A Review of Late Effects in Pediatric Cancer: Implications for Rehabilitation

It is estimated that there are currently over 500,000 childhood cancer survivors (CCS) currently living in the United States.¹ Multimodal treatment strategies for childhood cancer have drastically improved survival rates from just 30% in the 1960s to over 85% today,² however these treatments often result in adverse late effects, which can last years after completion of treatment.^2,3 Late effects can occur as a result of treatment from chemotherapeutics, radiation, surgery, immunotherapy and/or targeted therapies and can affect multiple systems within the body. Taken together, late effects can lead to increased incidence of frailty.⁴ It has been noted that the prevalence of frailty among young adult childhood cancer survivors as young as 18 years is similar to a population of adults aged 65 years.⁴ Additionally, children are at increased risk of developing a secondary malignancy.^2,3,5 These late effects can significantly impact functional mobility and rehabilitation outcomes, and physical therapists should be able to recognize these late effects, with the intention of intervening to mitigate effects when possible. In attempts to succinctly describe late effects and the implications on function, late effects will be categorized by body system and summarized in Table 1.

Table 1.

Summary of late effects by body system

Body System	Medical Treatment	Late Effect	Functional Impact
Musculoskeletal	Alkylating agents, anthracyclines, taxanes, hormonal therapy	Osteoporosis	Increased risk of fracture, reduced mobility, poor posture, pain with movement
	Corticosteroids, radiation, various chemotherapies (often in combination with chronic steroid use)	Osteonecrosis	Impaired joint function, limited mobility, weight-bearing restrictions
	Various chemotherapeutics, particularly anthracyclines	Impaired muscle properties: rate of muscle activation, muscle thickness, rate of torque development	Reduced strength, limited ROM, fatigue, gait dysfunction, impaired gross motor performance
Neuromotor	Vinca alkaloids, platinum-based agents, taxanes	Chemotherapy Induced Peripheral Neuropathy (CIPN)	Poor balance, gait abnormalities, impaired mobility, impaired gross motor performance
	Dinutuximab	Neuropathic pain	Reduced mobility
	Methotrexate, alkylating agents, vinca alkaloids	Cognitive impairment	Impaired multi-tasking capabilities, reduced attention span, motor learning difficulties, impaired visuomotor function, fatigue
	Platinum-based agents, radiation to head/neck	Hearing loss	Potential for vestibular and/or balance deficits
Cardiovascular/Pulmonary	Anthracyclines, thoracic radiation	Left ventricular dysfunction	Poor endurance, impaired exercise capacity, impaired walking ability, difficulty ascending/descending multiple flights of stairs
	Anthracyclines, thoracic radiation	Pulmonary dysfunction	Poor endurance, impaired exercise capacity, impaired walking ability, difficulty ascending/descending multiple flights of stairs
	Brentuximab in combination with chemotherapy	Pulmonary toxicity	Poor endurance, impaired exercise capacity, impaired walking ability, difficulty ascending/descending multiple flights of stairs
Integumentary	Radiation, various chemotherapeutics	Fibrosis and scar tissue formation	Reduced range of motion, limited mobility of affected area
	Surgery	Edema, skin grafts, wound management	Reduced range of motion, limited mobility of affected area, pain with movement
Endocrine	Radiation, various chemotherapeutics	Endocrine changes	Change in body composition which can lead to reduced strength, endurance, functional mobility and fatigue

Musculoskeletal

Chemotherapeutic agents, including alkylating agents, anthracyclines, taxanes, and hormonal therapies can result in osteoporosis.⁶ Osteoporotic changes in young childhood cancer survivors can lead to pain, reduced mobility and increased risk of fracture.⁶ In addition to reduced bone mineral density, treatments, including chemotherapy, radiation and chronic corticosteroid use may lead to osteonecrosis.^5,7,8 While often asymptomatic, osteonecrosis is a serious condition impacting joint function, and mobility.⁸ Severe, late stage lesions may require surgery, and children with osteonecrosis often have weight-bearing restrictions.^5,8 Bone tumors including osteosarcoma and Ewing sarcoma are common cancers in adolescence.⁹ Primary treatment for bone tumors includes surgical removal, often in combination with neoadjuvant and/or adjuvant chemotherapy, which can result in altered musculoskeletal characteristics, including postural changes such as kyphosis, scoliosis, and/or leg length discrepancy.^7,9 It is not surprising that children who have survived bone cancer, are at increased risk for developing severe musculoskeletal complications later in life.³ Additionally, many chemotherapeutic agents, particularly anthracyclines, impair muscle tissue resulting in a reduced ability to generate force.¹⁰ Reduced strength, therefore, is a common late effect reported in CCS.^11–13 Intramuscular properties, including muscle thickness, rate of muscle activation and rate of torque development are impaired in CCS.^12,14,15 Impaired muscle characteristics can contribute to reduced range of motion,⁶ limited strength and endurance,^11–13,15 decreased functional ability,⁶ fatigue,⁶ gait dysfunction,^6,16 and impaired gross motor performance.^12,15

