Health issues in survivors of childhood cancer. (Featured CME Topic: Pediatrics).

APPROXIMATELY 8,000 children and 11,500 adolescents (aged 15 to 19 years) were diagnosed with cancer in the United States in 1999. (1) Acute lymphoblastic leukemia (ALL), Hodgkin's and non-Hodgkin's lymphoma, and Wilms' tumor are the most common highly curable malignancies, with 75% of such patients surviving disease-free for more than 5 years. Currently, an estimated 200,000 Americans are survivors of childhood cancer. (1) Improvements in diagnosis and therapeutics translate into a growing population of childhood cancer survivors who will continue to need medical care as they enter adulthood. Pediatric oncologists will deliver some of this care to adolescents and young adults, but the health care system will return most long-term survivors back to their medical primary care providers. Accomplishing this process is critical to provide the appropriate health screening and timely interventions for cancer-related complications and to fulfill the true definition of cure from these catastrophic diseases.

Although most of these children will lead healthy and productive lives, complications from a malignancy or its therapies are apparent with improved survival and longer follow-up. Sequelae that present or develop 5 or more years after cancer diagnosis include both medical and psychosocial problems that affect a survivor's physical functioning, quality of life, and increased risk of early death. The consequences of late effects must not be forgotten as childhood cancer survivors transition back to normal health maintenance in the primary care setting.

EVALUATION OF THE CHILDHOOD CANCER SURVIVOR

Three major factors should be considered in the approach and evaluation of the survivor of a childhood cancer: (1) patient factors (age at treatment, sex, cancer-predisposing genetic mutations, and genetic polymorphisms); (2) tumor factors (tumor histology, stage at diagnosis, and degree of organ invasion at outset); and (3) treatment variables (surgery, radiation therapy, chemotherapy, or combined modality therapy). The intensity of therapy (ie, drug and radiation doses) and procedures such as hematopoietic stem-cell transplantation further increase the risks of adverse health outcomes. By understanding these concepts, the adult or primary care practitioner can more accurately assess cancer-related health risks and anticipate the follow-up needs of survivors of childhood cancers.

Long-term monitoring is necessary to confirm continued remission status, to monitor for therapy-related toxicities, and to provide education/interventions that can prevent or ameliorate cancer-related morbidities. The approach to long-term follow-up should be tailored to the survivor's specific treatment exposures, including surgery (Table 1), chemotherapy (Table 2), and radiation therapy (Table 3), as appropriate, as well as to acute toxicities that are experienced at cancer presentation or during therapy. Treatment era is significant in assessing the risk of some late effects, since curative therapy was not available for many pediatric malignancies before 1975; hence, the various health risks posed by early cancer treatments were not well appreciated. More recent treatments have evolved concurrent with advances in cancer biology and therapeutics, and with improved understanding of late treatment effects. Consequently, contemporary treatment intensity has been reduced for patients with favorable pediatric ca ncers in an effort to decrease treatment complications, while therapy has been further intensified for those with unfavorable malignancies in an effort to improve primary disease control.

Several investigators have evaluated cause-specific mortality in cohorts of long-term childhood cancer survivors. (2-6) In all of these studies, a survivor of childhood cancer is more likely to die at a younger age, compared with age-matched and sex-matched control subjects. Recurrence of the initial malignancy is the most common cause of death in the first 10 years after diagnosis; however, with longer follow-up, treatment-related complications, particularly cardiovascular disease and secondary malignancies, predominate as causes of death. These studies underscore the need for more effective (possibly more intensive) therapeutic approaches for the pediatric malignancies with poor prognoses, but the benefits must be balanced against the risk of late complications from intensified drug regimens. Long-term monitoring with careful assessment for late therapy-related toxicity is crucial in establishing which therapies are ultimately both effective and safe for the child with cancer.

SYSTEM-BASED SCREENING

The late effects of cancer treatment can be anticipated on the basis of the specific therapy to which the patient is exposed and the age at the time of that exposure. For example, many of radiotherapy's adverse effects on growth and development may not become apparent for many years. Conversely, chemotherapy is likely to result in acute toxicities, which are more often temporary, but sometimes persist or may become clinically significant when the patient matures. The growing child is particularly vulnerable to delayed treatment sequelae, such as growth disturbances, infertility, and neurocognitive dysfunction. The approach to a late-effects evaluation should begin with a thorough physical examination, followed by screening laboratory tests and diagnostic imaging determined by the individual patient's risks of treatment sequelae. The following sections outline specific systemic evaluations that should be considered based on the survivor's presenting symptoms and treatment history.

