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Childhood and Adolescent Cancer Survivorship
Ernest H. Rosenbaum, MD
Chronic comorbid diseases
Health Behaviors, Medical Care, and Interventions to Promote Healthy Living
Potential Screening Techniques
Over the last four decades, there has been a dramatic improvement in the survivorship of those with both childhood and adolescent cancers, in part due to improved research and treatment , development of new and better drugs, and a better understanding of the complications and morbidity of cancer treatment. The current five-year survival is approximately 80%, but survivors face many new problems due to the complications and side effects from therapy and long- and late-term toxicity and comorbidities.1
The National Cancer Institute funded the Childhood Cancer Survivor Study to address these problems, and the May 2009 issue of the Journal of Clinical Oncology is devoted to reviewing the results of this study. The Childhood Cancer Survivor Study was established in 1994 with the goal of improving survivorship. The results have shown an improvement in survival from about 30% in 1960 to approximately 80% in 2004 through knowledge of potential problems in the future, and how best to treat them through improved supportive care, including both physical and psychosocial issues.
It is important to improve the survival rate. Long-term survivors have the risk of toxic side effects, which are now being seen as survivors are living longer, and often includes impaired cognitive function, fertility problems, psychosocial and employment problems as these children and adolescents advance into extemnded (up to 30 years) adulthood years.
Following successful treatment, a new and different life develops. Through research, we now better understand some of the consequences of treatment, toxic side effects, which can occur late (up to 30 years) and the risk of disease recurrence as some of the problems that are now being faced.
Fortunately, a consortium of institutions treating childhood and adolescent cancers in the United States and Canada are now working together to help study and resolve problems. Together, they are addressing the major issues facing young adults, including prevention of comorbid diseases, reproductive infertility issues, second malignancies, secondary toxic problems from chemotherapy, surgery or radiation, neurologic and neuropsychiatric problems, as well as problems of cancer control. This is being accomplished through a cooperative effort, involving systematic surveillance of these potential problems.
This large cooperative of centers specializing in childhood cancers has been able to improve survivorship for these young people as they mature into and through adulthood through the resources of the scientific community at these specialized centers.
The goal is to improve the well-being of cancer survivors through the efforts of pediatric oncologists, primary care physicians, and cancer researchers. The goals, in part, have been attained, and future improvements are planned for better survivorship.
Studies years ago, as therapy was being developed for childhood cancers, detected a variety of late side effects of therapy. With expansion of the cooperative of the Childhood Cancer Survivors Study, knowledge and data are being acquired and analyzed to help improve a healthier survivorship. It is a new field, requiring the cooperation of many institutes ten years following diagnosis to better appreciate potential problems.2
The CCSS, being a cooperative of many childhood cancer centers in the U.S. and Canada, has appreciated the heterogeneity of both the follow-up, as well as the consequences of therapy. The success of the CCSS after twenty-five years in the United States and one in Canada, is a more accurate follow-up on the health of childhood and adolescent
Outcomes of Therapy
Through careful follow-up surveillance after therapy and through standardized medical records, information has now become available on outcomes as young adults are living longer and providing necessary information on potential problems.
Approximately 42 different chemotherapeutic agents are used in treating childhood and adolescent cancers, and subsequent problems relate to the duration of therapy and the cumulative dose used. Agents, such as anthracyclines or alkylating, have well-known side effects, which were reviewed by a panel to reach a consensus on potential and actual toxicities. For example, cardiac toxicity from anthracyclines for potential congestive heart failure (CHF) was validated in one study, showing 292 survivors. Telephone and Internet follow-up and self-reporting methods were utilized.
With the success of the CCSS, we will end up with a better understanding of the risks and sequelae of treatment and have the opportunity of developing focused interventions, improved screening and follow-up surveillance.
With childhood cancer survivors now living longer with about an 80% five-year survival rate, they have become vulnerable to late morbidity and mortality secondary to either cancer recurrence of the primary disease, second malignancies, or toxicities from surgery, radiotherapy and chemotherapy. The improvement in diagnosis and therapy has contributed to the increased survival rate, with a growing population of long-term survivors. The results are late long-term morbidity and mortality.3
Liu has reported an 83% overall survival at twenty years. Certain primary cancers have a higher death rate, such as acute lymphoblastic leukemia, often seen with central nervous system relapse and disease, often with late mortality. The five-year survival for Hodgkin's lymphoma is about 90%, and the ten-year survival is approximately 50% for all. 4
In 1971, cardiovascular deaths due to myocardial infarction and cerebral vascular accidents had a five-fold increase in incidence. Of 37,324 and the mortality experience of 20,483 survivors, there were 2,821 deaths as of 2002. That is 18.1% at thirty years from diagnosis. The mortality rate is decreasing for recurrence or progression of primary disease, and the increased mortality rate is attributable to subsequent neoplasms, about 15.2%, and death, about 7%. Part of these are related to cardiac deaths and anthracycline therapy and deaths related to radiation therapy, with a relative risk of 2.9, alkylating agent therapy with a relative risk of 2.2, as well as risks to other drugs, and to subsequent malignancies. Cardiac radiation exposure relative risk is 3.3, and high-dose anthracycline exposure relative risk is 3.1 and is related to cardiac deaths.
