New technologies in radiation therapy for pediatric brain tumors: the rationale for proton radiation therapy

BACKGROUND: Pediatric brain tumors are frequently treated with radiation therapy and often cured. The long-term side effects of treatment with high-energy X-rays (photons) can be substantial. Proton radiation therapy may limit these late effects. PROCEDURE: The physical difference between photon and proton irradiation is compared. The clinical benefits of the superior physical properties of proton beam radiation therapy are explained for children with brain tumors. RESULTS: At biologically equivalent doses, proton radiation therapy offers tumor control similar to photon radiation therapy. The superior physical properties of proton beams make this mode of radiation therapy less likely to cause late effects. CONCLUSIONS: For many children with brain tumors, proton beam radiation therapy may limit the late effects of radiation therapy and therefore offer an advantage over techniques using photons.     

Proton therapy for central nervous system tumors in children

Proton therapy is a form of particle therapy with physical properties that provide a superior dose distribution compared to photons. The ability to spare healthy, developing tissues from low dose radiation with proton therapy is well known. The capability to decrease radiation exposure for children has been lauded as an important advance in pediatric cancer care, particularly for central nervous system (CNS) tumors. Favorable clinical outcomes have been reported and justify the increased cost and burden of this therapy. In this review, we summarize the current literature for proton therapy for pediatric CNS malignancies, with a focus on clinical outcomes to date.     

Radiation therapy for children: evolving technologies in the era of ALARA

The evolution of ever more sophisticated oncologic imaging and technologies providing far more precise radiation therapy have combined to increase the utilization of sophisticated radiation therapy in childhood cancer. For a majority of children with common central nervous system, soft tissue, bone, and dysontogenic neoplasms, local irradiation is fundamental to successful multi-disciplinary management. Along with more precise target volume definition and radiation delivery, new technologies provide added certainty of patient positioning (electronic portal imaging, cone beam CT) and conformality of dose delivery (3-D conformal irradiation, intensity modulated radiation therapy, proton beam therapy). Each of the major areas of technology development are able to better confine the high-dose region to the intended target, but they are also associated with the potential for larger volumes of uninvolved tissues being exposed to low radiation doses. The latter issue plays a role in documented levels of secondary carcinogenesis, sometimes with greater anticipated incidence than that seen in conventional radiation therapy. Parameters related to carcinogenesis, such as dose–volume relationships and neutron contamination that accompanies high-energy photon irradiation and proton therapy, can be identified, sometimes modulated, and accepted as part of the clinical decision process in fine tuning radiation therapy in this more vulnerable age group.     

Comparison of parameters of chronic kidney disease following paediatric preemptive versus non‐preemptive renal transplantation

Sinha R, Marks SD. Comparison of parameters of chronic kidney disease following paediatric preemptive versus non‐preemptive renal transplantation.
Pediatr Transplantation 2010: 14:583–588. © 2010 John Wiley & Sons A/S. Abstract: PRT is the preferred modality for renal replacement therapy in children. Despite this, there are no studies CKD parameters as per K/DOQI criteria between PRT and NPRT in children. This was a single‐centre cross‐sectional study of RTR with at least one yr of post‐transplant follow‐up. CKD parameters as per K/DOQI were compared between PRT and NPRT. Thirty percent (39/129) of our study population was PRT. Despite similar baseline characteristics at the time of transplantation and similar post‐transplantation follow‐up period, a significantly lower proportion of PRT (1, 2%) were in Stage 4 CKD in contrast to NPRT (14, 16%); p = 0.03. This was also reflected in better CKD parameters among PRT with significantly lower incidences of hypertension and acidosis (p = 0.02). CKD medications were also more commonly prescribed in NPRT (p = 0.002). We demonstrated improved CKD parameters and lower use of CKD medications among PRT when compared with NPRT. This finding should act as an added impetus for PRT programmes.     

