Long-Term Survivorship: Late Effects

Debra L. Friedman

INTRODUCTION

During the last several decades, multi-modal therapy for childhood cancer has resulted in markedly improved survival and currently 80% of children are cured. In the United States, there are currently >300,000 survivors of childhood cancer, and it is estimated that 1 in every 620 young adults between the ages of 20 and 39 is a survivor of childhood cancer (1,2,3). With this improvement in survival, the earlier expectation that a large proportion of childhood cancer survivors will now reach adulthood has become a reality. However, this cure comes at a cost. We have known for some years that the very therapy responsible for this survival can also produce adverse long-term outcomes that may limit survival and reduce survivors’ quality of life. Cancer, its treatments, and other factors, such as genetic predisposition and environmental exposures, place survivors of childhood cancer at risk for long-term adverse physiological and psychological sequelae, many of which are not yet evident during the childhood years (4,5,6,7,8,9,10,11,12,13,14,15).

Although research regarding long-term health-related outcomes has been carried on for over 25 years, changes in therapeutic approaches and increased survivorship mandate the need for ongoing studies that focus on health-related outcomes that are not only limited to a simple analysis of cure but also consider the quality of survivorship. These data can help direct appropriate clinical care for patients and also assist in the development of effective screening to reduce long-term morbidity. In this chapter, we briefly review some of the more common medical and psychosocial conditions for which childhood cancer survivors are at risk, discuss models of care and the need for risk-based monitoring for said health conditions, and provide information on resources available to healthcare providers following childhood cancer survivors. We also address some of the unique issues faced by patients who are diagnosed with cancer during their adolescent and young adult years.

COMMON PHYSIOLOGIC AND PSYCHOSOCIAL SEQUELAE OF CHILDHOOD CANCER

Tables 65.1 and 65.2 display some of the more common late effects associated with radiation and chemotherapy and further details are provided in the section below. Table 65.3 lists the common first-line therapies for the common pediatric cancers.

Cardiovascular

Childhood cancer survivors with a history of exposure to anthracyclines (doxorubicin, daunorubicin, and idarubicin) or thoracic radiotherapy are at risk for long-term cardiac toxicity. Current therapy, which attempts to decrease anthracycline exposure, and modern radiotherapy techniques, which result in a smaller volume of the heart receiving high doses of radiation, are likely to reduce these risks.

Anthracyclines are an important group of therapeutic agents used in the treatment of childhood cancer and approximately 50% of children currently receive anthracycline as treatment for cancer. Anthracycline-related cardiac abnormalities include cardiomyopathy, heart failure, and cardiac death and may be symptomatic or asymptomatic depending on severity. Cardiac abnormalities are reported with increased frequency in females, as well as those treated with doses >200 to 300 mg/m², at a younger age and risk increases from time of exposure (16,17,18,19,20,21,22,23,24,25,26,27,28,29,30).

The effects of thoracic radiation therapy are difficult to separate from those of anthracyclines because few children undergo thoracic radiation therapy without the use of anthracyclines. However, the pathogenesis of the injury differs, with radiation primarily affecting the fine vasculature of the heart that can present as pericarditis, pancarditis, myopathy, coronary artery disease, myocardial infarction, valve disease, and conduction defects (16,31,32,33). These cardiac toxic effects are related to age at exposure, time since exposure, total radiation dose, individual radiation fraction size, and the volume of the heart that is exposed.

In addition to direct cardiac toxicity, survivors of childhood acute lymphoblastic leukemia (ALL), the most common malignancy of childhood, are at risk for components of the metabolic syndrome, which include obesity with visceral adiposity, insulin resistance, hypertension, and dyslipidemia (34,35,36,37,38).

Pulmonary

Pulmonary toxicity, which manifests as restrictive defects with fibrosis, may follow exposure to total body radiation as part of hematopoietic cell transplant, thoracic radiotherapy, or exposure to several chemotherapeutic agents, bleomycin, busulfan, and the nitrosoureas (carmustine and lomustine). Risk is largely related to dose (39,40,41,42).

