Guidelines for identification of, advocacy for, and intervention in neurocognitive problems in survivors of childhood cancer: a report from the Children's Oncology Group

With modern therapies and supportive care, survival of childhood cancer has increased considerably. Patients who have survived cancers involving the central nervous system or who have received therapy toxic to the developing brain are at risk of long-term neurocognitive sequelae. Negative outcomes are observed most frequently in survivors of acute lymphoblastic leukemia and brain tumors. The Children's Oncology Group Long-term Follow-up Guidelines Task Force on Neurocognitive/Behavioral Complications After Childhood Cancer has generated risk-based, exposure-related guidelines designed to direct the follow-up care of survivors of pediatric malignancies based on a comprehensive literature review and expert opinion. This article expands on these guidelines by reviewing the risk factors for the development of neurocognitive sequelae and describing the expected pattern of these disabilities. We herein present recommendations for the screening and management of neurocognitive late effects and outline important areas of school and legal advocacy for survivors with disabilities. Finally, we list resources that can guide patients, their parents, and their medical caregivers as they face the long-term neurocognitive consequences of cancer therapy.     

Educational and occupational outcomes among survivors of childhood cancer during the transition to emerging adulthood

PURPOSE: To examine educational and occupational outcomes among survivors of childhood cancer and peers during the transition from adolescence to emerging adulthood. METHODS: Families were recruited when children with cancer were 8 to 15 years old and receiving initial treatment for a malignancy that did not primarily affect the central nervous system (CNS). At that time, each child with cancer was matched to a classmate of similar age, gender, and race for inclusion in a comparison group. For the current follow-up (7.29 years postdiagnosis), 56 survivors, 60 peers, and their parents completed questionnaires soon after the youth's 18th birthday. Severity of treatment and late effects were rated by healthcare providers. RESULTS: Survivors and peers were similar on a variety of outcomes, including family background, scholastic and occupational self-concept, and academic competence. However, survivors were more likely to report repeating a grade and having more school absences. The proportion of participants who graduated from high school, were working, and expressed plans to attend postsecondary education or seek employment were similar between groups. Initial treatment intensity, time since diagnosis, and severity of late effects were associated with several indices of educational and occupational attainment. CONCLUSIONS: Despite being more likely to repeat a grade and miss school, survivors of nonCNS cancer were similar to peers on most educational and occupational outcomes during the transition from adolescence to emerging adulthood. Interventions to assist academic or occupational functioning may not be necessary for all survivors, but additional research is needed to identify subgroups at risk for difficulties.     

Assessment of health-related quality of life of adolescent cancer patients using the Minneapolis-Manchester Quality of Life Adolescent Questionnaire

BACKGROUND: Improved survival after childhood cancer has shifted the focus to health-related quality of life (HRQL)-an understudied problem, especially among adolescents. PROCEDURE: We assessed HRQL among adolescents utilizing a validated self-report tool, the Minneapolis-Manchester Quality of Life (MMQL) Adolescent Form, consisting of 46 items comprising seven domains: physical, cognitive, psychological and social functioning, body image, intimate relations, and outlook on life, and computed an overall QoL score. The MMQL Adolescent Form was administered to 226 adolescent survivors of childhood cancer a median of 7.8 years from diagnosis (off therapy-median age: 16.2 years), 136 adolescent cancer patients undergoing therapy (on therapy-median age: 16.4 years), and 134 healthy adolescents (controls-median age: 15.5 years). Primary diagnoses included leukemia (46%), lymphoma (26%), brain tumors (5%), and other solid tumors (23%). RESULTS: Compared to healthy controls, on-therapy patients were at increased risk for reporting poor overall QoL [Odds Ratio (OR) = 3.3, P = 0.002)] and poor physical functioning (OR = 11.8, P < 0.001). Off-therapy survivors did not differ significantly from healthy controls for overall QoL (OR = 1.6, P = 0.5) or any HRQL domains. Female patients, both on- and off-therapy, were more likely to report poorer overall QoL, physical, psychological and cognitive functioning as well as poorer body image when compared with male patients. CONCLUSIONS: While adolescent cancer patients undergoing active therapy report poor physical functioning, there is no evidence of long-term QoL sequelae.     