Conformal proton radiation treatment for retroperitoneal neuroblastoma: introduction of a novel technique

BACKGROUND: Postoperative irradiation for locoregionally advanced neuroblastoma requires coverage of the paraspinal retroperitoneum. The proximity of both kidneys and the liver, and a more complex target configuration, can pose a dosimetric challenge for conventional X-ray treatment and intraoperative irradiation. We utilized proton radiation therapy (PRT) to reduce dose to uninvolved kidneys, liver, intestine, and spinal cord. PROCEDURE: A 4-year-old male underwent PRT for neuroblastoma of the right adrenal gland, following chemotherapy and delayed surgical resection. Clinical target volume (CTV), boost volume, and normal structures were outlined on the 3D treatment planning CT scan. The patient received 25.2 CGE (cobalt Gray equivalent) to the CTV and 34.2 CGE to the boost region, using 1.8 CGE per fraction, five treatments per week. Dose-volume histograms (DVHs) were obtained for target and nontarget structures. RESULTS: The 95% isodose volume enclosed CTV and boost volumes. The dose to 50% of the ipsilateral kidney, with tumor involvement of the medial renal surface, was < or = 16 CGE (47% of prescribed total dose). Doses to 50% and 20% of the contralateral kidney in close proximity to deep left-side, paraspinal soft tissue involvement were restricted to 1 CGE and 10 CGE, respectively. Eighty percent of the liver received 27 CGE (80% of prescribed dose). Using a patch technique, unique to charged particle therapy, the spinal cord was almost completely spared during boost volume irradiation. CONCLUSIONS: PRT can achieve excellent dose conformity for advanced retroperitoneal, paraspinal lesions, while respecting normal tissue tolerance levels.     

Current perspectives on childhood brain tumours: a review

Tumours of the brain and spinal cord are the commonest solid tumour in children and the leading cause of cancer related morbidity and mortality. The increasing availability of modern imaging techniques has resulted in peak of incidences in the 1990s. Current challenges for the general public, paediatricians and general practitioners lie in increasing awareness of the presenting features so that an earlier diagnosis can be made. Specific issues and peculiarities relating to congenital/infantile brain tumours have been explored. Improved histological classification supported by biological markers and subgroup allocation has enabled better treatment planning and increased survival. The emphasis is now focussing on formulating treatment strategies associated with reduced risks of toxicities for favourable risk groups and intensification of treatment for those with worst prognosis. The interface between brain tumours and epilepsy, effects of anti-epileptic medications, antineoplastic medications and tumour surgery on epilepsy were touched upon. Advances in radiotherapy through the increasing availability of proton beam radiotherapy and its advantage over photon radiation therapy in brain tumours has also been discussed.     

Pediatric radiation oncology in Germany: a study of availability and application

BACKGROUND: Radiotherapy plays a pivotal role in many multimodal therapy concepts in pediatric oncology. However, the absolute number of irradiated children is estimated to be quite low. The aim of this study was to evaluate the availability and application of pediatric radiation oncology in Germany. METHOD: In summer 2007, a standardized questionnaire was sent to all radiotherapy facilities in Germany. The questions regarded the structure of the departments, the number of irradiated children each year including the distribution of the different diagnoses, the number of curative treatments, inclusion in study trials, and existence of special contact persons for pediatric radiotherapy as well as technical aspects of irradiation of children. RESULTS: Answers to the questionnaires were obtained from 171 departments (77.4%). Of these, 67 (39%) stated to regularly treat children. These departments treated one to nine children in median each year (<5 children/year: 23 departments; >or=20 children: 15 departments). Most of these children suffered from brain tumors, Hodgkin's disease and acute lymphatic leukemia (ALL). Three-dimensional conformal radiotherapy was the most frequent treatment technique; special techniques like intensity-modulated radiotherapy (IMRT) or brachytherapy were rare. CONCLUSIONS: Due to quite low patient numbers treated in most radiotherapy facilities, individual experiences in pediatric radiation oncology can be assumed to be quite limited. As radiotherapy is part of multimodal therapy approaches in pediatric oncology and children treated with radiotherapy are at special risk for potential side effects, pediatric radiation oncology remains a sophisticated area. Therefore radiotherapy reference-institutions implemented by the therapy optimizing protocols are of fundamental importance.     