Long-term cancer survivors often develop chronic diseases, which involve one or several organ systems. This, in part, is related to their general health, as well as prior treatment risks. 5
Various comorbidities, including endocrine diseases, such as thyroid disorders, disorders of growth and weight, and pubertal maturation, cardiac disease, osteonecrosis, pulmonary and neurological comorbidities, are seen. Outcomes differ for each disease entity. A lot depends on the exposure of the body or an organ to the disease process or the treatments. An example might be having a stroke after neck radiation therapy or disorders of the kidneys or urinary tract, or gastrointestinal tract diseases. Another example might be long-term neurologic sequelae with varied symptomatology, such as seen in childhood brain tumors with both physical and psychological adverse neurological compromises.
Thirty years ago, it was noted that there was an increased incidence of second malignant neoplasms in childhood cancer survivors.. This was believed to be related to host disease factors and therapy-related risk factors.
Among 14,358 cohort members, there were 730 who reported 802 second malignancies. These excluded non-melanoma skin cancers. That is a 2.3-fold increase in SMs. There is a relationship to both the host as well as the therapy as probable causes of the second malignancies. Non-melanoma skin cancers and meningiomas were more common.6
Potential long-term morbidity and mortality
There is often a potential long-term morbidity and mortality associated with the treatment of childhood cancers. Although this may involve a minority of survivors, functional impairment, limitations in physical activity and psychological dysfunction are some of the problems faced by these young survivors. 7
The CCSS evaluated groups with the highest risk for morbidities, who could benefit from risk-based surveillance. This included a wide variety of potential late toxicities based, in part, on sex, race, ethnicity, and age at diagnosis. Some of the toxicities related to radiation therapy plus bleomycin, anthracyclines, chest, abdominal, or pelvic radiation, or alkylating agents. In general, there was at least a ten-fold excess risk of having a severe or life-threatening chronic health condition.
Side effects included both cardiopulmonary disease and secondary cancers, which are problems noted in the older age group. Therapy with alkylating agents, abdominal, pelvic or chest radiation, of radiation to the ovaries or testes added the potential for infertility and comorbidities as well.
Thyroid abnormalities in function, as well as other endocrinological dysfunctions, were often seen secondary to chest radiation for Hodgkin's disease or brain radiation. Screening for thyroid dysfunction requires annual monitoring of thyroid function via laboratory tests, as well as measurements of growth, reproduction, cardiovascular disease, neurocognitive function, and psychosocial/emotional function, to assess for hypo- and hyperthyroidism.
Patients with central nervous system tumors and leukemia, especially those treated with craniospinal radiation therapy, were at risk, and an estimated 40% had a deficit in linear growth and adult stature.
There were also abnormalities in both weight and body mass index from the therapies, and there was an increased risk of being overweight or obese. Overweight is a BMI >25, and obese is >30 kg/m2.
There were also deficits in sexual development and reproductive function with premature ovarian failure and infertility, as well as the effects of pituitary gland and other glandular failure secondary to cranial radiation therapy. This often resulted in growth hormone deficiency with overweight and obesity.
For men, reproductive organ deficiency secondary to radiation of the testes or use of alkylating agents led to testicular dysfunction and often sterility and delayed puberty.
Pulmonary toxicity was increased secondary to radiation therapy and/or cumulative chemotherapy drug use, especially for leukemia and Hodgkin's disease, as well as those undergoing bone marrow transplants.
Strokes are rare in children and healthy young adults; although, the prevalence of stroke factors was increased in childhood cancer survivors, especially survivors of leukemia and brain tumors. The most prominent treatment risk factor for subsequent stroke was radiation therapy.
