The Evolving Classification of Meningiomas: Integration of Molecular Discoveries to Inform Patient Care.

Meningioma classification and treatment have evolved over the past eight decades. Since Bailey, Cushing, and Eisenhart's description of meningiomas in the 1920s and 1930s, there have been continual advances in clinical stratification by histopathology, radiography and, most recently, molecular profiling, to improve prognostication and predict response to therapy. Precise and accurate classification is essential to optimizing management for patients with meningioma, which involves surveillance imaging, surgery, primary or adjuvant radiotherapy, and consideration for clinical trials. Currently, the World Health Organization (WHO) grade, extent of resection (EOR), and patient characteristics are used to guide management. While these have demonstrated reliability, a substantial number of seemingly benign lesions recur, suggesting opportunities for improvement of risk stratification. Furthermore, the role of adjuvant radiotherapy for grade 1 and 2 meningioma remains controversial. Over the last decade, numerous studies investigating the molecular drivers of clinical aggressiveness have been reported, with the identification of molecular markers that carry clinical implications as well as biomarkers of radiotherapy response. Here, we review the historical context of current practices, highlight recent molecular discoveries, and discuss the challenges of translating these findings into clinical practice.

Predictors of salvage therapy for parasagittal meningiomas treated with primary surgery, radiosurgery, or surgery plus adjuvant radiotherapy.

OBJECTIVE: Parasagittal meningiomas (PM) are treated with primary microsurgery, radiosurgery (SRS), or surgery with adjuvant radiation. We investigated predictors of tumor progression requiring salvage surgery or radiation treatment. We sought to determine whether primary treatment modality, or radiologic, histologic, and clinical variables were associated with tumor progression requiring salvage treatment. METHODS: Retrospective study of 109 consecutive patients with PMs treated with primary surgery, radiation (RT), or surgery plus adjuvant RT (2000-2017) and minimum 5 years follow-up. Patient, radiologic, histologic, and treatment data were analyzed using standard statistical methods. RESULTS: Median follow up was 8.5 years. Primary treatment for PM was surgery in 76 patients, radiation in 16 patients, and surgery plus adjuvant radiation in 17 patients. Forty percent of parasagittal meningiomas in our cohort required some form of salvage treatment. On univariate analysis, brain invasion (OR: 6.93, p < 0.01), WHO grade 2/3 (OR: 4.54, p < 0.01), peritumoral edema (OR: 2.81, p = 0.01), sagittal sinus invasion (OR: 6.36, p < 0.01), sagittal sinus occlusion (OR: 4.86, p < 0.01), and non-spherical shape (OR: 3.89, p < 0.01) were significantly associated with receiving salvage treatment. On multivariate analysis, superior sagittal sinus invasion (OR: 8.22, p = 0.01) and WHO grade 2&3 (OR: 7.58, p < 0.01) were independently associated with receiving salvage treatment. There was no difference in time to salvage therapy (p = 0.11) or time to progression (p = 0.43) between patients receiving primary surgery alone, RT alone, or surgery plus adjuvant RT. Patients who had initial surgery were more likely to have peritumoral edema on preoperative imaging (p = 0.01). Median tumor volume was 19.0 cm3 in patients receiving primary surgery, 5.3 cm3 for RT, and 24.4 cm3 for surgery plus adjuvant RT (p < 0.01). CONCLUSION: Superior sagittal sinus invasion and WHO grade 2/3 are independently associated with PM progression requiring salvage therapy regardless of extent of resection or primary treatment modality. Parasagittal meningiomas have a high rate of recurrence with 80.0% of patients with WHO grade 2/3 tumors with sinus invasion requiring salvage treatment whereas only 13.6% of the WHO grade 1 tumors without sinus invasion required salvage treatment. This information is useful when counseling patients about disease management and setting expectations.

Bilateral Wilms tumor with anaplasia: A report from the Children's Oncology Group Study AREN0534.

INTRODUCTION: The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas to target in future clinical trials. METHODS: Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia [FA], or diffuse anaplasia [DA]) were compared. Event-free survival (EFS) and overall survival (OS) were reported using Kaplan-Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log-rank tests. The impact of margin status was analyzed. RESULTS: Twenty-seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty-six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty-six percent with BWT had bilateral nephron-sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow-up for EFS and OS was 8.6 and 8.7 years from enrollment. Four- and 8-year EFS was 53% [95% confidence interval (CI): 34%-83%] for DA; 4-year EFS was 80% [95% CI: 59%-100%], and 8-year EFS 70% [95% CI: 47%-100%] for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p = .79; HR = 0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18 months. CONCLUSION: Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed.