Radiation therapy in the neonate

Radiation therapy (RT) is frequently used in the management of children with cancer, but neonatal neoplasms are rare. Newborns represent 1.5% of the children with malignant diseases in the Tumor Registry at the Children's Hospital of Philadelphia over the last 30 years. Thus, occasionally the pediatrics radiation therapist must consider treating the very young infant. The specific radiation effects on growth and development must be weighed in reaching a therapeutic decision. All children are vulnerable to the late effects of radiation therapy, but the neonates may be more susceptible because of the immaturity of important organs such as the brain, lung, liver, kidney, and bone. In general, radiation therapy, should be avoided during the first several weeks of life because of the potential increased sensitivity of the liver and kidneys during that period. If radiation therapy is used at all during infancy, the benefits must be weighed against the possibility of significant late effects. Increasing knowledge of pediatric neoplasms has shown that some tumors (such as mesoblastic nephroma) require no treatment except for surgical excision; and other tumors, such as Stage IV-S neuroblastoma, may require very little treatment. In those tumors that require radiation therapy, the use of chemotherapy may allow reduction of the radiation dose. Furthermore, alterations of time-dose-fractionation schemes and careful attention to tumor volume with the use of special techniques, such as "shrinking fields," may decrease the late adverse effects of treatment.     

Romiplostim for therapy‐related thrombocytopenia in pediatric malignancies

Therapy‐related thrombocytopenia (TRT), due to chemotherapy and/or radiation therapy, is common with pediatric cancer treatments, and it can result in dose reductions and therapy delays. Romiplostim, a thrombopoietin mimetic, is efficacious as a second‐line treatment for immune thrombocytopenia in children and for TRT in adult cancer patients. However, there are no data for its use for TRT in children. We report a case series of five children treated for solid tumors where romiplostim was used without adverse effects to successfully resolve and prevent therapy‐limiting refractory TRT. Prospective studies on this use of romiplostim are warranted.     

Preservation of fertility in pediatric and adolescent patients with cancer

Many cancers that present in children and adolescents are curable with surgery, chemotherapy, and/or radiation therapy. Potential adverse consequences of treatment include sterility, infertility, or subfertility as a result of either gonad removal or damage to germ cells from adjuvant therapy. In recent years, treatment of solid tumors and hematologic malignancies has been modified in an attempt to reduce damage to the gonads. Simultaneously, advances in assisted reproductive techniques have led to new possibilities for the prevention and treatment of infertility. This technical report reviews the topic of fertility preservation in pediatric and adolescent patients with cancer, including ethical considerations.     

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.     

Radiation-sensitive genetically susceptible pediatric sub-populations

Major advances in pediatric cancer treatment have resulted in substantial improvements in survival. However, concern has emerged about the late effects of cancer therapy, especially radiation-related second cancers. Studies of childhood cancer patients with inherited cancer syndromes can provide insights into the interaction between radiation and genetic susceptibility to multiple cancers. Children with retinoblastoma (Rb), neurofibromatosis type 1 (NF1), Li-Fraumeni syndrome (LFS), and nevoid basal cell carcinoma syndrome (NBCCS) are at substantial risk of developing radiation-related second and third cancers. A radiation dose-response for bone and soft-tissue sarcomas has been observed in hereditary Rb patients, with many of these cancers occurring in the radiation field. Studies of NF1 patients irradiated for optic pathway gliomas have reported increased risks of developing another cancer associated with radiotherapy. High relative risks for second and third cancers were observed for a cohort of 200 LFS family members, especially children, possibly related to radiotherapy. Children with NBCCS are very sensitive to radiation and develop multiple basal cell cancers in irradiated areas. Clinicians following these patients should be aware of their increased genetic susceptibility to multiple primary malignancies enhanced by sensitivity to ionizing radiation.     

