Proton beam irradiation in pediatric oncology: an overview

The greatest challenge for the treatment of children with cancer is to attain the highest probability of cure with the least morbidity. This has stimulated advances in radiotherapy technology. In recent literature published regarding proton radiation therapy (PRT) for pediatric cancer patients, PRT has been shown to have a distinct advantage over conventional photon therapy because of the ability to confine the high-dose treatment area to the tumor volume and minimize the radiation dose to the surrounding tissue. This is particularly important in children, in whom late effects of radiation to normal tissue can include developmental delay and increased risk of second malignant neoplasms. Several proton facilities are operating world-wide, and several medical centers in the United States and Europe are in the midst of planning and constructing new proton facilities. This may enlarge the role of radiation therapy in the multimodal management of children with cancer.     

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??Radiation therapy??RT?? is used to treat children with CNS tumors??solid tumors or Hodgkin lymphoma??including TBI. Pediatric radiation oncologists have provided critical input into the development and implementation of concepts for clinical trials to further define the modality’s role and test newer methods to reduce side effects or intensify therapy. The quality of pediatric oncology clinical trials that include radiation therapy is linked to the quality of guidelines. Radiation oncology is an adult medical specialty??thus??pediatric radiation oncologists are uniquely positioned to work with adult cancer investigators.     

Children's Oncology Group's 2013 blueprint for research: Radiation oncology

Radiation therapy (RT) is used to treat children with CNS tumors, solid tumors or Hodgkin lymphoma. Pediatric radiation oncologists have provided critical input into the development and implementation of concepts for clinical trials to further define the modality's role and test newer methods to reduce side effects or intensify therapy. The quality of pediatric oncology clinical trials that include radiation therapy is linked to the quality of guidelines. Radiation oncology is an adult medical specialty; thus, pediatric radiation oncologists are uniquely positioned to work with adult cancer investigators in the reorganized US National Cancer Institute Clinic Trials Network. Pediatr Blood Cancer 2013; 60: 1037–1043. © 2012 Wiley Periodicals, Inc.     

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.     

Germ cell tumours of the central nervous system in children-controversies in radiotherapy

BACKGROUND: Primary germ cell tumours (GCT) of the central nervous system (CNS) are rare tumours of children and adults. As few prospective, randomised trials have been published, management decisions are often based on retrospective and historical studies, histology, age, performance status, and extent of disease at diagnosis. This article reviews the current controversies in the radiotherapeutic management of primary GCT of the CNS. PROCEDURE: A computerised literature search was performed using the Medline database from 1975 to 2000, this being limited to publications written in the English language on CNS GCT in children up to the age of 16 years. RESULTS: Issues in radiation therapy currently undergoing review include the role of cranio-spinal irradiation (CSI), radiation therapy field sizes, the radiation therapy dose, the extent of surgery in combination with radiotherapy, and the role and timing of chemotherapy in combination with radiotherapy. CONCLUSIONS: The excellent outcome in children with pure germinoma of the CNS and the long-term morbidity associated with standard therapy justifies attempts to limit both the total radiation dose and field sizes, with or without the addition of chemotherapy. The poorer outcome associated with non-germinoma GCT justifies a more aggressive approach in children, combining chemotherapy, surgery and virgule, or radiation therapy, based on known prognostic factors.     

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.     

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.     

Training and education of pediatric radiation oncologists: A survey from the 2019 Pediatric Radiation Oncology Society meeting

To examine the educational background, clinical practice, and preferences regarding continuing medical education (CME) among radiation oncologists who attended the 2019 meeting of the Pediatric Radiation Oncology Society (PROS), a survey consisting of 20 questions was distributed asking for demographic and educational background, clinical practice, and preferences regarding pediatric radiation oncology CME. Of 188 participants, 130 (69.2%) returned the questionnaire. More than 80% reported access to CT simulation, three‐dimensional radiotherapy, and general anesthesia while <30% had access to intraoperative radiotherapy, proton, and heavy particle therapy. After residency, 12.1% did further training in pediatric radiation oncology. When asked about further training in pediatrics after residency, 88.8% answered that there should be a formal training program beyond residency in order to treat children. More than 75% acquired knowledge in pediatric radiation oncology through journals, books, live meetings, and tumor boards. The results of this survey may help Pediatric Radiation Oncology Society (PROS) in creating guidelines and recommendations for improvement in pediatric radiation oncology training and practice support as well as the development of CME activities most likely to benefit practitioners.     