TABLE 65.1 Radiation late effects

System	Radiation Dose Range	Potential Effects
Neurological	>18 Gy >40-60 Gy	Precocious puberty and growth hormone deficiency Cognitive dysfunction, leukencephalopathy, and second CNS tumors (worsens with increased dose) Stroke, ototoxicity, myelitis, blindness, peripheral neuropathy, and pituitary and hypothalamic dysfunction
Eye	10-15 Gy >40-50 Gy	Cataracts Cornea, lacrimal duct, retina, conjunctiva, sclera, and optic neuropathy
Cardiac	>30-40 Gy (may be synergistic with anthracyclines)	Cardiomyopathy Pericarditis Coronary artery disease Valvular disease
Pulmonary	>10 Gy (may be synergistic with bleomycin)	Pulmonary fibrosis
Thyroid	>20 Gy	Overt or compensated hypothyroidism Thyroid nodules or cancer Hyperthyroidism
Gonadal	>4-12 Gy (20 in younger females) >1-6 Gy >24 Gy	Ovarian failure Oligospermia/azoospermia Leydig cell dysfunction
Second malignancies	>20-30 Gy	Sarcomas CNS tumors Breast cancer Melanoma Non-melanoma skin cancer Thyroid
Any	Dose dependent	Any organ within the field of radiation may sustain dysfunction or may be at risk for development of a second cancer
CNS, central nervous system.

Gastrointestinal and Hepatic

Gastrointestinal and hepatic effects are rare. Following high doses of radiotherapy for abdominal sarcoma, intestinal fibrosis, obstruction, strictures, colitis, malabsorption, and diarrhea can occur. Similarly, rare are hepatic fibrosis, venoocclusive disease, and portal hypertension following hepatic radiation or exposure to methotrexate, mercaptopurine, thiopurine, and dactinomycin (43).

Renal

Chronic nephrotoxicity can occur following exposure to cisplatin, carboplatin, ifosfamide, and rarely methotrexate,
radiation therapy, or removal of a kidney in the setting of other risk factors. Both glomerular and tubular injuries can be seen and many patients are asymptomatic (44,45,46,47,48,49).

TABLE 65.2 Chemotherapy late effects

System	Agents and Dose Range	Potential Effects
Neurological	Intrathecal chemotherapy methotrexate (>3 g/m²)	Cognitive dysfunction Cognitive dysfunction and leukencephalopathy (risk increases with increased dose)
Cardiac	Anthracyclines >200-300 mg/m² (less with XRT to chest)	Cardiomyopathy Arrhythmias
Hearing	Platinums	Hearing loss
Pulmonary	Bleomycin >200 u/m² (less with XRT to chest) Carmustine (BCNU)	Restrictive lung disease
Urological	Cyclophosphamide Ifosfamide	Chronic hemorrhagic cystitis Second bladder cancers Chronic hemorrhagic cystitis
Hepatic	Methotrexate Thioguanine Mercaptopurine Dactinomycin Busulfan	Hepatic dysfunction Veno-occlusive disease (dactinomycin, busulfan, and thioguanine)
Renal	Platinums Ifosfamide	Renal insufficiency or failure Renal electrolyte wasting/insufficiency
Gonadal	Alkylating agents Nitrosoureas	Ovarian failure; early menopause Testicular failure; Leydig cell dysfunction
Second malignancies	Alkylating agents: Mechlorethamine>>others Topoisomerase II inhibitors Platinums Cyclophosphamide	Leukemia Transitional bladder carcinoma
XRT, radiation therapy; BCNU, carmustine.

Endocrine Function and Fertility

Thyroid dysfunction, as manifested by hypothyroidism, hyperthyroidism, goiter, or nodules, is a common delayed effect of radiation therapy for Hodgkin disease, brain tumors, and ALL (50,51). Other endocrine abnormalities can occur following cranial irradiation, including growth hormone deficiency, delayed or precocious puberty, and hypopituitarism (14,52,53,54). These effects are related to dose, age at time of exposure, and gender.

