Identifying and Monitoring the Late Effects of Childhood Cancer
The number of adults who have survived childhood cancer is rapidly increasing. The likelihood that naturopathic doctors will be responsible for monitoring the late effects of cancer treatment is also increasing. This article reviews the common complications, symptoms, and monitoring tools for this unique patient population.
Every year, approximately 20,000 children in the United States are diagnosed with cancer. With a cure rate approaching 80%, the number of childhood cancer survivors grows by more then 15,000 each year. [i] [ii] Currently one in every four hundred and fifty individuals are childhood cancer survivors.[iii] A 2003 study by Oeffinger, et al revealed that one in three survivors remains free of late term effects from cancer treatment, implying that the other two-thirds will suffer from chronic and potentially life threatening complications. [iv] Late term effects are defined as the long term side effects from radiation, surgery, or chemotherapy with an onset following the completion of treatment. Some late term effects can take up to 30 years to manifest.
The late effects of cancer treatment can affect a survivor’s physical, mental, and psychosocial health. Survivors at the highest risk for late term effects are those who have, as children, been treated for bone tumors, central nervous system tumors, and Hodgkin’s Lymphoma. The risks of late term effects do not plateau or decline over time and survivors remain at risk their entire lifeiv. Providing appropriate health care and screenings for survivors of childhood cancers can be challenging, but a proactive approach reduces the associated risks and life threatening complications[v].
Due to the effects of corticosteroids, methotrexate, and radiation therapy on weight bearing bones, childhood cancer survivors are at an increased risk for osteoporosis. Secondary causes of decreased bone mineral density in childhood cancer survivors include low levels of estrogen or testosterone, growth hormone deficiency, hyperthyroidism, and prolonged periods of bed rest. It is important to educate childhood cancer survivors on the importance of weight bearing exercise, appropriate levels of vitamin D, daily calcium rich foods, and other bone building nutrients. A baseline DEXA scan is recommended 2 or more years after completion of therapy[vi]. Other monitoring options include Quantitative Compute Tomography (QCT), N-telopeptide, calcium, phosphorus, magnesium, estrogen, testosterone, parathyroid hormone, FT4, T4, TSH, and bone specific alkaline phosphatase[vii].
Survivors of childhood cancers have an increased risk of developing scoliosis and kyphosis, particularly if they had radiation to the trunk, combined surgery and radiation to the chest abdomen or spine, or the tumor was near the spine[viii]. Diagnosis of scoliosis or kyphosis may be detected on physical exam or x-ray. Treatment can include bracing or surgery.
An additional late skeletal effect is osteonecrosis. Symptoms of unresolved joint pain that is aggravated by motion and rest should be investigated with an x-ray, CT, MRI, or bone scan[ix].
Radiation to the pituitary, brain surgery, secondary cancers, and multiple medications can cause long term endocrine effects in the Hypothalamic Pituitary Adrenal (HPA) axis. Common late effects include hyperprolactenemia, hypopitutaryism, and central adrenal insufficiency[x]. Hyperprolactinemia can affect both men and women with symptoms of galactorrhea, irregular or absent menstrual periods in women, and decreased testosterone in men. Screening blood levels of prolactin can dictate further treatment if needed.
The risk of growth hormone deficiency is increased if the cancer treatment occurred before reaching adult height, radiation to any area of the head, total body irradiation, or after cranial surgery[xi]. Growth screening should occur once every 6 months until the childhood cancer survivor reaches puberty. If any concerns are raised during physical exam, evaluation for growth hormone insufficiency is recommended. Treatment options include synthetic growth hormone and treatment may persist well into adult hood.
Adult survivors of childhood cancer are also at risk of central adrenal insufficiency. This risk increases if they were treated with brain surgery or brain radiation. Symptoms include fatigue, weakness, poor appetite, and dizziness. Screening recommendations include annual cortisol screening for 15 years after radiation therapy[xii].
Certain treatments affect the ovaries and the reserve supply of eggs. If damage occurs, early ovarian failure and early menopause ensues. Common causes of ovarian failure are treatment with alklyating agents such as carboplatin or cisplatin, oopherectomy, or radiation to the abdomen, pelvis, lower spine or region of pituitary gland. Monitoring can include FSH, LH, estradiol, estrone, total estrogen, and regular gynecologic[xiii] [xiv].
For men, cancer treatment can cause testosterone, LH, and FSH deficiency. Treatments that increase risk of hormonal or functional infertility are alkylating agents, radiation to the pelvis or near the testicles, radiation to or near the pituitary gland, castration, cystectomy, and retroperitoneal lymph node dissection. Monitoring can include blood levels of FSH, LH, and testosterone. If testosterone levels are low, replacement with exogenous testosterone may be warranted. It can take up to 10 years post cancer treatment for azoospermia or oligospermia to resolve[xv].
Adult childhood cancer survivors that received radiation to the chest, neck, cervical spine, head or brain are at risk for hypothyroidism. Thyroid problems may not occur until adulthood. Annual levels of TSH and T4 are recommended, particularly for female survivors that are planning to become pregnant since untreated hypothyroidism can cause birth defects. Childhood cancer survivors are also at an increased risk of thyroid cancer, thyroid nodules, and hyperthyroidism[xvi].
While most adult survivors of childhood cancers will not have cardiovascular complications, certain treatments increase future risk. These treatments include anthracyclines, radiation therapy to the chest, thorax, thoracic spin, abdomen, or total body irradiation. Antrhacylines can cause left ventricular dysfunction, cardiomyopathy, and arrhythmias. Radiation therapy is more likely to cause scarring and stiffening of the heart leading to arrhythmias, cardiomyopathy, coronary artery disease, valvular stenosis or insufficiency, and pericarditis or pericardial fibrosis. Symptoms and complications from late cardiovascular effects can occur up to 30 years after initial cancer treatment[xvii].
