Survey of long‐term follow‐up programs in the United States for survivors of childhood brain tumors

Introduction

Despite recognition that childhood brain tumor survivors often suffer multiple late effects following therapy, little is known regarding the long‐term follow‐up (LTFU) programs for these patients.

Methods

A 16‐question survey was mailed to member institutions of the Children's Oncology Group in the United States. Institutions were asked about the size of their brain tumor program, activities of the LTFU programs and perceived barriers to follow‐up.

Results

One hundred forty‐five (74%) of 197 institutions returned surveys. Care for patients <21 years old at diagnosis who are >2 years following completion of therapy was provided at a designated neuro‐oncology LTFU clinic (31.2%), a general LTFU program for childhood cancer survivors (30.4%), or a general pediatric oncology program (29.7%). Institutions with a neuro‐oncology LTFU clinic were more likely to use neuro‐psychological testing following radiation therapy (P = 0.001), have longer duration of continued surveillance imaging (P = 0.02), use growth hormone replacement for medulloblastoma survivors (P < 0.001) and continue the use of growth hormone into adulthood (P = 0.05) than those with a general pediatric oncology program. Perceived barriers to care of brain tumor survivors included limited access and lack of insurance (32.1%), lack of funding or dedicated time for providers (22.9%), patients' uncertainty about need to follow‐up (20.6%), and patients' desire to not be followed in a pediatric cancer program (12.2%).

Conclusions

Considerable variation exists across institutions in the United States in the delivery of follow‐up care for survivors of childhood brain tumors. We encourage additional investigation to better define and implement optimal follow‐up care for childhood brain tumor survivors. Pediatr Blood Cancer 2009; 53:1295–1301. © 2009 Wiley‐Liss, Inc.     

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.     

Role of radiotherapy in the treatment of brain tumors]

Tumors of the central nervous system represent about 25% of malignant tumors in children. They differ by their histological subtypes and evolution. Surgery is often incomplete and chemotherapy has not yet demonstrated its efficiency. Thus, radiotherapy (Rt), in spite of its late effects on the normal brain, remains widely used. The most severe complications of Rt can be avoided by precise multidisciplinary indications, judicious choice of volume to be irradiated, use of specific X-rays with a precise technology. Indications of radiotherapy are residual tumor after surgery and all malignant tumors, even if completely removed. The maximum tolerable doses are well known, but the volumes to be irradiated remain of debate for some types especially taking into account the risk of dissemination to cerebro spinal fluid. Overall 5-year survival rate is about 50% with great variations from one histological type to another. Brachytherapy may sometimes be useful but is a very sophisticated technique.     

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.     

Educational achievement of long-term survivors of childhood and adolescent cancer

In a retrospective cohort study, the level of education attained by 2,283 long-term survivors of childhood and adolescent cancer was investigated and compared with that of 3,270 sibling controls. Survivors of central nervous system tumors were significantly less likely than controls to complete eight grades of school or, if they completed high school, to enter college. No significant differences in educational achievement were found for survivors of non-central nervous system cancers. The educational deficit of survivors of brain tumors was especially striking for tumors of the ventricles or cerebral hemispheres, and the deficit was more severe for those treated with radiation therapy than by surgery alone. Early age at diagnosis of a central nervous system tumor was associated with a larger educational deficit than late age at diagnosis. These findings are reassuring for the majority of long-term survivors of childhood and adolescent cancers given therapies used prior to 1975.     