Second malignant neoplasms in survivors of childhood cancer

As the treatment of childhood cancer continues to improve, the number of survivors at risk for late effects rises. One such late effect is the risk of second malignant neoplasms. Large multicenter registries have been established to accumulate data on the incidence of second cancers. Relative risks and cumulative risks can now be calculated for retinoblastoma, Wilm's tumor and Hodgkin's disease. Early data are now available for leukemia, sarcomas and central nervous system tumors. Genetic cancer syndromes, radiation therapy and treatment with chemotherapeutic agents are known risk factors for second malignant neoplasms in survivors of childhood cancer.     

Marriage and divorce among childhood cancer survivors

Many childhood cancer survivors have psychosocial late effects. We studied the risks for cohabitation and subsequent separation. Through the Danish Cancer Register, we identified a nationwide, population-based cohort of all 1877 childhood cancer survivors born from 1965 to 1980, and in whom cancer was diagnosed between 1965 and 1996 before they were 20 years of age. A sex-matched and age-matched population-based control cohort was used for comparison (n=45,449). Demographic and socioeconomic data were obtained from national registers and explored by discrete-time Cox regression analyses. Childhood cancer survivors had a reduced rate of cohabitation [rate ratio (RR) 0.78; 95% confidence interval (CI): 0.73-0.83], owing to lower rates among survivors of both noncentral nervous system (CNS) tumors (RR 0.88; 95% CI: 0.83-0.95) and CNS tumors (RR 0.52; 95% CI: 0.45-0.59). Male CNS tumor survivors had a nonsignificantly lower rate (RR 0.47; 95% CI: 0.38-0.58) than females (RR 0.56; 95% CI: 0.47-0.68). The rates of separation were almost identical to those of controls. In conclusion, the rate of cohabitation was lower for all childhood cancer survivors than for the population-based controls, with the most pronounced reduction among survivors of CNS tumors. Mental deficits after cranial irradiation are likely to be the major risk factor.     

Treatment-associated subsequent neoplasms among long-term survivors of childhood cancer: the experience of the Childhood Cancer Survivor Study

With improvements in survival among individuals diagnosed and treated for cancer there is an increasing recognition of the risk of long-term adverse effects of therapy. Second neoplasms represent one of the more serious late effects of treatment and are associated with a substantial level of morbidity and mortality. Survivors of childhood cancers, because of their potential longevity, are at particular risk for this adverse outcome. The Childhood Cancer Survivor Study is a large cohort consisting of adult survivors of childhood cancer diagnosed and treated between 1970 and 1986. The CCSS has provided important data to quantify radiation-associated risk for subsequent cancers including neoplasms of the breast, thyroid and central nervous system.     

Hypertension and prehypertension in long-term survivors of childhood and adolescent cancer

BACKGROUND: Hypertension as a late effect following childhood and adolescent cancer has received little attention. Since obesity, a known risk factor for hypertension, is increased following some childhood cancers, it seems likely that significant numbers of survivors would have hypertension. PROCEDURES: The records of patients seen in the Long Term Follow Up Clinic of Children's National Medical Center were examined for a single institution, retrospective study of blood pressure in survivors of childhood and adolescent cancer. Of 103 consecutive survivors who attended the clinic from January 1 through June 30, 2004, 51 (49.5%) were female and 52 (50.5%) were male. Their mean age was 14.6 years. Systolic and diastolic blood pressures for children and adolescents under 18 years of age were evaluated for hypertension and prehypertensive according to standards for age, sex, and height. Blood pressures for adults 18 years of age and older were evaluated according to standard adult values. Children and adolescents were evaluated for obesity and overweight according to body mass index (BMI) standards for age and sex. Adults were evaluated according to standard adult values. RESULTS: Twenty-nine patients (28.2%) were hypertensive or prehypertensive, and 74 (71.8%) were normal. Thirty-eight patients (36.9%) were obese or overweight, and 65 (63.1%) were non-obese. Most Wilms tumor patients, 7 of 10 (70.0%), had hypertension or prehypertension, but only 4 of 10 (40.0%) were obese or overweight. CONCLUSION: Careful follow-up of their blood pressure status is warranted for long-term survivors of childhood and adolescent cancer, especially for those with an initial diagnosis of Wilms tumor.     