Dental/Oral

Chemotherapy administered to any child before development of secondary dentition may result in a variety of dental abnormalities, including adontia, hypodontia, microdontia, root stunting, and enamel hypoplasia. In addition to dental developmental abnormalities, head and neck radiation therapy produces salivary gland dysfunction, which may cause xerostomia and increase the risk of dental caries and periodontal disease. Radiation to the face and jaw during childhood (especially before the age of 6 years) may result in suboptimal growth of the maxilla and mandible, which makes corrective orthodontic procedures difficult. (7) In the setting of bone marrow transplantation, total body irradiation (TBI) and graft-versus-host disease may also adversely affect the oral mucosa.

Musculoskeletal

Surgical procedures and radiation therapy often result in skeletal and soft tissue deformities, especially if these treatments were done before the adolescent growth spurt. Consequently, young children treated with high-dose radiation therapy show the most pronounced effects, with muscle wasting and bone atrophy. Cosmetic and functional problems may result from the subsequent reduced or asymmetric growth and may be associated with chronic pain. Monitoring and timely orthopedic interventions can reduce functional deficits associated with scoliosis and limb-length discrepancy. Reconstructive surgeries, usually recommended after attainment of skeletal maturity, can significantly improve cosmetic outcomes and quality of life. Bone mineralization can also be adversely affected by cancer treatment, with development of early-onset osteopenia and osteoporosis in survivors of childhood cancers. Agents predisposing to bone demineralization include glucocorticoids and methotrexate. Radiation therapy involving the skelet al structures, particularly at high doses, may produce local osteopenia. More commonly, cranial or abdominopelvic radiation therapy is associated with osteopenia or osteoporosis as a consequence of hypothalamic endocrinopathy (eg, growth hormone deficiency or hypogonadism). Providing hormone replacement therapy optimizes bone mineralization in such cases. Treatment with glucocorticoids, particularly dexamethasone, has been implicated in the increasing frequency of osteonecrosis (avascular necrosis) observed in childhood cancer patients. This complication usually presents during therapy, occurs more frequently in adolescent patients, and most commonly involves the hips and knees. Treatment is symptomatic in mild to moderate cases; patients with severe, painful osteonecrosis that limits function and activity are candidates for orthopedic interventions (core decompression or arthroplasty). Currently, evaluation for osteoporosis in the pediatric and adolescent patient includes baseline and follow-up bone densitom etry, exercise, and calcium supplementation; bisphosphonate therapy is limited to clinical trials.

Endocrine

Endocrine dysfunction may result from direct effects on glandular function (primary gland failure) or secondary effects on hypothalamic-pituitary pathways (central gland failure). With the exception of gonadal dysfunction, these complications develop almost exclusively in childhood cancer patients with brain tumors or a history of head and neck radiation. Rarely, endocrinopathy has been reported in children treated with chemotherapy alone. Endocrine complications represent one of the most common late effects observed in childhood cancers for which corrective therapy is available. Appropriate monitoring facilitates timely therapeutic interventions that reduce morbidity and dramatically improve quality of life.

Thyroid. Hypothyroidism is the most common endocrinopathy observed in childhood cancer survivors treated with head and neck radiation therapy (mantle, cervical, facial, cranial, or craniospinal). This complication is frequent in young adults who have had mantle therapy for Hodgkin's disease or cranial irradiation for ALL or brain tumors. The incidence of hypothyroidism is directly related to radiation dose, and may develop right after or as late as 10 years after irradiation. (8) Hyperthyroidism is infrequently reported as a complication of childhood cancer therapy, though its frequency is in excess of that in the general population. With extended follow-up, thyroid nodules have been increasingly reported and should be monitored due to malignant potential. (9) Thyroid carcinoma is one of the most frequent second solid tumor malignancies observed in patients treated with cervical radiation, and occurred in 18-fold excess in a large cohort of Hodgkin's disease suvivors. (10)