De novo malignances in pediatric organ transplant recipients

A study of 10813 types of cancer that occurred in 10151 organ transplant recipients showed that the pattern of malignancies that occurred in pediatric recipients was very different from the general pediatric population and from adult recipients. Tumors (527) occurred in 512 pediatric patients (aged 18 years or less), and 9639 adults developed 10286 neoplasms. Post-transplant lymphoproliferative disease (PTLD) was the predominant neoplasm in pediatric recipients and comprised 52% of all tumors compared with 15% in adult recipients. Eighty-four percent of PTLD in the former patients presented during childhood. There was a disproportionately high incidence among nonrenal allograft recipients compared with renal recipients (81% vs. 31% of all tumors). The second most common malignancy in pediatric patients was skin cancer (19% of tumors), but this was less frequent than in adult recipients, in whom it comprised 39% of neoplasms. Only 16 pediatric patients (16%) with skin cancers developed their tumors during childhood (6 had malignant melanomas), with an average time of appearance after transplantation of 126 months (range 5.5-292). Malignant melanomas were more common in pediatric than adult recipients (12% vs. 5% of skin cancers), as were lip cancers (23% vs. 12%). Spread to lymph nodes was also more common in pediatric than in adult recipients (9% vs. 6%). Sarcomas comprised 4% of tumors compared with 1% in adults. Carcinomas of the vulva and perineum also comprised 4% of tumors. Females outnumbered males in a ratio of 8.5:1. These tumors appeared beyond childhood at an average of 142 months (range 42-262 months) post-transplantation. Other cancers observed in recipients transplanted during childhood were thyroid carcinomas (15), Kaposi's sarcomas (15), carcinomas of the liver (13), leukemias (13), carcinomas of the cervix (10), brain tumors (7), renal carcinomas (7), ovarian carcinomas (5), and miscellaneous tumors (19). Of all 527 malignancies, 314 (60%) appeared during childhood and 213 (40%) manifested themselves between the ages of 19 and 40 years. By far the most common tumor diagnosed during childhood was PTLD, which comprised 230 of the 314 (73%) malignancies.     

Congenital brain tumors: case series and review of the literature

Congenital brain tumors are rare and make up only 2% of all pediatric central nervous system tumors. We present 12 cases of congenital brain tumors of various histopathologies. Most of these tumors were of astrocytic lineage. One patient was diagnosed before birth with prenatal ultrasound, but the rest were diagnosed after birth owing to increased head circumference. Four patients received adjuvant chemotherapy after surgery. None received radiation therapy. Seven out of 12 (58%) are long-term survivors. Four of these survivors (57%) have significant neurocognitive or psychomotor impairment. Although rare, congenital brain tumors are one of the more common tumors presenting in the perinatal period and generally carry a poor prognosis. Novel therapies are needed to improve efficacy and decrease the devastating side effects of treatment in this age group.     

Application of stem cell transplant for brain tumors

Abstract:  Brain tumors are the second most common malignancy in children and the most common solid tumor. The majority of children are treated with surgery alone or in combination with radiation and/or chemotherapy. Recently investigators have used high dose chemotherapy with autologous stem cell rescue (ASCR) in patients with malignant brain tumors. This approach has been most successful in chemosensitive tumors including medulloblastoma, supratentorial primitive neuroectodermal tumors (SPNET) and central nervous system germ cell tumors (CNS GCT). In addition, the use of high dose chemotherapy has enabled the reduction and in many cases elimination of radiation therapy to very young children. To date there have been no prospective randomized studies comparing high dose chemotherapy and ASCR with conventional therapy. Radiation therapy is often not an option for patients with recurrent disease and conventional dose chemotherapy rarely if ever results in long-term survival. Unfortunately, the majority of studies using conventional therapy in order to delay irradiation in young children newly diagnosed with malignant brain tumors have been unsuccessful. Although the numbers are small, preliminary data suggest that not only is survival but also quality of life is superior with the use of high dose chemotherapy. Future studies will most likely include the use of new agents as part of the cytoreduction. In addition, through the use of peripheral blood stem cells and improvements in supportive care, multiple courses of high dose chemotherapy can be administered. High dose chemotherapy with ASCR is a foundation upon which many different types of therapies can be built. Several possibilities include the use of anti-angiogenesis agents, monoclonal antibodies and biologic response modifiers.     