Second malignancy in 597 patients with ewing sarcoma of bone treated at a single institution with adjuvant and neoadjuvant chemotherapy between 1972 and 1999

The relative risk of second tumors in patients with Ewing sarcoma is controversial, and little is known about their treatment and outcome. The purpose of the current study was to define the incidence and features of second tumors among 597 long-term survivors of nonmetastatic Ewing sarcoma treated with adjuvant and neoadjuvant chemotherapy, radiotherapy, and/or surgery. The authors found that the risk of secondary malignancy after adjuvant or neoadjuvant treatment of Ewing sarcoma is higher than that after other childhood or adolescent cancers only after radiotherapy. Based on this, postoperative radiotherapy should be avoided when surgery with adequate margins is feasible.     

Long-term effects of cancer therapy in children – functional effects,late mortality and long-term follow-up

Although over 75% of children with malignancy are cured by contemporary treatment protocols in developed countries, many survivors suffer from chronic side effects of treatment which may be severe or even life-threatening in 30%. Such late adverse effects may result in disturbed childhood and adolescent growth and development, or have profound consequences on future health status, even resulting in premature death. Some groups of survivors are at even higher risk of multiple or serious toxicities, for example those treated for a central nervous system (CNS) tumour or with a haemopoietic stem cell transplant (HSCT).The second part of this series of two reviews describes some of the chronic functional consequences of treatment for childhood and adolescent malignancy including impairment of neuropsychological, metabolic and immunological function, growth and quality of life. In addition, the increased risk of secondary malignant neoplasms and of late yet still premature mortality, and the nature of late toxicity in survivors of CNS tumours and HSCTs, will be highlighted. The development of appropriate long-term follow-up strategies intended to improve the health of long-term survivors will be described, and the growing focus on the provision of optimal long-term follow-up care and the quality of survivorship will be emphasized.     

Second neoplasms after treatment of childhood cancer in Slovenia

BACKGROUND: The number of long time survivors of childhood cancer treatment is constantly increasing over the last decades as a result of advances in diagnosis and treatment. The occurrence of second neoplasms is one of most serious late effects observed in cancer survivors. METHODS: The risk of secondary neoplasm was studied in a cohort of 1,577 patients treated for childhood cancer registered in the Cancer Registry of Slovenia (CRS) between 1961 and 2000. The time at risk was defined from the date of diagnosis of first malignancy to the time of death or the end of the study. RESULTS: The most frequent primary malignancies were: acute leukemia 28.5%, central nervous system (CNS) tumors 21.3%, and lymphomas 16.6%. Median observation time was 7.8 years. Forty-eight patients developed second neoplasms. CNS tumors, acute leukemias, and thyroid carcinoma were most frequent second neoplasms. The cumulative risk for second neoplasm in the entire cohort was 0.06% at 5 years, 5.1% at 15 years, and 12.6% at 25 years after diagnosis of first cancer. The overall survival after second neoplasm was 65% 10 years after the diagnosis of second neoplasm. CONCLUSIONS: Patients after treatment of childhood cancer are at special risk for subsequent neoplasms and long-term follow-up is mandatory.     

Pediatric Central Nervous System Tumor Diagnosis,Complications, and Emergencies

Central nervous system tumors are the most common solid malignancy in childhood and the leading cause of cancer-related mortality in children. With an average of 13 new patients being diagnosed daily with a central nervous system tumor, many of these patients will present to the emergency department for evaluation and management. Furthermore, many children experience complications and/or adverse effects directly from the tumor itself, from multimodality treatment (ie, surgery, radiation therapy, and/or chemotherapy), and/or as long-term survivors. Oncologic emergencies include increased intracranial pressure, spinal cord compression, seizures/status epilepticus, central diabetes insipidus, and adrenal insufficiency. Evaluation and management by emergency medicine practitioners are critically important for these patients in all phases of their diagnosis and treatment and can contribute significantly to an improved prognosis.     