Neuromotor

Childhood cancer treatment can affect both central and peripheral neural tissue having a significant impact on function. Perhaps the most well-known late effect of childhood cancer treatment is chemotherapy-induced peripheral neuropathy (CIPN).^6,11,17 CIPN, a direct result of chemotherapeutic treatment, is most commonly associated with vinca alkaloids, particularly vincristine.^6,17 CIPN is also noted to occur following treatment with platinum-based agents such as cisplatin and oxaplatin, and taxanes.^6,17 Symptoms of CIPN include distal paresthesias, loss of sensation, weakness, particularly in the distal extremities, loss of vibratory sense and loss of deep tendon reflexes.^6,17 Taken together, these symptoms can lead to significant impairments in function including gait abnormalities such as foot drop,¹⁶ mobility limitations,⁶ and reduced balance,^11,15,18 which increases the risk of falls.¹⁹ Reduced rate of muscle activation,^12,15 as mentioned above, further demonstrates the reduced ability of the peripheral nervous system to activate appropriate musculature to maintain desired strength and balance. High-frequency sensorineural hearing loss is a notable late effect following treatment with platinum-based chemotherapeutics such as cisplatin and carboplatin, or following radiation to the head/neck.²⁰ As hearing loss has been associated with vestibular dysfunction and impaired balance in other populations,^21,22 children with hearing loss as a result of childhood cancer treatment may have balance deficits which can otherwise go unrecognized if not for movement specialists such as physical therapists. Additionally, classes of immunotherapy, particularly dinutuximab, can secondarily cause neuropathic pain which can lead to reduced or impaired mobility.²³

Systemic chemotherapy as well as radiation, particularly radiation to the head/neck, can result in cognitive impairment as a result of heightened oxidative stress and cytotoxic effects of those treatment modalities on neural tissue.^3,5–7 While many classes of chemotherapeutics can result in cognitive impairment, antimetabolites (e.g. methotrexate), alkylating agents, and vinca alkaloids (e.g. vincristine) are most commonly associated with cognitive impairment.²⁴ Cognitive deficits include impaired executive function, visual processing, attention, learning, processing speed, visuomotor function and working memory.^20,24 It may therefore be important to screen for cognitive deficits in a rehabilitation setting, as cognitive impairment can lead to difficulties with motor learning, multi-tasking abilities and fatigue.

Cardiopulmonary

Cardiopulmonary complications following treatment for cancer have been of particular interest in the past few years, and in a recent systematic review of physical and functional outcome measures used in pediatric oncology, cardiopulmonary assessments were most commonly used.¹³ Anthracyclines, including doxorubicin and idarubicin, are associated with cardiac and pulmonary dysfunction, as is thoracic radiation.^5,6,25 Common cardiac complications include left ventricular dysfunction, cardiomyopathy, coronary artery disease, pericarditis and increased risk of myocardial infarction.^5–7 while pulmonary late effects include pulmonary dysfunction, often characterized with pulmonary function tests such as spirometry, pulmonary fibrosis, interstitial pneumonitis, and pulmonary toxicity.^7,23,25 Immunotherapies, particularly brentuximab, when used in combination with chemotherapy can increase risk of pulmonary toxicity.²³ Cardiac and pulmonary dysfunction, as described above, can lead to poor endurance, impaired exercise capacity, impaired walking ability, difficulty ascending/descending multiple flights of stairs and reduced aerobic fitness.^6,13,25

Integumentary

Fibrosis or scar tissue formation is a common complication following radiation in addition to many chemotherapy agents, and can result in reduced range of motion and limited mobility to the affected area.^5,6 Following surgical tumor resection, children may have skin grafts, require wound management, or present with significant pain and edema, each of which can limit mobility of the affected area.^9,26

Additional Late Effects

While musculoskeletal, neuromotor, cardiopulmonary, and integumentary late effects significantly impact mobility and function, late effects which are not isolated to those body systems can result in functional impairments. Endocrine changes as a result of various chemotherapeutics and radiation can result in impaired growth and development, precocious puberty, changes in body composition such as cachexia or obesity, and hypo- or hyperthyroidism, each of which can impair a child’s strength, endurance, functional mobility and lead to heightened levels of fatigue.^3,5–7

Conclusion

In summary, medical treatments provided to treat malignancy can result in harmful late effects that can have a significant impact on functional mobility and physical performance. With a growing number of children surviving cancer, it is increasingly important to understand and address late effects of childhood cancer treatment. Ongoing efforts to understand late effects of pediatric cancer treatment and guidelines for comprehensive follow-up care in childhood, adolescent and young adult cancer survivors have been published by the Children’s Oncology Group (http://survivorshipguidelines.org).²⁶ Further research is needed to determine long-term late effects of newer oncologic treatments as they are developed, including advanced targeted therapies. Cardiorespiratory fitness, muscle strength, flexibility and gross motor performance are the most common functional measures studied in children who have survived cancer, while gait, balance, and running speed are not as commonly studied.¹³ It is beneficial for clinicians to understand the physiological and functional impact of medical treatments in attempts to individualize a plan of care for their patients. Understanding physiological late effects of specific treatment modalities will allow rehabilitation professionals to provide targeted therapeutic interventions to optimize outcomes. Future research should guide the development and implementation of therapeutic interventions which target specific late effects of childhood cancer treatment to promote and optimize movement in survivors of childhood cancer.