Long-term endocrine sequelae of childhood cancer

PURPOSE OF REVIEW: To update knowledge related to the long-term endocrine sequelae of childhood cancer. RECENT FINDINGS: Endocrine deficiencies are common after cranial irradiation, chemotherapy and specific tumors. These deficiencies include growth hormone, thyrotropin, adrenocorticotropin and gonadotropin deficiencies, primary hypothyroidism, gonadal failure and obesity. Recent studies highlight the impact of radiation on the development of endocrine sequelae. Risks for obesity after childhood tumors include hypothalamic injury, with inactivity and daytime sleepiness. About 6% of adult female survivors of childhood cancer develop persistent ovarian failure. Risks for ovarian damage include ovarian irradiation and alkylating agents. Appropriate fertility-preservation options should be offered. Offspring of women who had uterine irradiation as children are more likely to be born preterm or have low birth weight. Secondary neoplasia or relapse should be considered when treating endocrine deficiencies in cancer survivors. Risk of secondary neoplasia is increased following radiation exposure and certain malignancies. Treatment with growth hormone does not increase cancer recurrence, but survivors may have a 2-fold risk of developing a secondary solid tumor, most commonly a meningioma. SUMMARY: Standardized, multidisciplinary long-term surveillance is important in childhood cancer survivors to identify and treat endocrine and other late effects of cancer and its therapy.     

Late effects of childhood malignancies seen in Western Australia.

Eighty-nine pediatric oncology patients, in remission and off treatment for at least 4 years, were reviewed annually in the Late Effects Clinic of Princess Margaret Hospital for Children in Perth, Western Australia. Interval from time of diagnosis to follow-up ranged from 4 to 23 years (mean 10.8 years). Acute lymphoblastic leukemia (ALL) (40%) and Wilms' tumor (27%) were the most common primary malignancies in this group. Late sequelae included musculoskeletal abnormalities (23 children), growth hormone deficiency (11), second tumors (9), learning difficulties (7), puberty and fertility problems (4), and hypothyroidism (4). These complications were most often related to radiation therapy. The need for prolonged, regular follow-up of survivors of childhood malignancy for early detection of late sequelae and subsequent intervention is stressed.     

Late effects of treatment for germ cell tumors during childhood and adolescence

PURPOSE: To evaluate the long-term sequelae of treatment for malignant germ cell tumors (GCT) during childhood and adolescence. PATIENTS AND METHODS: Of 128 patients treated for GCT at St. Jude Children's Research Hospital between 1962 and 1988, 73 are long-term survivors (continuously disease-free for > or =5 years after diagnosis), with a median follow-up of 11.3 years). Survivors' ages at diagnosis ranged from birth to 18.3 years (median, 9.2 years); 64% (47 patients) were female. Initial surgical resection was followed by observation for stage I germinomas (n = 2), testicular tumors (n = 13), and selected cases of ovarian or sacrococcygeal tumors (n = 2), and by radiation therapy (RT) for patients with stage II to III germinoma (n = 8). The remaining 48 patients received postoperative chemotherapy (vincristine, dactinomycin, and cyclophosphamide [VAC] +/- doxorubicin, 1962 to 1978; VAC and/or cisplatin, vinblastine, and bleomycin [PVB], 1979 to 1988). RT was added to the chemotherapy for 21 patients. Late complications involving various organ systems and their relationship to treatment were evaluated. RESULTS: More than two-thirds of long-term survivors (n = 50) had at least 1 complication, and half (n = 38) had > 1 organ system affected. The systems most often involved included the musculoskeletal (41% of survivors), endocrine (42%), cardiovascular (16% excluding those who had only abnormal chest radiograph), gastrointestinal (25%), genitourinary tract (23%), pulmonary (19%), and neurologic (16%) systems. High-frequency hearing loss occurred in 58% (11 of 19) of patients treated with cisplatin. Musculoskeletal, gastrointestinal, and urinary tract abnormalities were most frequent in patients whose treatment included RT. CONCLUSIONS: A high frequency of late effects after treatment for pediatric GCT, particularly in patients who received RT, was demonstrated. Treatment sequelae could be anticipated from the intensity and type of therapeutic modalities. Treatment-directed screening evaluations may improve quality of life in long-term survivors of pediatric GCT through timely identification of sequelae that can be prevented or ameliorated.     