A discourse: the 2002 Wataru W. Sutow lecture. Hodgkin disease in children--perspectives and progress

THE PIONEER: Wataru W. Sutow, 1912-1981, was a remarkable and pivotal leader in pediatric oncology. Early in his medical career, he conducted important clinical and anthropometric studies among Japanese and Marshall Island children exposed to atomic radiation. These studies established standards for childhood growth and development still in use today. Dr. Sutow pioneered the multidisciplinary approach to childhood cancer by combining multidrug chemotherapy protocols with surgery and radiotherapy in the common childhood solid tumors. The textbook "Clinical Pediatric Oncology," of which he was the senior editor, served to define the discipline of pediatric oncology and educate a new era of oncologists in the curative treatment for childhood cancer. THE PAST AND PRESENT: The first edition of "Clinical Pediatric Oncology," published in 1973, demonstrated that only children with early-stage localized Hodgkin disease had a realistic opportunity for cure. Soon the use of combined-modality therapy consisting of low-dose, involved-field radiation plus multi-agent chemotherapy emerged, and made the goal of cure realistic for all patients. This approach is now universal. Today, the 5-year relative survival rate for American children with Hodgkin disease, who are under 14 years of age, is 94%, a dramatic and remarkable achievement. FUTURE: Management of children with Hodgkin disease now involves clinical staging and risk-adapted, combined-modality therapy. Clinical and translational research initiatives that hold promise for children with Hodgkin disease in the future include: use of the WHO Classification System combining morphologic and biologic criteria; noninvasive staging procedures with increased sensitivity and specificity; development of a useful prognostic index to define groups for risk-adapted therapy; high-dose therapy with stem cell transplantation; and novel therapies.     

Cancer risks following diagnostic and therapeutic radiation exposure in children

The growing use of interventional and fluoroscopic imaging in children represents a tremendous benefit for the diagnosis and treatment of benign conditions. Along with the increasing use and complexity of these procedures comes concern about the cancer risk associated with ionizing radiation exposure to children. Children are considerably more sensitive to the carcinogenic effects of ionizing radiation than adults, and children have a longer life expectancy in which to express risk. Numerous epidemiologic cohort studies of childhood exposure to radiation for treatment of benign diseases have demonstrated radiation-related risks of cancer of the thyroid, breast, brain and skin, as well as leukemia. Many fewer studies have evaluated cancer risk following diagnostic radiation exposure in children. Although radiation dose for a single procedure might be low, pediatric patients often receive repeated examinations over time to evaluate their conditions, which could result in relatively high cumulative doses. Several cohort studies of girls and young women subjected to multiple diagnostic radiation exposures have been informative about increased mortality from breast cancer with increasing radiation dose, and case-control studies of childhood leukemia and postnatal diagnostic radiation exposure have suggested increased risks with an increasing number of examinations. Only two long-term follow-up studies of cancer following cardiac catheterization in childhood have been conducted, and neither reported an overall increased risk of cancer. Most cancers can be induced by radiation, and a linear dose-response has been noted for most solid cancers. Risks of radiation-related cancer are greatest for those exposed early in life, and these risks appear to persist throughout life.     

Radiation risks from imaging studies in children with cancer

Individuals exposed to high doses of ionizing radiation are known to be at risk of developing cancer. Recent reviews about the late effects of ionizing radiation indicate that even low doses of radiation can cause cancer. Significant radiation exposure occurs with commonly used imaging studies including CT scans, PET scans, and bone scans. Children with cancer, particularly those children with solid tumors, are exposed to frequent low doses of ionizing radiation from multiple imaging studies performed at initial diagnosis, throughout treatment, and during the follow-up period. This review provides estimates of cumulative radiation doses from imaging studies in children undergoing chemotherapy and/or surgery for various malignancies. Current risk estimates indicate that the radiation exposure from these imaging studies may be sufficient to increase the lifetime risk of cancer.     

Current developments in radiotherapy for paediatric brain tumours.

This review summarises current developments in radiation oncology and how they impact on the management of children with brain tumours. Improved understanding of radiobiology has led to attempts to improve the therapeutic ratio with hyperfractionated radiotherapy. Recent advances in planning and delivery of radiotherapy, including three-dimensional conformal radiotherapy, intensity modulated radiotherapy, and proton therapy allow a more precise localisation of the maximum dose region with maximum sparing of normal brain. Increasingly interactions between drugs and radiotherapy are exploited, but it is important to evaluate toxicity of combined modality therapy. The introduction of models to predict the impact of radiotherapy dose-volume parameters on long-term neuropsychological function will hopefully lead to further benefit with respect to sparing of normal tissue morbidity.     