A comprehensive review of 30 years of pediatric clinical trial radiotherapy dose constraints

Background

Radiation therapy normal tissue dose constraints are critical when treating pediatric patients. However, there is limited evidence supporting proposed constraints, which has led to variations in constraints over the years. In this study, we identify these variations in dose constraints within pediatric trials both in the United States and in Europe used in the past 30 years.

Procedure

All pediatric trials from the Children's Oncology Group website were queried from inception until January 2022 and a sampling of European studies was included. Dose constraints were identified and built into an organ-based interactive web application with filters to display data by organs at risk (OAR), protocol, start date, dose, volume, and fractionation scheme. Dose constraints were evaluated for consistency over time and compared between pediatric US and European trials

Results

One hundred five closed trials were included—93 US trials and 12 European trials. Thirty-eight separate OAR were found with high-dose constraint variability. Across all trials, nine organs had greater than 10 different constraints (median 16, range 11–26), including serial organs. When comparing US versus European dose tolerances, the United States constraints were higher for seven OAR, lower for one, and identical for five. No OAR had constraints change systematically over the last 30 years.

Conclusion

Review of pediatric dose-volume constraints in clinical trials showed substantial variability for all OAR. Continued efforts focused on standardization of OAR dose constraints and risk profiles are essential to increase consistency of protocol outcomes and ultimately to reduce radiation toxicities in the pediatric population.     

Image Gently: progress and challenges in CT education and advocacy

Significant progress has been made in radiation protection for children during the last 10 years. This includes increased awareness of the need for radiation protection for pediatric patients with international partnerships through the Alliance for Radiation Safety in Pediatric Imaging. This paper identifies five areas of significant progress in radiation safety for children: the growth of the Alliance; the development of an adult radiation protection campaign Image Wisely?; increased collaboration with government agencies, societies and the vendor community; the development of national guidelines in pediatric nuclear medicine, and the development of a size-based patient dose correction factor by the American Association of Physicists in Medicine, Task Group 204. However, many challenges remain. These include the need for continued education and change of practice at adult-focused hospitals where many pediatric CT exams are performed; the need for increased emphasis on appropriateness of pediatric imaging and outcomes research to validate the performance of CT studies, and the advancement of the work of the first pediatric national dose registry to determine the "state of the practice" with the final goal of establishing ranges of optimal CT technique for specific scan indications when imaging children with CT.     

Radiation doses in pediatric radiology: influence of regulations and standards

The benefits of x-ray examinations contribute to the quality of modern medicine; however the risk of using x-rays, a carcinogen, has always been a concern. This concern is heightened for pediatric patients, who have a much greater sensitivity to the carcinogenic effects of radiation than adults. The principle of as low as reasonably achievable, or ALARA, is essential for minimizing the radiation dose patients receive, especially for pediatric patients. In order to keep radiation doses ALARA, one must know the dose patients receive. The determination of radiation dose in a standard way is therefore necessary so that these doses can be compared with practice, and for meaningful comparison against voluntary standards. In extreme situations, where public health needs may require mandatory standards, or regulations, the quantitative measurement and calculation of radiation dose becomes essential. How some radiation dose metrics and standards have evolved, including the value of different metrics such as entrance air kerma, organ dose, and effective dose will be presented. Recent pediatric x-ray studies, whether or not dedicated pediatric equipment is necessary, and recent initiatives by the Food and Drug Administration for pediatric population will be discussed.     