Leaving home after cancer in childhood: a measure of social independence in early adulthood

BACKGROUND: Previous studies on psychosocial outcomes for childhood and adolescent cancer survivors have found diverse results concerning social independence. As a measure of social independence, we investigated whether cancer survivors displayed the same patterns of leaving home as population-based control group. PROCEDURE: We identified 1,597 patients in the Danish Cancer Register, born in 1965-1980, in whom a primary cancer was diagnosed before they reached the age of 20 in the period 1965-1995. The patients were compared with a random sample of the general population (n = 43,905) frequency matched on sex and date of birth. By linking the two cohorts to registers in Statistics Denmark, we obtained socioeconomic data for the period 1980-1997. The relative risk for leaving home was estimated with discrete-time Cox regression models. RESULTS: The risk for leaving home of survivors of hematological malignancies and solid tumors did not differ significantly from that of the control cohort. Adjustments for possible socioeconomic confounders did not change this pattern. In contrast, survivors of central nervous system (CNS) tumors had a significantly reduced risk for leaving home, which was most pronounced for men (relative risk, men: 0.66; 95% confidence interval, 0.55-0.80; women: 0.88, 95% confidence interval, 0.80-0.97). CONCLUSION: Overall, the psychosocial effects of cancer in childhood or adolescence and its treatment on the survivor and family did not appear to impede social independence in early adulthood, except for survivors of CNS tumors.     

Cognitive functions of adolescent childhood cancer survivors assessed by event-related potentials

BACKGROUND: Neurophysiological methods were applied to examine subtle central nervous system (CNS) adverse effects for adolescent childhood cancer survivors. We analyzed auditory event-related potentials (ERPs)-P300 and MMN/P3a complex-to find out whether there was impaired attention orientation in asymptomatic cancer survivors, and whether these ERP methods could be used as more objective tools in detecting those survivors who might need academic testing. Previous clinical studies of P300 have focused on leukemia survivors. MMN for cancer survivors has not been reported. PROCEDURE: The subjects were survivors of childhood leukemia (n=11) and solid tumors (n=8), as well as healthy controls (n=10). The mean age was 15.5 years for survivors and 15.9 years for controls. Pure sine-wave tones (500 and 553 Hz, 100 ms) were used as stimuli in an oddball paradigm. The ERPs to frequency change were measured. MMN recordings were performed in a passive non-attended situation where the subject was watching a voiceless video cartoon. P300 was produced thereafter, but in an active attend situation, by the same auditory oddball paradigm as MMN. RESULTS: A significant difference was detected between the groups for the latency of P300 at electrodes Cz (P = 0.03) and C4 (P = 0.05). The cancer survivors had prolonged P300 latencies as an indication of prolonged short-term memory processing. The area and latency parameters of MMN did not differ significantly between the study groups, but in cancer survivors, the area and the mean amplitude of the subsequent P3a wave were diminished. The results indicate that the discrimination process was not as easy for the survivors as for the controls. However, it seems that in cancer survivors the basic mechanism starting attention shift to novel stimuli is not impaired. CONCLUSIONS: These results indicate that it is important to carefully evaluate the proper methods for the teaching of children who are survivors of malignancies. The auditory information may not always lead to the best possible learning results.     

Smoking habits in survivors of childhood and adolescent cancer

Because of their increased risk for second cancers, childhood cancer survivors are people who really should not smoke, but available evidence suggests that they do. We studied the smoking habits of long-term childhood cancer survivors in data collected from 1289 adult survivors of childhood cancer and 1930 of their sibling controls. Survivors were diagnosed with cancer between 1945 and 1974 when they were less than 20 years old. Using matched analyses that controlled for the influence of family, survivors were 8% less likely than controls to be current smokers, 13% less likely to be eversmokers, but 12% less likely to have quit smoking; these differences were not statistically significant. In a logistic regression analysis there was a significant difference by year of diagnosis for current smoking rate ratios (RR); survivors were less likely to be current smokers if diagnosed in recent years (RR = 0.76; 95% confidence intervals = 0.58–0.98, between 1965–74) and quite similar to controls if diagnosed in earlier years (RR = 1.05 between 1945 and 1954). In our group of long-term cancer survivors, the reduction in current smoking came about because survivors were more inclined never to start smoking than controls. Once addicted to tobacco, they were less likely to quit. While the fact that survivors are less likely to start smoking is encouraging, the persistence of smoking habits strongly suggests the need for continuing efforts to prevent smoking in this most vulnerable group. © 1992 Wiley-Liss, Inc.     