Treatment and outcomes of clear cell sarcoma of the kidney: A report from the Children's Oncology Group studies AREN0321 and AREN03B2.

BACKGROUND: On the fifth National Wilms Tumor Study, treatment for clear cell sarcoma of the kidney (CCSK) included combined vincristine, doxorubicin, cyclophosphamide, and etoposide (regimen I) plus radiation therapy (RT), yielding 5-year event-free survival (EFS) rates of 100%, 88%, 73%, and 29% for patients who had with stage I, II, III, and IV disease, respectively. In the Children's Oncology Group study AREN0321 of risk-adapted therapy, RT was omitted for stage I disease if lymph nodes were sampled, and carboplatin was added for stage IV disease (regimen UH-1). Patients who had stage II/III disease received regimen I with RT. METHODS: Four-year EFS was analyzed for patients enrolled on AREN0321 and on those enrolled on AREN03B2 who received AREN0321 stage-appropriate chemotherapy. RESULTS: Eighty-two patients with CCSK enrolled on AREN0321, 50 enrolled on AREN03B2 only. The 4-year EFS rate was 82.7% (95% confidence interval [CI], 74.8%-91.4%) for AREN0321 and 89.6% (95% CI, 81.3%-98.7%) for AREN03B2 only (p = .28). When combining studies, the 4-year EFS rates for patients who had stage I (n = 10), II (n = 47), III (n = 65), and IV (n = 10) disease were 90% (95% CI, 73.2%-100.0%), 93.4% (95% CI, 86.4%-100.0%), 82.8% (95% CI, 74.1%-92.6%), and 58.3% (95% CI, 34%-100.0%), respectively. There were no local recurrences among seven patients with stage I disease who were treated without RT. One stage I recurrence occurred in the brain, which was the most common site of relapse overall. Among patients with local stage III tumors, neither initial procedure type, margin status, nor lymph node involvement were prognostic. CONCLUSIONS: Patients with stage I CCSK had excellent outcomes without local recurrences when treated without RT. Patients with stage IV disease appeared to benefit from a carboplatin-containing regimen, although their outcomes remained unsatisfactory. Further research is needed to improve outcomes for patients with advanced-stage disease (ClinicalTrials.gov identifiers NCT00335556 and NCT00898365).

Children's Oncology Group's 2023 blueprint for research: Radiation oncology.

Radiation oncology is an integral part of the multidisciplinary team caring for children with cancer. The primary goal of our committee is to enable the delivery of the safest dose of radiation therapy (RT) with the maximal potential for cure, and to minimize toxicity in children by delivering lower doses to normal tissues using advanced technologies like intensity-modulated RT (IMRT) and proton therapy. We provide mentorship for y ators and are actively involved in educating the global radiation oncology community. We are leaders in the effort to discover novel radiosensitizers, radioprotectors, and advanced RT technologies that could help improve outcomes of children with cancer.

Impact of Age on Overall Survival Among Children With Wilms Tumor: A Population-based Registry Analysis.

OBJECTIVES: International trials have reported conflicting findings on whether the association between age and worse overall survival (OS) among children with Wilms tumor (WT) is due to age as an independent prognostic factor or the observation of more advanced disease at older ages. We sought to further elucidate this relationship using a population-based registry analysis. METHODS: The Surveillance, Epidemiology, and End Results database was queried for all patients diagnosed with WT under the age of 20. The association between age and OS was assessed using multivariable Cox proportional hazards regression. RESULTS: In this study, 3463 patients (54% female) were diagnosed with WT between 1975 and 2016. More advanced stage, larger primary tumor size, lymph node involvement, disease requiring radiotherapy, and omission of surgery were associated with worse OS ( P <0.05). More advanced stage, larger primary tumor size, and disease requiring radiotherapy were also associated with older age, whereas bilateral disease was associated with younger age ( P <0.001). On average, each year of age conferred an incremental hazard ratio (HR) of 1.07 (95% CI, 1.01 to 1.12, P =0.018) independent of relevant covariates. The rise in adjusted OS HR was most pronounced after the transitions in diagnosis age from 2 to 3 (HR age 3-15 vs. 0-2 1.77, 95% CI, 1.11 to 2.82, P =0.016) and from 15 to 16 (HR age 16-19 vs. 3-15 2.58, 95% CI, 1.06 to 6.25, P =0.036). CONCLUSIONS: Diagnosis of pediatric WT at an older age was found to be independently associated with worse OS. Although additional prospective studies are warranted to examine tumor biology and other potential correlates, more aggressive treatment of older children based on age, especially as they approach early adulthood, may be considered in the multidisciplinary management of WT.

