for high-risk ALL, the 5-year cumulative incidence of symptomatic osteonecrosis was 1.0% for patients aged 1 to 9 years, 9.9% for patients aged 10 to 15 years, and 20% for patients aged 16 to 21 years (P < .0001).[60]
  • Race. Osteonecrosis also occurs more frequently in white patients than in black patients.[72,78]
  • Genetic factors. Genetic factors influencing folate metabolism, glucocorticoid metabolism, and adipogenesis have been linked to excess risk of osteonecrosis among survivors.[72,79,80]
    • Two candidate gene studies indicate that children homozygous for a 28–base pair repeat within the 5’ untranslated region of the TS gene are at increased risk of osteonecrosis.[72,80] This gene is associated with folate production and replacement and is inhibited by methotrexate.
    • St. Jude Children's Research Hospital investigators observed an almost sixfold (odds ratio, 5.6; 95% confidence interval, 2.7–11.3) risk of osteonecrosis among survivors with polymorphism of the ACP1 gene, which regulates lipid levels and osteoblast differentiation.[65]
    • Genome-wide association studies have identified potential risk variants in BMP7, PROX1-AS1, GRID2 (children younger than 10 years), and GRIN3A, which are all associated with glucocorticoid receptor activity.[79,81]
Studies evaluating the influence of sex on the risk of osteonecrosis have yielded conflicting results, with some suggesting a higher incidence in females [67,70,78] that has not been confirmed by others.[59,67]

Osteochondroma

Osteochondromas are benign boney protrusions that can be spontaneous or associated with radiation therapy. They generally occur as a single lesion; however, multiple lesions may develop in the context of hereditary multiple osteochondromatosis.[82] Approximately 5% of children undergoing myeloablative HSCT will develop osteochondroma, which most commonly presents in the metaphyseal regions of long bones.[82,83]
Evidence (risk of osteochondroma):
  1. A large Italian study reported a 6.1% cumulative risk of developing osteochondroma at 15 years posttransplant, with increased risk associated with younger age at transplant (≤3 years) and use of TBI.[84]
  2. Osteochondromas have been reported in patients with neuroblastoma who received local radiation therapy, anti-GD2 monoclonal antibody therapy, and isotretinoin. [85]
    • Osteochondromas occurred at a median of 8.2 years from diagnosis, and the cumulative incidence rate was 4.9% at 10 years from diagnosis among 362 patients younger than 10 years.
    • In this series, most of the osteochondromas were unrelated to radiation and had features characteristic of benign developmental osteochondroma.
    • The pathogenic role for chemotherapy, anti-GD2 monoclonal antibody therapy, or isotretinoin in the development of osteochondroma remains speculative.
Growth hormone therapy may influence the onset and pace of growth of osteochondromas.[21,86]
Because malignant degeneration of these lesions is exceptionally rare, clinical rather than radiological follow-up is most appropriate.[87] Surgical resection is only necessary when the lesion interferes with joint alignment and movement.[88]

Amputation and Limb-Sparing Surgery

Amputation and limb-sparing surgery prevent local recurrence of bone tumors by removal of all gross and microscopic disease. If optimally executed, both procedures accomplish an en bloc excision of tumor with a margin of normal uninvolved tissue. The type of surgical procedure, the primary tumor site, and the age of the patient affect the risk of postsurgical complications.[40] Complications in survivors treated with amputation include prosthetic fit problems, chronic pain in the residual limb, phantom limb pain, and bone overgrowth.[89,90] While limb-sparing surgeries may offer a more aesthetically pleasing outcome, complications have been reported more frequently in survivors who underwent these procedures than in those treated with amputation. Complications after limb-sparing surgery include non-union, pathologic fracture, aseptic loosening, limb-length discrepancy, endoprosthetic fracture, and limited joint range of motion.[89,91] Occasionally, refractory complications develop after limb-sparing surgery and require amputation.[92,93]
A number of studies have compared functional outcomes after amputation and limb-sparing surgery, but results have been limited by inconsistent methods of functional assessment and small cohort sizes. Overall, data suggest that limb-sparing surgery results in better function than amputation, but differences are relatively modest.[89,93,94] Similarly, long-term quality of life outcomes among survivors undergoing amputation and limb sparing procedures have not differed substantially.[92] A longitudinal analysis of health status among extremity sarcoma survivors in the CCSS indicates an association between lower extremity amputation and increasing activity limitations with age, and an association between upper extremity amputation and lower educational attainment.[95]

Joint Contractures

HSCT with any history of chronic GVHD is associated with joint contractures.[96-98]
Table 13 summarizes bone and joint late effects and the related health screenings.
Table 13. Bone and Joint Late Effectsa
Predisposing TherapyMusculoskeletal EffectsHealth Screening
CT = computed tomography; DXA = dual-energy x-ray absorptiometry; GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplantation.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer.
Radiation impacting musculoskeletal systemHypoplasia; fibrosis; reduced/uneven growth (scoliosis, kyphosis); limb length discrepancyExam: bones and soft tissues in radiation fields
Radiation impacting head and neckCraniofacial abnormalitiesHistory: psychosocial assessment, with attention to: educational and/or vocational progress, depression, anxiety, posttraumatic stress, social withdrawal
Head and neck exam
Radiation impacting musculoskeletal systemRadiation-induced fractureExam of affected bone
Methotrexate; corticosteroids (dexamethasone, prednisone); radiation impacting skeletal structures; HSCTReduced bone mineral densityBone mineral density test (DXA or quantitative CT)
Corticosteroids (dexamethasone, prednisone)OsteonecrosisHistory: joint pain, swelling, immobility, limited range of motion
Musculoskeletal exam
Radiation with impact to oral cavityOsteoradionecrosisHistory/oral exam: impaired or delayed healing after dental work, persistent jaw pain or swelling, trismus
AmputationAmputation-related complications (impaired cosmesis, functional/activity limitations, residual limb integrity, chronic pain, increased energy expenditure)History: pain, functional/activity limitations
Exam: residual limb integrity
Prosthetic evaluation
Limb-sparing surgeryLimb-sparing surgical complications (functional/activity limitations, fibrosis, contractures, chronic infection, chronic pain, limb length discrepancy, increased energy expenditure, prosthetic malfunction [loosening, non-union, fracture])History: pain, functional/activity limitations
Exam: residual limb integrity
Radiograph of affected limb
Orthopedic evaluation
HSCT with any history of chronic GVHDJoint contractureMusculoskeletal exam
Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer for musculoskeletal system late effects information, including risk factors, evaluation, and health counseling.
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