Pituitary. Growth hormone (GH) deficiency is the most common anterior pituitary endocrinopathy observed after cranial irradiation. The risk of GH deficiency is related to the radiation dose, and occurs more frequently when higher doses (exceeding 1800 to 2000 cGy) are used. Radiation-induced GH deficiency increases in incidence 2 or more years after therapy. (11) Radiation-induced hypo thalamic-pituitary dysfunction may also predispose to early or delayed pubertal progression through its affect on gonadotropin-releasing hormone or gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH] production). True precocious puberty (sexual development before the age of 8 years in a girl or before the age of 9 years in a boy) is rare, while earlier onset of puberty relative to timing in the general population is more common. Girls treated with low-dose cranial irradiation more commonly present with this complication and show an accelerated progression through puberty that can adversely affect their long-term height potential, due to premature closure of bone epiphyses. Adrenocorticotropic hormone deficiency and hyper-prolactinemia are less common pituitary endo-crinopathies that are more often seen in the setting of panhypopituitary dysfunction after high-dose cranial irradiation.

Gonadal. Both chemotherapy and radiotherapy can adversely affect gonadal function. In girls, loss of ovarian follicular function is associated with loss of sex hormone production and infertility. Ovarian damage may occur after high doses of abdominopelvic radiation and/ or alkylating agent (cyclophosphamide, ifosfamide, mustard/procarbazine) chemotherapy are given. Compared with the level of germ cell disruption in boys, girls' ovarian function is maintained at higher cumulative doses of alkylating-agent chemotherapy, but young women remain at risk for early menopause due to oocyte depletion. (12) Ovarian dysfunction may present with the arrest of pubertal development, primary or secondary amenorrhea, and infertility. In boys, sperm production occurs in the seminiferous tubules of the testes and is sensitive to treatment with alkylating drugs or radiotherapy. Sex hormone production proceeds independently in the testicular Leydig's cells, which can tolerate higher cumulative doses of gonadotoxic therapy. Thus, it is common for a young man to report infertility after alkylating-drug-based cancer therapy, despite a history of normal pubertal progression and sexual function. The incidence and duration of alkylating-drug-induced azoospermia is related to proximity in timing to puberty and to the drug combination and doses used. Some of the alkylating effects on azoospermia are reversible over time. Radiotherapy to the testes or brain may permanently affect both sperm and testosterone production, resulting in the additional need for testosterone replacement.

Evaluation of menstrual cycle history and pubertal development is the easiest way to assess whether cancer therapy has adversely affected sex hormone production (testosterone and estradiol) in a child. In postpubertal patients, a rise in the gonadotropin-stimulating hormones (FSH and LH) that control testicular and ovarian function indicates gonadal injury. Regular, unassisted menses in a young woman is consistent with ovulation and potential fertility. Follicle-stimulating-hormone elevation in a young man with atrophic testes suggests germ cell depletion, though semen analysis is required to definitively confirm azoospermia.

Cardiovascular

Both radiation therapy and anthracycline drug exposure predispose to cardiovascular sequelae, and should be considered when survivors present with exercise intolerance, chest pain, shortness of breath, or symptoms of congestive heart failure. Anthracycline drugs (doxorubicin, daunorubicin, and mitoxantrone) are the most common cardiotoxic agents used to treat pediatric malignancies. The risk of anthracycline-induced cardiomyopathy has been related to young age at treatment (those <4 years of age are the most predisposed), female sex, and cumulative anthracycline dose. Historically, doses in excess of 550 mg/[m.sup.2] are associated with an increased risk of cardiomyopathy in adults. The threshold dose for pediatric patients is still debated, but age at treatment and concomitant use of other cardiotoxic modalities (eg, thoracic radiation) appear to enhance risk in younger patients treated with lower total doses. (13) Thoracic irradiation accelerates atherosclerosis, predisposing patients to early-onset coronar y artery disease and myocardial infarction. This complication was more common when anteriorly weighted administration of high-dose thoracic radiotherapy was the standard of care (1960s through the early 1970s). These and other cardiovascular complications related to radiation fibrosis, like constrictive pericarditis, are less common since the introduction of treatment protocols limiting radiation dose and treatment fields in pediatric patients. Clinicians should be also aware that portions of the heart are included in several commonly used radiation treatment volumes, including mantle, mediastinal, spinal, upper abdominal fields, and TBI.