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.     

Spectrum of Pediatric Brain Tumors: A Report of 341 Cases from a Tertiary Cancer Center in India

Brain tumors are the second most common cancers after hematological malignancies accounting for approximate 21 % of all childhood malignancies in children between ages of 0 and 14 y. The present study was undertaken to determine the spectrum of the brain tumors diagnosed in a tertiary cancer center in South India. A retrospective analysis of the data of pediatric brain tumors diagnosed between 2003 and 2009 was done and data was classified according to the age, gender and histology types. Out of 2,844 pediatric patients, 341 (11.99 %) were diagnosed as having brain tumors. Most of the patients were in the age group of >5–14 y. Male to female ratio was 1.58:1. The most common pediatric brain tumor was medulloblastoma followed by astrocytoma and ependymoma. Glioblastoma multiforme was the most common subtype of astrocytoma. Other common tumors were glioma, oligodendroglioma, periphereral neuroectodermal tumor and germ cell tumor. As compared to western data, incidence of brain tumors in children was found to be less in the present study.     

Colorectal adenocarcinoma as a second malignant neoplasm following Wilms' tumor and rhabdomyosarcoma

Colorectal carcinoma is one of the most common primary malignancies in adults and occurs in older patients after pelvic radiation. It is rare in children and young adults. We report two cases of colonic adenocarcinoma which were second malignant neoplasms following treatment for early childhood malignancies. One child had Wilms' tumor at 9 months of age treated with preoperative radiation and surgery. He developed radiation colitis and multifocal intestinal adenocarcinomas 42 years later and died with abdominal carcinomatosis. The second child had retroperitoneal embryonal rhabdomyosarcoma at age 1 year and was treated with preoperative radiation, surgery, and chemotherapy. At age 2 years he had radiation colitis; at age 11 years he had rectal adenocarcinoma associated with adenomatous polyps, focal adenomatous change and radiation colitis. Immunohistochemical studies revealed p53 positivity in both adenocarcinomas and in adenomas from the second patient, suggesting that p53 mutation was involved in carcinogenesis. The history of high-dose radiation in early childhood and the multifocal lesions suggest the adenocarcinomas in both patients were second malignant neoplasms, with associated reactive and benign neoplastic and premalignant lesions well documented in one case. These two cases document the phenomenon of early onset of adult type tumors in survivors of childhood cancer and emphasize the need for continued clinical evaluation of patients at risk for second malignant neoplasms. © 1996 Wiley-Liss, Inc.     

Pediatric tumors of the eye and orbit

Most ocular and orbital tumors of childhood are distinct from tumors that occur in adults. Many are congenital with early presentations. Most pediatric orbital tumors are benign; developmental cysts comprise half of orbital cases, with capillary hemangioma being the second most common orbital tumor. The most common orbital malignancy is rhabdomyosarcoma. The most common intraocular malignant lesion is retinoblastoma. Choroidal melanoma, which is common in adults, is extremely rare in children. The orbit is the most common location for metastases in children, whereas the choroid is the predominant site in adults. Pediatricians play a vital role in diagnosis of pediatric ocular tumors. They are the first to recognize ocular problems that may not be apparent to parents. It is therefore important to recognize the signs and symptoms of ocular tumors of childhood so that prompt ophthalmologic evaluation and treatment may be undertaken. Whereas the malignant tumors may be life-threatening, both malignant and benign tumors may be vision-threatening.     