Guidelines for pediatric cancer centers

Since the American Academy of Pediatrics published guidelines for pediatric cancer centers in 1986 and 1997, significant changes in the delivery of health care have prompted a review of the role of tertiary medical centers in the care of pediatric patients. The potential effect of these changes on the treatment and survival rates of children with cancer led to this revision. The intent of this statement is to delineate personnel and facilities that are essential to provide state-of-the-art care for children and adolescents with cancer. This statement emphasizes the importance of board-certified pediatric hematologists/oncologists, pediatric subspecialty consultants, and appropriately qualified pediatric medical subspecialists and pediatric surgical specialists overseeing the care of all pediatric and adolescent cancer patients and the need for facilities available only at a tertiary center as essential for the initial management and much of the follow-up for pediatric and adolescent cancer patients.     

Risk factors for cognitive decline in children treated for brain tumors

The long term effects of central nervous system therapy for children with brain tumors have been the subject of research since the 1970s. Many studies have demonstrated that children treated for brain tumors with surgery and standard radiation therapy have developed intellectual decline which is progressive over at least a decade. Risk factors for this cognitive deterioration have been identified and include perioperative complications, possibly hydrocephalus, high radiation dose, large volume radiation, chemotherapy (especially methotrexate), radiation vasculopathy and young age at the time of treatment. In an effort to reduce long-term neurotoxicity, efforts have been made to develop treatment regimens that reduce the impact of these risk factors. Some of these include reduced neuraxis radiation with and without adjuvant chemotherapy, conformal radiation, chemotherapy only protocols for children with optic pathway-hypothalamic tumors and a series of baby brain tumor studies in which chemotherapy (standard and high dose) has allowed radiation to be delayed, reduced or omitted. Whether these changes in therapy will ultimately improve the quality of life of the long-term survivors is uncertain. Close follow-up of these children will be required throughout their lives.     

Subsequent malignant neoplasms in survivors of childhood cancer: Childhood Cancer Survivor Study (CCSS) studies

Survival of children diagnosed with cancer has improved markedly, because of improvements in chemotherapy and radiation treatment protocols, better diagnosis, and risk classification and improved supportive care. Significant numbers of survivors are now entering their 30s and 40s, and data indicate that excess mortality continues in this group at least as long as 25 to 30 years after treatment. The Childhood Cancer Survivor Study (CCSS) is a large cohort study of 14,054 childhood cancer survivors who have been followed for over 13 years, with a median time from diagnosis now approaching 20 years. This cohort offers an extraordinary opportunity to study therapy-associated subsequent malignant neoplasms, and has allowed improved definition of incidence and risk factors for subsequent breast and thyroid cancer. The collection of genetic samples from members of the cohort has allowed the inclusion of studies of genetic susceptibility to subsequent malignant neoplasms in this population with a uniquely well-defined carcinogenic exposure. The planned formation of a new CCSS cohort, treated with more modern therapy, will allow the extension of these studies to younger populations and will define their experience of subsequent malignant neoplasms.     

Radiotherapy in the SIOP (international society of pediatric oncology) nephroblastoma studies: A review

For decades radiation has generally been accepted as a valuable supplement to surgery in the treatment of Wilms' tumor; unfortunately, it may produce undesirable late effects. It turned out, however, that when treatment is adjusted to known variables, the risk for late sequelae can be diminished in some groups of children. SIOP clinical trials have been based on children with unilateral tumors of standard histology and free of metastasis at diagnosis. The first two clinical trials, SIOP-1 (started in 1971) and SIOP-2 (started in 1974), established the beneficial effect (such as less ruptures, lower stage) of preoperative radiation and actinomycin D (AMD) in SIOP-2, with all children having radiation therapy either pre-operatively, postoperatively, or both. In the SIOP-5 trial (started in 1977), preoperative radiation therapy and AMD were compared with preoperative chemotherapy resulting in only 50% of children having radiation. The result permitted disuse of preoperative radiation in the SIOP-6 trial (started in 1980), where only one-third of the patients received postoperative radiation therapy. At present, in the SIOP-9 trial (started in 1987), fewer than 20% of children are having radiotherapy. The survival rates meanwhile have been increasing steadily from 64% in SIOP-1 to 84% in SIOP-6 for stages I, II, and III combined. © 1994 Wiley-Liss, Inc.