Pulmonary

Antineoplastic therapy toxic to the pulmonary system includes chemotherapeutic agents like bleomycin, nitrosoureas, and carmustine, and any radiation field that includes the lungs. In the absence of direct pulmonary radiation, asymptomatic mild to moderate restrictive pulmonary changes are observed, which may be accompanied by reduced pulmonary diffusion. Anticipatory guidance regarding abstinence from cigarette smoking and avoidance of environmental tobacco smoke exposure is the most important intervention to provide for these young adults.

Genitourinary

Chemotherapy and radiotherapy may produce glomerular or tubular injury. Hypertension is a nonspecific presentation of either condition. Tubular injury is most common after cisplatin and ifosfamide therapy and is associated with electrolyte wasting (eg, magnesium, potassium, phosphorus) which may require lifelong replacement therapy. Ifosfamide administration may produce a Fanconi tubulopathy, characterized by aminoaciduria, hypo-phosphaturia, glucosuria, and inability to acidify the urine. Nephrectomy may predispose to hyperfiltration of the remaining kidney; proteinuria and hypertension in a Wilms' tumor patient should prompt a nephrology referral. Angiotensin-converting enzyme inhibition therapy in these patients may preserve renal function. While mild renal insufficiency is a common sequela during cancer therapy, end-stage renal disease is relatively uncommon, due to the standard monitoring of renal function during treatment and dose adjustment of antineoplastic agents based on renal function. Conversely, hemorrhagic cystitis is a relatively common urinary tract sequela in patients treated with high cumulative doses of ifosfamide or cyclophosphamide. The use of the urinary bioprotective agent, mesna, during therapy lessens this toxicity. Abdominopelvic radiation may enhance chemotherapy-induced bladder injury and increase the risk of chronic cystitis and bladder malignancy. Screening for most urinary tract sequelae is easily accomplished by assessment of blood pressure, serum electrolyte levels (including calcium, magnesium and phosphorus), blood urea nitrogen and creatinine levels, and urinalysis. Abnormalities in these evaluations should prompt more thorough evaluation of creatinine clearance or glomerular filtration.

Gastrointestinal

Late effects in the gastrointestinal tract relate to either the extent of surgical intervention and radiotherapy or the risk of subsequent adhesions causing small-bowel obstruction. Although many chemotherapy regimens produce acute hepatic injury, long-term hepatotoxicity from chemotherapy is rare. Chronic viral hepatitis due to transfusion-transmitted pathogens, particularly hepatitis C, should be considered in long-term survivors with abnormal liver function who were treated before the 1990s, however. Chronic infection occurs in 75% to 80% of infected individuals, and is associated with increased risk of adverse liver outcomes, including cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Confirmation of chronic infection by demonstration of viral RNA by polymerase chain reaction testing should prompt referral to the appropriate hepatic specialist for consideration of antiviral therapy.

Vision and Hearing

Survivors of intracranial and other head and neck tumors have the highest risk of neurosensory deficits affecting vision and hearing. Cranial neuropathy or optic atrophy present at tumor diagnosis may persist after completion of therapy. Radiation retinopathy after radiotherapy for retinoblastoma or orbital rhabdomyosarcoma may result in xerophthalmia and photophobia. Cataract development is a relatively common sequela of head and neck irradiation (including TBI). Chronic steroid use may also predispose patients to premature cataract formation. In patients treated with lower-dose radiation (<3000 cGy), cataracts are usually tiny, posterior, subcapsular lesions that are not visually significant. Fundoscopic and visual-acuity screening will facilitate identification of survivors with significant cataracts who would benefit from intervention.

While hearing loss may be related to primary tumor location in some long-term survivors, this sequela is most frequently associated with high cumulative doses of cisplatin and/or other ototoxic drugs, such as aminoglycosides. Head and neck irradiation may further exacerbate sensorineural or conductive hearing loss. In the latter, conductive loss is most. frequently associated with chronic cerumen impaction. Audiology screening permits timely behavioral interventions to optimize school performance (eg, preferential classroom seating and institution of amplification devices).

Neuropsychologic

Therapy directed at the central nervous system in the form of cranial/craniospinal irradiation, intrathecal treatment for leukemia, or high-dose systemic methotrexate therapy may affect neurocognitive function. Factors correlated with risk include younger age at treatment, female sex, and higher cumulative irradiation dosage. Cognitive deficits can be subtle and are often revealed only by specific questioning of parents. Assessment of academic performance and behavior should be performed yearly. Formal neuropsychologic testing may be required to define subtle deficits and recommend specific academic interventions.