Children and adolescents with cancer are at increased risk for serious morbidity and premature mortality. They often have decreased quality of life, depending on their exposure to various treatments, and they are at increased risk for coronary artery disease, cerebrovascular disease, diabetes, hypertension, dyslipidemia, renal insufficiency and subsequent secondary malignancies, as well as potential infections. 9
Knowing these risks, it is important to utilize behavior modifications that could potentially decrease the risk of subsequent illnesses - comorbidities. Preventive health programs have been developed for Hodgkin's lymphoma and acute lymphoblastic leukemia. Hodgkin's lymphoma patients who had chest radiation have an increased risk of lung cancer. Use of tobacco has been estimated to increase the risk about twenty-fold.9
Strategies to prevent childhood cancer survivors from smoking are important for optimal disease prevention, not only for cancer but also for heart disease, stroke, and secondary cancers.
Women who receive chest wall radiation are at risk for breast cancer at a younger age and merit mammograms and follow-up, starting around age twenty-five. Magnetic resonance imaging is recommended and has improved survival.
All chemotherapy treatments increase the risk of different comorbidities, including obesity, osteoporosis, insulin resistance, cardiovascular and cerebrovascular diseases, and chronic hepatitis C.
Excessive drinking is also a promoter of cancer survivors' risk of comorbidities. Dietary habits with a recommended low-fat, Mediterranean-type diet plus calcium and vitamin D should be promoted. Physical exercise is recommended as part of the healthy lifestyle.
Health benefits are achieved through healthy behaviors and lifestyle habits adopted to help promote a healthier longevity.
The use of tobacco by smoking harms almost every organ in the body, and causes increased risk for serious morbidity. There is a relationship to ischemic heart disease, cerebrovascular disease, and pulmonary disease and is a preventable potential cause of death, as well as diminishing the quality of life. Smoking can also potentiate side effects of therapy, especially when drugs like bleomycin or carmustine were used.
In a large study, 28% of survivors reported that they smoked at least 100 cigarettes in their lifetime (19% male and 15% female). In 1999, this compared to 23.5% of the U.S. population admitting to smoking. The current smoking rate is about 20%.
Over half of these smokers related there was smoking in their social network, family or friends, and many had a lower level of education and economic status which increases health problems.
Smoking cessation programs were common, and 41% of smokers reported that they had joined a quit program over the prior two years. They did have a lot of encouragement from family and friends to stop smoking, but the social networks were often the compromise. Being younger than fourteen, not having graduated from high school and having received brain radiation therapy were associated with failure to quit smoking.
Excessive alcohol intake has been related to head and neck cancer, esophageal, breast, and liver cancers, as well as depression, stroke, hypertension, osteoporosis and liver cirrhosis. Those having hepatitis C from transfusions were at risk for liver disease (hepatic steatosis), as well as heart disease and liver dysfunction. Increased alcohol intake was also associated with a poor self-assessment, depression, anxiety, and cancer-related fears and uncertainty. Blacks and Hispanics drank less than white survivors; although, there may have been a reporting discrepancy.
Additional Health Behavior Risk Factors
In a smoking cessation trial, behavior risk factors, such as inactivity, poor diet, and increased alcohol, were also noted. Eleven percent had one or more additional risk factors to smoking; 31% had 0-1 additional risk factors, 63% engaged in two or more behavioral risk factors in addition to smoking, and 6% had four or five health risk factors. Eighty-four percent of current smokers also drank alcohol described as risky drinking.
Moderate-to-intense physical activity is protective against osteoporosis, hypertension, non-insulin dependent diabetes, and cardiovascular disease, all risks for increased mortality.
Exercise is important in all versus inactive activity. Those receiving anthracycline drugs have some risk for cardiac failure, and exercise is recommended to reduce risk factors.
About 30% of survivors will have dental problems, meriting dental care.
Dental problems usually occur before five years or with those who receive cranial radiation therapy. Regular dental care is recommended.
Approximately 60% of survivors had seen a dentist within a year, due either to lack of health insurance or education of risks. Dental compliance care is, in general, considered suboptimal.
Health Care for the Future
Following completion of the initial cancer therapy, children enjoy a period of relatively good health. Unfortunately, many have unhealthy lifestyles, which can contribute to an increased risk for cancer or comorbid problems.
The CCSS is planning three interventional health studies, and Emmons completed the first intervention study to promote healthy lifestyles and smoking cessation.10 Fifteen percent quit smoking for at least eight months.
There are several studies of children and their health behaviors with the goal to promote better health and improve survival.
1. Cerebrovascular Disease
Head and neck radiation often increase vascular problems, including strokes, following radiation therapy. Patients with leukemia or Hodgkin's disease often presented with sensory or motor deficits - at risk were those with brain tumors, leukemia, or Hodgkin's disease. Smoking was associated with a three-fold excess risk of stroke in Hodgkin's disease survivors in the CCSS Cohort.