Developing pre-school surveillance tools for adaptive functioning: Lessons for neuro-oncology

Advances in neuro-oncology have resulted in dramatic increases in the survival of children with pediatric brain tumors, including those with medulloblastoma, the most common early childhood central nervous system (CNS) malignancy. Because of this increased survival, there is heightened awareness and recognition that an understanding of the impact of treatments and interventions on children’s development, learning, and adaptive behaviors is essential for optimization of long-term outcomes. One of the major reasons for studying these outcomes is that the developing nervous system has its unique vulnerabilities with respect to the primary tumor, its complications (hydrocephalus, increased intracranial pressure, hazards of tumor resection), and the late effects of treatments on children’s developmental, learning, and adaptive status. In addition, very young children are especially vulnerable to the toxic effects of radiation and other therapies, highlighting the importance of measuring emerging communication, coordination, and social adaptive skills. Lastly, there is increased concern about the long-term consequences of chemotherapy on specific neural populations and neural connectivity that affect memory, learning, and executive function.The purpose of this article is to review ways of conceptualizing CNS adaptive functioning in children diagnosed with brain tumors in early childhood. The international classification of functioning (ICF) model will be used to describe the spectrum of health and developmental outcomes of child neurodisability. An integrated strategy of surveillance for motor, communicative, and adaptive skills that can be linked to neuropsychological assessments will also be highlighted. This health, development, and functional surveillance framework will help us better evaluate how our management impacts on child and family well-being and how our interventions lessen severe multiple motor, communicative, and neurobehavioral morbidities.     

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.     

Cardiorespiratory fitness in survivors of pediatric posterior fossa tumor

Advances in medical therapies have greatly improved survivorship rates in children diagnosed with brain tumor; as a result, morbidities associated with survivorship have become increasingly important to identify and address. In general, pediatric posterior fossa tumor survivors tend to be less physically active than peers. This may be related to late effects of diagnosis and treatment, including cardiovascular, endocrine, psychological, and neurocognitive difficulties. Exercise has been shown to be effective in improving physical functioning, mood, and even cognitive functioning. Consequently, the benefits of physical exercise need to be explored and incorporated into the daily lives of pediatric posterior fossa tumor survivors. The primary aim of the present study was to establish the feasibility and safety of cardiorespiratory fitness testing in pediatric posterior fossa tumor survivors who had received cranial radiation therapy. In addition, comparing our cohort with previously published data, we found that pediatric posterior fossa tumor survivors tended to be less fit than children with pulmonary disease and healthy controls and approximately as fit as children with chronic heart disease and survivors of other types of childhood cancer. The importance of cardiorespiratory fitness in pediatric posterior fossa tumor survivors is discussed along with implications for future directions.     

Childhood brain tumors: current status of clinical trials in newly diagnosed and recurrent disease

Primary childhood brain tumors are the second most common form of childhood cancer. Though progress in this area has been slow, the field has evolved considerably over the past 10 years. This article focuses on new information that will influence our treatment of the more common pediatric brain tumors.     

Pediatric brain tumor treatment: growth consequences and their management

Tumors of the central nervous system, the most common solid tumors of childhood, are a major source of cancer-related morbidity and mortality in children. Survival rates have improved significantly following treatment for childhood brain tumors, with this growing cohort of survivors at high risk of adverse medical and late effects. Endocrine morbidities are the most prominent disorder among the spectrum of longterm conditions, with growth hormone deficiency the most common endocrinopathy noted, either from tumor location or after cranial irradiation and treatment effects on the hypothalamic/pituitary unit. Deficiency of other anterior pituitary hormones can contribute to negative effects on growth, body image and composition, sexual function, skeletal health, and quality of life. Pediatric and adult endocrinologists often provide medical care to this increasing population. Therefore, a thorough understanding of the epidemiology and pathophysiology of growth failure as a consequence of childhood brain tumor, both during and after treatment, is necessary and the main focus of this review.