With contemporary treatment protocols, peripheral sensory or motor neuropathy typically develops acutely during therapy with vinca alkaloids (vincristine, vinblastine) or cisplatin. Full recovery is typical for most patients, though the rare patient with residual paresthesias may benefit from treatment with agents like gabapentin. Paralytic syndromes (eg, hemiparesis) or cranial neuropathies are more likely the residual sequelae of the primary tumor presentation but may be associated with cerebrovascular accidents that occur during therapy or many years after completion of therapy.

Psychosocial

Psychosocial needs of the survivor are related to the long-term effects on mental and physical abilities. Concerns about relapse and second cancers are ever-present in these children, who have often been protected from peer experiences. Separation from family and re-integration into peer groups can be difficult, especially if there are permanent physical stigmas of therapy. In addition, access to health insurance and finding adequate medical care are often sources of stress for patients and their families. Clinicians should assess family dynamics and adjustment after the cancer experience and explore ongoing concerns about relapse and current or potential future health problems. Behavioral services (social work, psychology) referral may be beneficial for families having difficulties overcoming barriers to finding medical services and for those experiencing excessive stress related to their cancer experience.

SECOND MALIGNANT NEOPLASMS

The incidence of having a subsequent malignant neoplasm ranges from 2% to 12% in reported series of childhood cancer survivors. The risk is largely related to the specific type of therapy used, and is influenced by patient's age at treatment, sex, and time interval from completion of therapy. The presence of a cancer-predisposing genetic mutation or polymorphism may markedly increase the risk of secondary carcinogenesis. (14) As survivors age, acquired risk factors (eg, cigarette smoking or excessive sun exposure) may enhance genetic and treatment risk factors. Acute myeloid leukemia (AML) and solid tumors comprise the 2 main types of second malignancies. Predisposition to treatment-related AML is primarily due to chemotherapy with alkylating agents (nitrogen mustard, cyclophosphamide, procarbazine) or epipodophyllotoxins (etoposide, teniposide) (Table 3). Alkylating-agent-induced AML typically develops 5 to 10 years after treatment, with risk dependent upon cumulative dose. Secondary leukemias due to epipodo phyllotoxin therapy are characterized by a relatively brief latency (1 to 6 years; median, 33 months) and are associated with frequency of administration of alkylating agents or L-asparaginase, and, to a lesser extent, the cumulative dosage. Youngsters treated with leukemogenic chemotherapy regimens need yearly complete blood cell count surveillance for 10 to 15 years after treatment.

Second solid tumors exhibit a long latency, with an increasing incidence 10 years after diagnosis. These malignancies develop primarily in previously irradiated tissues (Table 2). Common adult cancer histologies predominate, including carcinomas of the breast, thyroid gland, skin (squamous cell carcinoma and melanoma), lungs, and gastrointestinal tract. Patients treated with high-dose radiotherapy to extended treatment volumes have the highest risk of this complication; alkylating-agent and epipodophyllotoxin chemotherapy may enhance radiotherapy-induced carcinogenesis in the lungs and gastrointestinal tract. In some secondary tumors, the age at treatment and sex influence risk; for example, numerous studies have shown higher risks of second malignancies in female versus male survivors from Hodgkin's disease. The risk of breast cancer appears to be greatest in female Hodgkin's disease survivors irradiated during puberty. The estimated actuarial incidence of secondary breast cancer in female survivors of child hood Hodgkin's disease ranges from 4% to 35% at 20 years, (15) a fact that has implication for early initiation of breast cancer screening. The primary care physician should carefully evaluate areas of radiation exposure during routine health maintenance visits, since secondary malignancies usually present as an unexplained lump or mass.