Reduction of adult height in childhood acute lymphoblastic leukemia survivors after prophylactic cranial irradiation

BACKGROUND: Impaired linear growth is a well-recognized complication in long-term childhood ALL survivors who received cranial irradiation. However, as many patients achieve a final height between the 5th and the 95th centile, the true incidence of linear growth impairment might be underestimated. METHODS: Reduction of adult height (RAH) was estimated in adult childhood ALL survivors with and without cranial irradiation. RAH was calculated as the difference between target height (TH) and final height (FH). TH was calculated according to the formula TH = {[(height father + height mother +/- 12)/2] + 3}. RAH was assessed in 79 adult childhood ALL survivors in first complete remission who had received cranial irradiation 25 Gy (Group I, n = 53), 18 Gy (Group II, n = 10) or chemotherapy alone (controls, n = 16). RESULTS: RAH was 8.6 +/- 8.2 cm in Group I (P = 0.001 vs. controls), 6.2 +/- 3.2 cm in Group II (P = 0.01 vs. controls), and 1.7 +/- 4.6 in controls (chemotherapy only). There was no significant difference between Group I and Group II. In Group I females had more RAH than males (P = 0.02). RAH was related to younger age at diagnosis (P = 0.001). CONCLUSIONS: The deficit between target height and final height highlights the reduction of adult height in the majority of male and female childhood ALL survivors who had received prophylactic cranial irradiation, in particular in those who were diagnosed at a younger age. This reduction would have been masked if patients FH was only compared with standard methods. RAH might be a sensitive predictor for growth hormone deficiency as these results suggest that radiation-induced growth hormone deficiency in these patients is the rule rather than the exception.     

Smoking habits in survivors of childhood and adolescent cancer.

Because of their increased risk for second cancers, childhood cancer survivors are people who really should not smoke, but available evidence suggests that they do. We studied the smoking habits of long-term childhood cancer survivors in data collected from 1289 adult survivors of childhood cancer and 1930 of their sibling controls. Survivors were diagnosed with cancer between 1945 and 1974 when they were less than 20 years old. Using matched analyses that controlled for the influence of family, survivors were 8% less likely than controls to be current smokers, 13% less likely to be ever-smokers, but 12% less likely to have quit smoking; these differences were not statistically significant. In a logistic regression analysis there was a significant difference by year of diagnosis for current smoking rate ratios (RR); survivors were less likely to be current smokers if diagnosed in recent years (RR = 0.76; 95% confidence intervals = 0.58-0.98, between 1965-74) and quite similar to controls if diagnosed in earlier years (RR = 1.05 between 1945 and 1954). In our group of long-term cancer survivors, the reduction in current smoking came about because survivors were more inclined never to start smoking than controls. Once addicted to tobacco, they were less likely to quit. While the fact that survivors are less likely to start smoking is encouraging, the persistence of smoking habits strongly suggests the need for continuing efforts to prevent smoking in this most vulnerable group.     

NEUROPSYCHOLOGIC SEQUELAE IN THE LONG-TERM SURVIVORS OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

The neurotoxicity of either systemic chemotherapy or central nervous system prophylaxis was studied in 19 children treated for acute lymphoblastic leukemia (ALL). They had completed ALL therapy at least a year before and survived more than 5 years after diagnosis. The duration between age at diagnosis and age at investigation was 8.6 2.7 years (5-15 years). Neuropsychologic tests, cranial magnetic resonance imaging (MRI), and evoked potentials (EP) were studied. Seventeen healthy siblings were taken as a control group. Emotional evaluation was done using the childhood depression inventory and Beck depression inventory. Cognitive functions were evaluated using Wechsler's Intelligence Scale for Children-Revised (WISC-R) or the Wechsler's Adult Intelligence Scale-Revised (WAIS-R) tests, which were adapted to Turkish children. Performance and total IQ scores (94.0 16.8 and 92.2 16.5) were significantly low as compared to the control group (112.1 18.9 and 105.4 14.2) (p=.007 and p=.02). Abnormal MRI findings were found in 33.3% (6/18). Three out of 18 patients (16.6%) had abnormal auditory while 5 out of 17 patients (29.5%) displayed abnormal visual EPs. Abnormal findings in MRI, cognitive examination, and electrophysiologic testing were not associated with age at diagnosis, radiotherapy doses, intermediate/high-dose systemic methotrexate administration or central nervous system involvement. But more patients must be studied to demonstrate discrete outcomes of neurotoxicity in long-term survivors of childhood leukemia.     