Imaging of GBM in the Age of Molecular Markers and MRI Guided Adaptive Radiation Therapy.

Glioblastoma (GBM) continues to be one of the most lethal malignancies and is almost always fatal. In this review article, the role of radiation therapy, systemic therapy, as well as the molecular basis of classifying GBM is described. Technological advances in the treatment of GBM are outlined as well as the diagnostic imaging characteristics of this tumor. In addition, factors that affect prognosis such as differentiating progression from treatment effect is discussed. The role of MRI guided radiation therapy and how this technology may provide a mechanism to improve the care of patients with this disease are described.

Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric BRAFV600E Brain Tumor Models.

PURPOSE: We investigated why three patient-derived xenograft (PDX) childhood BRAFV600E-mutant brain tumor models are highly sensitive to trametinib. Mechanisms of acquired resistance selected in situ, and approaches to prevent resistance were also examined, which may translate to both low-grade glioma (LGG) molecular subtypes. EXPERIMENTAL DESIGN: Sensitivity to trametinib [MEK inhibitor (MEKi)] alone or in combination with rapamycin (TORC1 inhibitor), was evaluated in pediatric PDX models. The effect of combined treatment of trametinib with rapamycin on development of trametinib resistance in vivo was examined. PDX tissue and tumor cells from trametinib-resistant xenografts were characterized. RESULTS: In pediatric models TORC1 is activated through ERK-mediated inactivation of the tuberous sclerosis complex (TSC): consequently inhibition of MEK also suppressed TORC1 signaling. Trametinib-induced tumor regression correlated with dual inhibition of MAPK/TORC1 signaling, and decoupling TORC1 regulation from BRAF/MAPK control conferred trametinib resistance. In mice, acquired resistance to trametinib developed within three cycles of therapy in all three PDX models. Resistance to trametinib developed in situ is tumor-cell-intrinsic and the mechanism was tumor line specific. Rapamycin retarded or blocked development of resistance. CONCLUSIONS: In these three pediatric BRAF-mutant brain tumors, TORC1 signaling is controlled by the MAPK cascade. Trametinib suppressed both MAPK/TORC1 pathways leading to tumor regression. While low-dose intermittent rapamycin to enhance inhibition of TORC1 only modestly enhanced the antitumor activity of trametinib, it prevented or retarded development of trametinib resistance, suggesting future therapeutic approaches using rapamycin analogs in combination with MEKis that may be therapeutically beneficial in both KIAA1549::BRAF- and BRAFV600E-driven gliomas.

Mean Brain Dose Remains Uninfluenced by the Lesion Number for Gamma Knife Stereotactic Radiosurgery for 10+ Metastases.

OBJECTIVE: Gamma Knife (GK) stereotactic radiosurgery (SRS) is increasingly used as an initial treatment for patients with 10 or more brain metastases. However, the clinical and dosimetric consequences of this practice are not well established. METHODS: We performed a single-institution, retrospective analysis of 30 patients who received Gamma Knife SRS for 10 or more brain metastases in 1 session. We utilized MIM Software to contour the whole brain and accumulated the doses from all treated lesions to determine the mean dose delivered to the whole brain. Patient outcomes were determined from chart review. RESULTS: Our cohort had a median number of 13 treated lesions (range 10-26 lesions) for a total of 427 treated lesions. The mean dose to the whole brain was determined to be 1.8 ± 0.91 Gy (range 0.70-3.8 Gy). The mean dose to the whole brain did not correlate with the number of treated lesions (Pearson r = 0.23, P = 0.21), but was closely associated with tumor volume (Pearson r = 0.95, P < 0.0001). There were no significant correlations between overall survival and number of lesions or aggregate tumor volume. Fourteen patients (47%) underwent additional SRS sessions and 6 patients (20%) underwent whole-brain radiotherapy with a median of 6.6 months (range 3.0-50 months) after SRS. Two patients (6.6%) developed grade 2 radionecrosis following SRS beyond earlier whole-brain radiotherapy. CONCLUSION: The mean dose to the whole brain in patients treated with Gamma Knife SRS for 10 or more brain metastases remained low with an acceptable rate of radionecrosis. This strategy allowed the majority of patients to avoid subsequent whole-brain radiotherapy.