ANTICIPATORY GUIDANCE FOR CANCER SURVIVORS

Because of the variety of health risks predisposed by cancer and its therapy, it is particularly important for childhood cancer survivors to receive periodic health surveillance. A primary care physician knowledgeable about the survivor's cancer treatment history and its associated health risks is typically the ideal person to orchestrate and coordinate multispecialty care. Evaluations should include a thorough history and physical examination, with attention to skin and soft tissues in radiation treatment fields. Laboratory tests, diagnostic imaging, and other evaluations should be performed based upon the results of physical examination findings and the predisposition to anticipated health risks due to cancer treatment or suggested by family history. In patients with treatment exposures associated with excess risk of premature onset of health problems, screening for common adult cancers or cardiovascular disease should be instituted at an earlier age. Suggested guidelines for cardiovascular screening of chi ldhood cancer survivors is depicted in Table 4, in which young adults treated with high doses of anthracyclines or with documented left ventricular dysfunction have restrictions on isometric exercise programs, and high-risk medical management during pregnancy is recommended. A young woman treated with thoracic radiotherapy during puberty who has a markedly increased risk of breast cancer should initiate breast cancer screening programs at a younger age. For most centers, this has involved teaching adolescent females proper breast self-examination technique, more frequent clinician examinations, and earlier institution of mammographic screening (Table 5). (16)

The role of vitamin therapy as chemoprevention in these patients is unknown. Studies of adults are ongoing but have not shown a chemopreventive benefit for subjects taking single-agent vitamin E or [beta]-carotene. The current consensus is that a healthy diet, including fruits, vegetables, and fiber (which contain antioxidants as well as nonvitamin phytochemicals), is more advantageous than single vitamin therapy for cancer prevention.

The general lack of consensus regarding specific health screening has been problematic for clinicians caring for long-term survivors of childhood cancer, particularly when the majority of young adult survivors are apparently healthy. Communication with treating oncologists and late-effects specialists is helpful in organizing an appropriate treatment-directed follow-up plan. Lifestyle factors contributing to disease risks predisposed by cancer treatment should be reviewed, since behavioral modification may be the primary method of risk reduction available to most survivors. These discussions should emphasize the importance of abstinence from tobacco use and routine practice of sun protection measures, due to the survivor's increased vulnerability to tobacco carcinogens and ultraviolet radiation. To reduce health risks associated with obesity and cardiovascular disease, survivors should be encouraged to maintain a healthy weight, adopt a physically active lifestyle, adhere to a diet with a variety of healthful foods (especially plant sources), and limit alcohol consumption. These health behaviors have been shown to reduce the risk of developing cardiovascular disease and impact on development of common adult malignancies, including breast, colon, uterine, and prostate cancer.

TABLE 1.

Late Effects of Surgery

     Procedure                     Sequelae

Splenectomy           Impaired immune function, increased
                        risk of sepsis
Amputation            Functional issues, phantom pain,
                        back or contralateral extremity
                        pain, cosmetic, psychosocial
Limb-sparing surgery  Functional issues, pain, leg-length
                        discrepancy, endoprosthesis
                        loosening  or fracture
Abdominal surgery     Bowel adhesion/obstruction
Nephrectomy           Renal hyperfiltration
Pelvic surgery        Erectile dysfunction, retrograde
                        ejaculation, urinary incontinence
TABLE 2.

Late Effects of Radiotherapy

Organ System                   Sequelae

All tissues                    Second malignancies, functional and
                               cosmetic problems
Teeth and salivary glands      Dry mouth, dental development
                               abnormalities, periodontal
                               disease, tooth decay (accelerated)
                               cosmetic problems
Bones                          Short stature, scoliosis, limb-
                               length discrepancies, chronic pain
Muscles and soft tissues       Atrophy or hypoplasia, fibrosis and
                               contracture, lymphedema
Eye                            Cataract, retinopathy, dry eye,
                               vision loss, photophobia
Ear                            Chronic cerumen impaction
Heart                          Pericardial effusion, constrictive
                               pericarditis, early-onset coronary
                               artery disease
Chest                          Pulmonary fibrosis, restrictive
                               lung disease, recurrent
                               pneumothorax, breast cancer
Central nervous system         Neurocognitive deficits, chronic
                               seizure disorder, cerebrovascular
                               accident (stroke), imaging
                               changes: cerebral atrophy
                               encephalomalacia, lacunes, and
                               ventriculomegaly
Kidneys                        Hypertension, renal insufficiency
Bladder and collecting system  Bladder fibrosis, dysfunctional
                               voding, urinary incontinence,
                               urinary tract obstruction
Pituitary gland                Reduced growth or growth failure,
                               early or delayed puberty, other
                               hypothalamic-pituitary
                               endocrinopathies
Thyroid gland                  Hypothyroidism, hyperthyroidism,
                               thyroid nodules
Gonads                         Males: sterility, Leydig's cell
                               dysfunction. Females: ovarian
                               failure, early menopause
Gastrointestinal tract         Malabsorption, intestinal stricture
                               hepatic dysfunction, chronic
                               enterocolitis
TABLE 3.