Alkylating agents are the chemotherapeutic agents that are most responsible for gonadal toxicity. Males retain endocrine function following higher cumulative doses than do females, but spermatogenesis is highly sensitive to even relatively low doses of alkylating agents, such as cyclophosphamide, ifosfamide, and procarbazine. Passage through puberty and retention of normal male hormonal production and function is possible after relatively high doses of alkylating agent’s radiation (55,56,57,58,59,60). Unlike the situation in males, hormonal function and potential for fertility are synchronous in females. Prepubertal females possess their lifetime supply of oocytes with no new oogonia formed after birth. This may protect them against the effects of chemotherapy and radiation therapy. As the number of oocytes is fixed, and they are extruded during ovulation, risk of menstrual irregularity, ovarian failure, and infertility increases with age at treatment (61,62,63,64,65,66). Given the high risk of infertility and sterility following childhood cancer treatment, efforts are
underway to help preserve function. This includes reduction in cumulative doses of radiation and chemotherapy as well as ovarian and sperm cryopreservation, which includes some yet experimental and evolving methodologies for women and prepubertal males (67,68).

TABLE 65.3 Common pediatric cancers and common first-line treatments

Disease	Treatment
Acute lymphoblastic leukemia	Cranial and craniospinal radiotherapy (some high risk or central nervous system disease) Testicular radiotherapy (only with testicular involvement) Vincristine, corticosteroids, asparaginase, daunorubicin, doxorubicin, cyclophosphamide, cytarabine, mercaptopurine, methotrexate, and thiopurine
Acute myeloid leukemia	Daunorubicin, idarubicin, mitoxantrone, cytarabine, etoposide, and thioguanine
Lymphomas	Radiation to involved sites Doxorubicin, bleomycin, vincristine, vinblastine, etoposide, prednisone, cyclophosphamide, cytarabine, dexamethasone, rituximab, methotrexate. procarbazine, mechlorethamine, dacarbazine, and mercaptopurine
Central nervous system malignancy	Cranial or craniospinal radiation Vincristine, cyclophosphamide, carmustine, lomustine, carboplatin, cisplatin, methotrexate, and etoposide
Soft tissue sarcomas (rhabdomyosarcoma and others)	Radiation to involved sites Vincristine, doxorubicin, cyclophosphamide, irinotecan, topotecan, etoposide, ifosfamide, and dactinomycin
Bone sarcomas (osteosarcoma and Ewing sarcoma)	Radiation to involved sites (Ewing only) Vincristine, doxorubicin, cyclophosphamide, irinotecan, topotecan, etoposide, ifosfamide, dactinomycin, methotrexate, and cisplatin
Germ cell tumors	Radiation to involved site (rare) Cisplatin, carboplatin, etoposide, and bleomycin
Wilms tumor	Radiation to involved sites Vincristine, dactinomycin, doxorubicin, cyclophosphamide, carboplatin, and etoposide

When fertility is preserved, pregnancy outcomes and health of offspring become of paramount importance. Treatment in females with high doses of radiation can lead to uterine vascular insufficiency, spontaneous abortion, neonatal death, low-birth-weight infants, fetal malposition, and premature labor (69,70). However, outside of these risks, offspring of childhood cancer survivors have not been found to have an excess of birth defects or adverse health outcomes (70,71,72,73,74).

Musculoskeletal Late Effects

Normal cells are affected by radiation therapy in growing children, and this can result in soft tissue hypoplasia, diminution of bone growth, and decreased bone mineral density, the latter of which can also be adversely affected by corticosteroid use, vitamin D deficiency, and estrogen deficiency. Avascular necrosis is also reported following corticosteroid exposure (75,76,77,78,79,80,81,82,83,84).

Neurocognitive and Psychological Late Effects

Neurocognitive dysfunction is most commonly seen following cranial radiotherapy in survivors of ALL or central nervous system tumors and need for special education services is not uncommon. Younger age at the time of treatment and higher dose are associated with increased risk. Treatment intensity and length of treatment can also adversely affect cognitive performance, due to absences from school and psychologic problems. Intrathecal and intravenous methotrexate and oral corticosteroids (dexamethasone > prednisone) may also contribute to cognitive dysfunction, but findings are not consistent across studies (85,86,87,88,89,90,91,92,93,94,95,96,97).

Psychological effects of cancer and its treatment are now being recognized because of the efforts of investigators who are examining the adjustment of long-term survivors and their parents and siblings. Findings are very diverse,
with some studies among survivors reporting normal function, less risk taking, and post-traumatic growth while many others reporting increases in mental health disorders and symptoms such as stress, distress, anxiety, depression, posttraumatic stress disorder, impaired health-related quality of life (HRQOL), fatigue, and chronic pain (90,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115).

Only gold members can continue reading. Log In or Register to continue