2. Secondary Neoplasms
Assessment after primary therapy can give information for the potential risk of a secondary neoplasm. The risk was increased because of therapy and the cancer itself, and special efforts for screening and detection were merited. Contributing factors were treatment exposure and diagnostic groups, as well as sex, age, and treatments that could lead to potential secondary neoplasms.
Radiation exposure was one of the leading causes of secondary neoplasms, especially in females with Hodgkin's disease, or tissue sarcomas, and those treated with alkylating agent chemotherapy. Familial cancer predisposition also played a role for the risk of breast cancer - radiation therapy between age 10 and 16 increased the risk, as this was the time of rapid breast tissue proliferation. Hereditary predisposition also played a role, as well as the association with thyroid disease, especially when the thyroid was treated with radiation, often in high doses.
3. Skin Cancer
The occurrence of non-melanoma skin cancer represented the most frequent secondary neoplasm in survivors of childhood cancer, and although it not as life threatening, it still merits careful attention. Often, there may be multiple occurrences with cumulative morbidity unless properly diagnosed early and treated.
4. Additional Cancers
Additional cancers included parotid, lung, gastrointestinal, and genitourinary, which were significant but less common in occurrence. These cancers can occur at a younger age and were often related to prior chemotherapy. One-third occurred in persons, who did not receive radiation therapy or in sites distant from where the radiation therapy was administered.
Screening is important. Potential tumors are numerous, including breast, thyroid, CNS, bone, skin, and soft tissue.
Simple measures, such as avoidance of excess sunshine, can reduce the risk of skin cancer recurrence or secondary malignancy. Following Hodgkin's disease, chest wall radiation therapy, thyroid assessment, as well as screening mammograms starting at age 25, and assessment for potential lung cancer are part of the screening techniques necessary for optimal follow-up.
Patients with childhood cancers were at risk for many secondary problems from the toxicity and late results from cancer with an increased morbidity and mortality, suggesting that healthy lifestyle behavior habits be adhered to and appropriate screening and follow up 20-30 years after the end of treatment was vital to improve and increase longevity and decrease risk of recurrent disease, morbidities and mortality.
- Robison, LI, Armstrong, GT, Boice, JD, et al., The Childhood Cancer Survivor Study: A National Cancer Institute-Supportive Resource for Outcome and Intervention Research. J Clin Oncol, 2009; 27: 2308-2318.
- Leisenring, WM, Mertens, AC, Armstrong, GT, et al., Pediatric Cancer Survivorship Research: Experience of the Childhood Cancer Survivorship Study, J Clin Onc, 2009; 27: 2319-2327.
- Robison, LI, Armstrong, GT, Boice, JD, et al., The Childhood Cancer Survivor Study: A National Cancer Institute-Supportive Resource for Outcome and Intervention Research. J Clin Oncol, 2009; 27: 2308-2318.
- Armstrong, GT, Liu, Q, Yasui, Y, et al., Late Mortality among Five-year Survivors of Childhood Cancer: A Summary from the Childhood Cancer Survivorship Study, J Clin Onc, May, 10, 2009; 27(14): 2328-2338.
- Tiller, L, Chow, EL, Gurney, JG, et al., Chronic Disease in the Childhood Cancer Survivor Study Cohort: A Review, JCO, 2009; 27(14): 2339-2355.
- Meadows, Anna T, Friedman, TI, Neglia, JP, et al., Second Neoplasms in Survivors of Childhood Cancer: Findings from the Childhood Cancer Survivorship Study Cohort, JCO, 2009; 27(14): 2356-2362.
- Oelfinger, KC, Mertens, AC, Sklar, CA, et al.., Chronic Health Conditions in Adult Survivors of Childhood Cancer, NEJM, 2006; 355: 1572-1682.
- Nathan, PC, Ford, JS, Henderson, TO, et al., Health Behaviors, Medical Care, and Interventions to Promote Healthy Living in the Childhood Cancer Survivor Cohort, JCO, 2009; 27(14): 2363-2373.
- Travis, LB, Gospodarowi, CZ, Curris, RE, et al., Lung Cancer Following Chemotherapy and Radiotherapy for Hodgkin's Disease, J Natl CA Inst, 2002; 94; 182-192.
- Emmons, KM, Euleo, E, Park, F, et al., Care-Delivered Smoking Counseling for Childhood Cancer Survivors Increases Rate of Cessation The Partnership for Health Study, J Clin Onc, 2005; 23: 6516-6523.
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