Late Effects of Chemotherapy

               Organ                           Drug

Bones                              Corticosteroids, methotrexate


Teeth                              Any chemotherapy administered
                                    before development of secondary
                                    dentition
Cardiovascular                     Anthracyclines (doxorubicin,
                                    daunorubicin)
                                   Cyclophosphamide (high dose)
                                   Vincristine, vinblastine
Lungs                              Bleomycin/BCNU (carmustine)
                                   Methotrexate
Central/peripheral nervous system  Methotrexate


                                   Cisplatin
                                   Vinca alkaloids, vincristine,
                                    vinblastine
Kidneys                            Ifosfamide
                                   Cisplatin

                                   Carboplatin
                                   Methotrexate (high dose)
                                   Nitrosoureas
Bladder and collecting system      Cyclophosphamide/ifosfamide

Gonads                             Alkylating agents
                                    (cyclophosphamide, procarbazine,
                                    nitrogen mustard)
Gastrointestinal tract             Methotrexate

                                   BCNU (carmustine)

Bone marrow                        Alkylating agents
                                    (cyclophosphamide, procarbazine,
                                    nitrogen mustard)
                                   Epipodophylltotoxins
                                    (etoposide, teniposide)

               Organ                          Sequelae

Bones                              Osteopenia, osteoporosis,
                                    osteonecrosis (avascular
                                    necrosis)
Teeth                              Enamel hypoplasia, microdontia,
                                    hypodontia, adontia, root
                                    stunting
Cardiovascular                     Cardiomyopathy/congestive heart
                                    failure
                                   Cardiac failure
                                   Raynaud's syndrome
Lungs                              Pulmonary fibrosis
                                   Interstitial pneumonitis
Central/peripheral nervous system  Leukoencephalopathy, neurocognitive
                                    dysfunction, neuropsychiatric
                                    changes, seizures
                                   Peripheral neuropathy, hearing loss
                                   Peripheral neuropathy

Kidneys                            Fanconi syndrome
                                   Renal insufficiency, electrolyte
                                    wasting, renal tubular acidosis
                                   Renal insufficiency
                                   Renal insufficiency
                                   Delayed-onset renal failure
Bladder and collecting system      Hemorrhagic cystitis, bladder
                                    fibrosis, carcinoma
Gonads                             Infertility


Gastrointestinal tract             Hepatic dysfunction, hepatic
                                    fibrosis, cirrhosis (rare)
                                   Hepatic dysfunction, hepatic
                                    failure
Bone marrow                        Acute myeloid leukemia,
                                    myelodysplasia
TABLE 4.

Cardiovascular Guidelines for Childhood Cancer Survivors *


Anthracycline exposure < 300 mg/[m.sup.2] and normal
echocardiogram/electrocardiogram at end of treatment

   Symptom review: Shortness of  breath, chest pain, exertion,
     other risk factors
   Electrocardiogram/echocardiogram: assess QTc, heart block,
     ectopy, ejection fraction every 2 years (annually if
     mediastinal radiation was given)
   Heart-healthy diet
   Behavioral guideliness
   No restrictions on activities

Anthracycline exposure [greater than or equal to]300 mg/
[m.sup.2] or abnormal echocardiogram/electrocardiogram
at end of treatment (any anthracycline dose)

   Symptom review
   Evaluate all female patients for pregnancy plans
   Blood pressure review, lipid profile
   Control high blood pressure
   Limit use of growth hormone, sex hormones
   Restrictions: no isometric exercise; cardiologist to help
     manage pregnancy

* May need increased monitoring if concomitant mediastinal radiation was
received

QTc = corrected QT interval.
TABLE 5.