Central nervous system pharmacology of antileukemic drugs

The blood-brain barrier provides a pharmacologic sanctuary for leukemic cells within the central nervous system (CNS), protecting them from the cytotoxic effects of systemic antileukemic therapy. Attempts to overcome this problem have included specific CNS-directed treatment in the form of direct intrathecal drug injection, cranial irradiation, and alteration in the dose and schedule of systemic agents to enhance their CNS penetration. Use of these treatments and strategies has led to the effective prevention and control of meningeal leukemia. Intrathecal therapy, primarily with methotrexate or cytosine arabinoside, is a form of regional chemotherapy that can achieve very high drug concentrations at the target site [i.e., in the meninges and cerebrospinal fluid (CSF)] with a low total dose. Therefore, there is minimal systemic toxicity. The dose and schedules, clinical pharmacology, and toxicities of the commonly used intrathecal agents are discussed in detail in this article. Another approach to overcoming the limited penetration of antileukemic drugs into the CNS has been the use of high-dose systemic therapy. Methotrexate and cytosine arabinoside in high doses have produced favorable clinical responses in patients with overt meningeal disease, and pharmacokinetic studies have documented cytotoxic concentrations of these drugs within the cerebrospinal fluid. A clear understanding of the CNS pharmacology of the antileukemic drugs is required in order to use these agents in the safest and most efficacious manner for the treatment of meningeal leukemia.     

Neuro-ocular damage in pediatric oncology patients: predictor of long-term visual disability or tool for limiting toxicity?

We present a group of eight pediatric cancer patients with a spectrum of visual afferent pathway abnormalities. Changes include decreased visual acuity, visual field alterations, abnormal visual evoked potentials, changes in the optic disc and nerve fiber layer of the retina, radiation retinopathy, and CNS injury. These changes occur in long term survivors of pediatric malignancy (especially those with prolonged, multimodal, and multicourse therapy), but they may be minimally symptomatic. The changes appear to be analogous to the CNS changes (leukoencephalopathy) described in patients with leukemia and attributed to multimodal therapy. By taking advantage of opportunities to detect adverse effects earlier in the treatment course, the present excellent cure rate may be improved by refinements in therapy that also improve the quality of survival.     

Dosisreduzierte Multidetektorcomputertomographie (MDCT) in der Kinderradiologie

During the past decades technical innovations have improved image quality of multidetector computed tomography (MDCT) leading to an enormous expansion of clinical applications worldwide. The major drawback of MDCT is radiation exposure which might lead to induction of secondary malignancies thus limiting its use within the pediatric age group. Reasonable application of MDCT in pediatric radiology always presumes clinical justification and optimization of scanning protocols in order to lower radiation dose applied to the patient. Whenever possible, image procedures without radiation exposure including ultrasound and MRI should be preferred. If a pediatric MDCT study is indicated, individual adjustment of acquisition parameters should be warranted to ensure optimal balance of sufficient image quality and dose reduction. Moreover, application of contrast agents must be used with caution in the pediatric age group.     

Management of pediatric radiation dose using Philips digital radiography

Digital radiography systems based on flat-panel detectors have been introduced into clinical practice in the past few years. The high detective quantum efficiency of these detectors allows the radiation dose to be reduced while maintaining image quality, an issue particularly significant for pediatric radiography. Another important aspect for dose optimization and monitoring is the integration of the detector into a computer-controlled x-ray examination system. This enables full control and complete reporting of all dose-relevant exposure parameters, including the determination of the exposure indicator and the patient dose (kerma-area product). In this paper the implementation of these principles in the Philips Digital Diagnost DR system is described and their relevance for pediatric applications is discussed.     

Use of the Ommaya reservoir in the prevention and treatment of CNS leukemia—an update

The prophylaxis of the CNS in ALL with intraventricular methotrexate therapy via an Ommaya reservoir in 18 patients resulted in a reduction of the CNS relapse rate to 11% with a 6-10+ year follow-up. This procedure proved to be safe and effective in our hands, but with newer, equally effective and less invasive methods of CNS prophylaxis now available, its use is no longer indicated. Intraventricular therapy via the Ommaya reservoir was also evaluated for its role in improving CNS remission duration after a leukemic recurrence in the CSF. The treatment of CNS relapse with intraventricular chemotherapy and low dose (600r) neuraxis radiation is encouraging. Of the ten patients treated for CNS leukemia, three are long-term (8-11+ years) survivors. Isolated CNS relapse occurred in three. The median CNS disease-free survival and the median relapse-free survival are 39 months and 21 months respectively.     