Long-term survival in a pediatric patient with supratentorial primitive neuro-ectodermal tumor and extraneural metastasis at diagnosis

Extraneural metastases of central nervous system (CNS) tumors are rare occurrences most commonly observed in medulloblastomas. Survival outcomes are generally dismal. Supratentorial primitive neuroectodermal tumors (stPNET) are rare childhood tumors with few documented cases of extraneural metastases. We present a rare occurrence of a 23-month-old patient with long-term survival after diagnosis of stPNET with metastases to the lungs. This patient was treated with surgical resection, induction chemotherapy, tandem autologous hematopoietic cell rescues, and focal radiotherapy. We report long-term survival for a patient with a stPNET and extraneural metastases at diagnosis following an intensive approach to treatment.     

Long-term survivors of childhood central nervous system malignancies: The experience of the Childhood Cancer Survivor Study

In the last four decades, advances in neurosurgical technique, delivery of radiation therapy (RT), supportive care, and use of chemotherapy have improved 5-year survival for children with central nervous system (CNS) malignancies. Currently, in the United States 74% of children will become 5-year survivors of their primary CNS malignancy. This improved outcome has resulted in a new and growing population of childhood cancer survivors. Surgery, RT and chemotherapy, while essential components of primary treatment for most childhood CNS malignancies, have also been associated with risk of long-term morbidity and late mortality. The Childhood Cancer Survivor Study, a retrospective cohort of over 14,000 survivors of childhood cancer diagnosed between 1970 and 1986, has been an important resource for quantification of associations between these therapeutic modalities and risk of long-term adverse health and quality of life outcomes. CNS malignancy survivors are at significant risk for late mortality, development of second neoplasms, as well as increased risk for multiple endocrinopathies and adverse neurologic health conditions. Importantly, the CCSS has identified a number of dose–response relationships between RT and development of subsequent malignant neoplasms of the central nervous system, abnormal timing of menarche and neurocognitive function. Ongoing study of childhood cancer survivors is needed to establish long-term risks and evaluate impact of newer techniques such as conformal RT or proton beam delivery that limit RT exposure and may reduce long-term effects.     

Mortality among 5-year survivors of cancer diagnosed during childhood or adolescence in British Columbia, Canada

BACKGROUND: Ongoing monitoring of late mortality among survivors of a childhood or adolescent cancer is essential to appropriately evaluate risk in more recent cohorts and with longer follow-up. We examined overall and cause-specific mortality in a population-based cohort of 2,354 individuals diagnosed with a cancer or tumor prior to 20 years of age between 1970 and 1995 in British Columbia (BC), Canada who survived at least 5 years. PROCEDURE: Late deaths in a survivor cohort ascertained from the BC Cancer Registry were identified using death registrations. Standardized mortality ratios, absolute excess risk of death, and cumulative risk of death were determined. Demographic, temporal, and disease-related factors in risk of late mortality were also assessed. RESULTS: After 24,491 person-years of follow-up, there were 181 deaths, 139 of which were cancer related. Excess risk of late mortality among survivors was 7 deaths per 1,000 person-years at risk (AER = 6.6). Standardized mortality ratio (SMR) was ninefold higher relative to the underlying BC population (SMR = 9.1, 95% CI, 7.8-10.5), and was greatest for those with a recurrence within 5 years of diagnosis, and for those diagnosed with acute lymphoblastic leukemia and nervous system tumors. Absolute excess risk of late death was significantly higher for males and for those diagnosed prior to 1980, but did not vary according to age at diagnosis. Relative mortality was significantly increased due to cancer-related causes of death (SMR = 81.7, 95% CI, 68.6-95.8), as well as circulatory (SMR = 9.7, 95% CI, 4.2-19.1) and respiratory (SMR = 16.8, 95% CI, 4.6-43.0) diseases. CONCLUSIONS: In this population-based cohort with long follow-up, there continues to be excess late mortality among childhood and adolescent cancer survivors due to both cancer and non-cancer causes, even among more recently diagnosed survivors.