Guidelines for Breast Cancer Screening for Women With History of Chest
Irradiation (15)

Age                   Screening Test and Frequency

Beginning at puberty  Breast self-examination monthly
20-40 years           Breast examination by doctor twice a year
25 years              Baseline mammogram; repeat every 3 years until
                        age 40
>40 years             Breast examination every year
                      Mammogram every year

Selected Books

* Schwartz CL, Hobbie WL, Constine LS, et al: Survivors of Childhood Cancer. Assessment and Management. St. Louis, CV Mosby, Co 1994. 413 pages

* Keene N, Hobbie W, Ruccione K: Childhood Cancer Survivors. A Practical Guide to Your Future. Cambridge, O'Reilly and Associates Inc, 2000. 482 pages

* Halperin EC: Pediatric Radiation Oncology. Philadelphia, Lippincott Williams & Wilkins, 3rd Ed, 1999. 606 pages

Selected Community Resources

* Candlelighters Childhood Cancer Foundation, PO Box 498, Kensington, MD 20895; 1-800-366-2223; www.candlelighters.org

* American Cancer Society Inc, 1599 Clifton Rd NE, Atlanta, GA 30329; 1-800-ACS-2345; www.cancer.org

* National Cancer Survivors Day Foundation, PO Box 682285, Franklin, TN 37068-2285; 615-794-3006; www.ncsd.com

* Children's Oncology Group; http://www.children'soncologygroup.org

* St. Jude Children's Research Hospital; http://www.stjude.org

References

(1.) Steen G, Mirro J (eds): Childhood Cancer. A Handbook from St. Jude Children's Research Hospital. Cambridge, Perseus Publishing, 2000, p 605

(2.) Linet MS, Ries LAG, Smith MA, et al: Cancer surveillance series: recent trends in childhood cancer incidence and mortality in the United States. J Natl Cancer Inst 1999; 91:1051-1058

(3.) Hawkins MM: Long term survival and cure after childhood cancer. Arch Dis Child 1989; 64:798-807

(4.) Nicholson HS, Fears TR, Byrne J: Death during adulthood in survivors of childhood and adolescent cancer. Cancer 1994; 73:3094-3102

(5.) Mertens AC, Yasui Y, Neglia JP, et al: Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol 2001; 19:3163-3172

(6.) Hudson MM, Jones D, Boyett JM, et al: Late mortality of long-term survivors of childhood cancer. J Clin Oncol 1997; 15:2205-2213

(7.) Donahue B, Meyerowitz C, Handler S, et al: Head and neck. Survivors of Childhood Cancer: Assessment and Management. Schwartz CL, Hobbie WL, Constine LS, et al (eds). St. Louis, CV Mosby Co, 1994, pp 133-149

(8.) Costine L, Schwartz CL, et al: The thyroid gland. Survivors of Childhood Cancer: Assessment and Management. Schwartz CL, Hobbie WL, Constine LS, et al (eds). St. Louis, CV Mosby Co, 1994, pp 151-158

(9.) Hancock ML, Cox R, McDougall I: Thyroid diseases after treatment of Hodgkin's disease. N Engl Med 1991; 325:599

(10.) Sklar C, Whitton J, Mertens A, et al: Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 2000; 85:3227-3232

(11.) Sklar M, Charles A: Growth and neuroendocrine dysfunction following therapy for childhood cancer. Pediatr Endocrinol 1997; 44:489-503

(12.) Byrne J: Infertility and premature menopause in childhood cancer survivors. Med Pediatr Oncol 1999; 33:24-28

(13.) Green DM, Grigoriev YA, Nan B, et al: Congestive heart failure after treatment for Wilms' tumor: a report from the National Wilms' Tumor Study group. J Clin Oncot 2001; 19:1926-1934

(14.) Felix CA, Hosler MR, Provisor D, et al: The p53 gene in pediatric therapy-related leukemia and myelodysplasia. Blood 1996; 87:4376-4381

(15.) Bhatia S, Robinson LL, Oberlin O, et al: Breast cancer and other second neoplasms after childhood Hodgkin's disease. N Engl J Med 1996; 334:745-751

(16.) Kaste SC, Hudson MM, ones DJ, et al: Breast masses in women treated for childhood cancer: incidence and screening guidelines. Cancer 1998; 82:784-792

From the Department of Pediatrics, East Tennessee State University College of Medicine, Johnson City, and the Division of Hematology/Oncology, St. Jude Children's Research Hospital Memphis, Tenn,

Reprint requests to Sharon Castellino, MD, East Tennessee State University, Department of Pediatrics, PO Box 70578, Johnson City, TN 37614-1708.