Effects of radiotherapy on the growth of children with leukemia

The five-year over all survival rates of childhood lymphoblastic leukemia (ALL) have recently increased to more than 80%. During recent years, CNS radiation doses delivered to all children with ALL according to international guideline protocols have decreased. In the 1980s, the prophylactic radiation dose to the CNS decreased from 2400 cGy to 1800 cGy; in the 1990s chemotherapy alone with intrathecal chemotherapy demonstrated that there was no need for prophylactic CNS radiation in standard risk ALL, except in CNS relapse and high risk patients. Late effects on pituitary function and growth were reported by most endocrinologists involved in the follow-up of the cancer survivors. The long-term effects of cranial irradiation on growth in children treated for ALL are reviewed, specifically addressing the deficit in final height, contributing factors for height deficits, growth catch-up after stopping therapy, and growth hormone replacement therapy.     

Intraventricular rituximab and systemic chemotherapy for treatment of central nervous system post-transplant lymphoproliferative disorder after kidney transplantation

Twombley K, Pokala H, Ardura MI, Harker-Murray P, Johnson-Welch SF, Weinberg A, Seikaly M. Intraventricular rituximab and systemic chemotherapy for treatment of central nervous system post-transplant lymphoproliferative disorder after kidney transplantation. Abstract: PTLD of the CNS is a rare complication of solid organ transplantation, and there are only case reports/series available in the literature. Current literature suggests that CNS PTLD carries a worse prognosis than PTLD outside the CNS, and most are of B-cell lineage, predominately monomorphic, and are associated with EBV infection. Because this disorder is so rare, there is no standard chemotherapy for pediatric patients with CNS PTLD and reported therapies for EBV-associated CNS PTLD are heterogeneous with mixed results. Since outcomes of CNS PTLD are historically poor, we attempted to develop a novel therapeutic treatment regimen. Based on a review of the literature and with the help of a multidisciplinary team, we created a regimen of chemotherapy that included dexamethasone and high-dose methotrexate in addition to intravenous and intraventricular Rituximab in two pediatric patients. The intraventricular chemotherapy succeeded in shrinking the tumor in both of our patients; however, as shown in the second case, the clinical outcome depends on the location of the tumor. Systemic and intraventricular therapies hold promise in the management of EBV-associated CNS PTLD; however the rarity of this entity prevents the development of well-designed studies necessary for the establishment of an evidence-based treatment standard.     

小儿急性淋巴细胞白血病中枢神经系统白血病诊治现状

中枢神经系统白血病(CNSL)的防治是小儿急性淋巴细胞白血病(ALL)治疗的一部分。诊断时高白细胞计数、T细胞型及分子遗传学为t(4;11)和Ph 是CNS复发的危险因素,脑脊液不同检查结果的预后价值有待明确。头颅放疗已不用于标危ALL患儿,头颅放疗的预防剂量已减为12Gy,鞘内及全身化疗对CNSL的治疗有重要作用。部分小儿CNS复发经挽救治疗可以长期存活,早期CNS复发的患儿应在第2次CR期进行异基因骨髓移植。     

Pediatric Burkitt's Lymphoma and Diffuse B-Cell Lymphoma: Are Surveillance Scans Required?

Outcomes in pediatric B-Non-Hodgkin Lymphoma (B NHL) have improved with intensive chemotherapy protocols, with long-term survival now over 80%. However, long-term adverse effects of therapy and poor outcomes for patients who relapse remain challenges. In this study, we aimed to evaluate the potential risks and benefits of routine relapse surveillance imaging after the completion of therapy. We reviewed 44 B NHL patients diagnosed and treated at Texas Children's Cancer Center in the period between 2000 to 2011. All cross-sectional diagnostic imaging examinations performed for disease assessment after completion of chemotherapy were reviewed and cumulative radiation dosage from these examinations and the frequency of relapse detection by these examinations were recorded. Only 3 patients of the 44 relapsed (6.8%), though none of the relapses were initially diagnosed by computed tomography (CT) or fludeoxyglucose positron emission tomography (FDG-PET) scans. Median effective dose of ionizing radiation per patient was 40.3 mSv with an average of 49.1 mSv (range 0–276 mSv). This single-institution study highlights the low relapse rate in pediatric B-NHL with complete response at the end of therapy, the low sensitivity of early detection of relapse with surveillance CT or FDG-PET imaging, and the costs and potential increased risk of secondary malignancies from cumulative radiation exposure from surveillance imaging. We propose that routine surveillance CT or FDG-PET scans for these patients may not be necessary.