Symptoms of cardiovascular disease following treatment for childhood cancer include shortness of breath, dizziness, severe fatigue, chest pain, perspiration, nausea, vomiting, edema, unresolved cough or wheezing, arrhythmia, and palpitations. Ongoing monitoring may be recommended, especially if as young adults these survivors choose to play high school sports. Performing activities that require heavy lifting or sustained isometric activity (such as wrestling) may increase risk of heart failure. Special caution also needs to be in place during pregnancy and illnesses with high fever.
Monitoring for cardiac complications can be done with electrocardiogram, MUGA scan, or cardiac stress test. It is recommended to do the first base line test 2 years after completion of treatment and followed up yearly to every 5 years depending on age of initial treatment and dose of chest radiation or total anthracycline dose. Specific screening guidelines are provided by The Children’s Oncology Group[xviii]. Lipid profiles and fasting glucose are recommended as a screening tool once every two years to check for and modify other cardiac risk factors.
Several treatments for childhood cancers can cause permanent lung damage. These treatments include bleomycin, camustine, lomustine, chest or total radiation, busulfan, , surgery to the chest or lung, bone marrow or stem cell transplant, and anthracyline chemotherapy. A prior medical history of asthma, lung infection, or exposure to second hand smoke also increases the risk of late pulmonary effects. Common long term health problems that develop are pulmonary fibrosis, frequent lung infections, restrictive airway disease, obstructive airway disease, and broncholitis obliterans. Symptoms of reduced pulmonary function include exercise intolerance, shortness of breath, chronic fatigue, chest pain, wheezing, and frequent infections. Monitoring includes a chest x-ray and pulmonary function tests performed 2 years after the completion of treatment, with follow up pulmonary function tests as needed[xix].
Adult survivors of childhood cancers can present with malabsorption, esophageal strictures, cholelithiasis, hepatic fibrosis, chronic enterocolitis, bowel obstruction, bowel adhesion, and colorectal cancer. These late effects are associated with abdominal and pelvic surgery, and radiation to the neck, chest, abdomen, or pelvis. Symptoms of late gastrointestinal effects include GERD, chronic nausea or vomiting, abdominal pain, chronic diarrhea or constipation, changes in weight, abdominal distention, and jaundice. Monitoring should include a comprehensive metabolic panel (liver enzymes), guaiac stool testing, ultrasound of the gall bladder, colonoscopy, and endoscopy[xx] as indicated by clinical symptomatology. A comprehensive metabolic panel should be performed annually.
Damage to the liver can be caused by abdominal radiation, liver radiation, methotrexate, mercaptopurine, and thioguanine. People that received blood products prior 1971 are at an increased risk of acquiring hepatitis B, and prior to 1992 have an increased risk of acquiring hepatitis C[xxi]. Obtaining viral titers may be recommended if symptoms of jaundice, right upper quadrant pain, or elevated liver function tests are noted.
Adult childhood cancer survivors that were treated with cisplatin, carboplatin, methotrexate, ifosamide, gentamucin, tobramycin, amphotericin, and cyclosporine are at an increased risk of late kidney damage. Radiation to the abdomen, flank, or total body also increases the risk of renal damage. Signs of chronic renal insufficiency or failure include edema, anemia, hypertension, fatigue, nausea, vomiting, pruritis, and headaches. Monitoring of renal function can include BUN, creatinine, electrolytes, and magnesium.
Bladder function and secondary bladder cancers are increased for people treated with cyclophosphamie, ifosamide, and pelvic radiation. The most common late effect is hemorrhagic cystitis. Monitoring includes urinary analysis when indicated. Hemorrhagic cystitis incidence can be reduced by avoiding caffeinated beverages and drinking plenty of fluids. Another late effect can be bladder fibrosis which often presents as urinary incontinence or incomplete bladder emptying. Bladder fibrosis can be diagnosed by cystoscopy[xxii].
Bladder cancer is a rare secondary cancer from treatment with cyclophosphamide or pelvic radiation[xxiii]. This most commonly presents as hematuria and suprapubic pain.
Women treated with radiation to the chest during childhood, adolescence, or young adulthood have an increased risk of developing breast cancer. They tend to develop breast cancer at a younger age and risk increases throughout their lifetime[xxiv]. Monitoring should include monthly self breast exams, annual clinical breast exam until age 25. After reaching 25 years of age, clinical breast exam should occur every 6 months. Yearly mammograms and breast MRI should start at age 25 or 8 years after radiation (which ever occurs last).
Colon cancer risk is increased if radiation to the abdomen, pelvis, or spine was performed[xxv]. If children received radiation doses of 30 gy or higher, a colonoscopy should be performed every 3 years starting at age 35, or ten years after radiation therapy (whichever occurs last).
Secondary leukemia usually occurs within 10 years after treatment for the original cancer. An increased risk of secondary leukemia is seen with alkylating agents, etoposide, teniposide, anthracylines, and hematopoetic cell transplants.
A secondary solid tumor is most likely to occur in someone that received radiation therapy, particularly if radiation was at a young age and a large field was used. The most common sites for secondary solid tumors include the skin, breast, spine, brain, thyroid, and bones. Secondary solid tumors tend to occur 10 or more years after initial cancer treatment.
As childhood cancer survival rates continue to improve, naturopathic doctors will become an important source for continued monitoring of late term effects. The symptoms of late term effects can vary between gastrointestinal upset, to chest pain, to endocrine disruption. By actively monitoring adult survivors of childhood cancers, potentially life threatening late effects can be caught and avoided. Naturopathic doctors can also educate survivors on risk reducing behaviors such as eating a vegetable and whole grain based diet, exercising, and promoting cancer preventing supplementation when indicated.
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