Outcomes based on histopathologic response to preoperative chemotherapy in children with bilateral Wilms tumor: A prospective study (COG AREN0534).

BACKGROUND: An objective of the Children's Oncology Group AREN0534 Study was to improve the survival of patients with bilateral Wilms tumors (BWT) by using preoperative chemotherapy of limited duration and tailoring postoperative therapy based on histopathologic response. The authors report outcomes based on postoperative histopathologic responses. METHODS: Patients with BWT received treatment with vincristine, dactinomycin, and doxorubicin for 6 or 12 weeks followed by surgery. Postoperative therapy was prescribed based on the highest risk tumor according to the International Society of Pediatric Oncology classification and the Children's Oncology Group staging system. RESULTS: Analyses were performed on data from 180 evaluable children. The 4-year event-free survival (EFS) and overall survival (OS) rates were 81% (95% CI, 74%-87%) and 95% (95% CI, 91%-99%), respectively. Seven patients who had completely necrotic tumors had a 4-year EFS rate of 100%. Of 118 patients who had tumors with intermediate-risk histopathology, the 4-year EFS and OS rates were 82% (95% CI, 74%-90%) and 97% (95% CI, 94%-100%), respectively. Fourteen patients who had blastemal-type tumors had 4-year EFS and OS rates of 79% (95% CI, 56%-100%) and 93% (95% CI, 79%-100%), respectively. Eighteen patients who had diffuse anaplasia had 4-year EFS and OS rates of 61% (95% CI, 35%-88%) and 72% (95% CI, 47%-97%), respectively; and the 4-year EFS and OS rates of 7 patients who had focal anaplasia were 71% (95% CI, 38%-100%) and 100%, respectively. There was no difference in the outcomes of patients who had different histopathologic subtypes within the intermediate-risk group (P = .54). CONCLUSIONS: A risk-adapted treatment approach for BWT results in excellent outcomes. This approach was not successful in improving the outcome of patients who had diffuse anaplasia.

Kidney Preservation and Wilms Tumor Development in Children with Diffuse Hyperplastic Perilobar Nephroblastomatosis: A Report from the Children's Oncology Group Study AREN0534.

INTRODUCTION: Diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) represents a unique category of nephroblastomatosis. Treatment has ranged from observation to multiple regimens of chemotherapy. Wilms tumors (WTs) develop in 100% of untreated patients and between 32 and 52% of treated patients. Renal preservation rates have not been previously reported. An aim of the Children's Oncology Group (COG) study AREN0534 was to prospectively evaluate the efficacy of chemotherapy in preserving renal units and preventing WT development in children with DHPLN. METHODS: Patients were enrolled through the COG protocol AREN03B2 with central radiological review. DHPLN was defined as the cortical surface of the kidney being composed of hyperplastic rests, with the entire nephrogenic zone involved, and with a thick rind capping all of one or both kidneys. Treatment was with vincristine and dactinomycin (regimen EE4A), with cross-sectional imaging at weeks 6 and 12. If the patient's disease was stable or decreasing, treatment was continued for 19 weeks. Renal preservation, WT development rates at 1 year, and overall survival (OS) are reported. RESULTS: Nine patients were enrolled (five females and four males), with a median age at enrollment of 10.22 months (range 2.92-29.11). One patient who was enrolled was deemed unevaluable because they did not meet the radiological criteria for DHPLN, resulting in eight evaluable patients. These eight patients had DHPLN confirmed via radiological criteria (all bilateral). Initial chemotherapy was EE4A for all eight patients, with seven of eight patients starting chemotherapy without tissue diagnosis.One patient who had an upfront partial nephrectomy was found to have DHPLN in the specimen and was subsequently treated with EE4A. All patients remained alive, with a median follow-up of 6.6 years (range 4.5-9.1). No patients were anephric; 14 of 16 kidneys were functioning (87.5%). Six of eight patients (75%) did not have WT on therapy, but two of these patients relapsed within 6 months of stopping therapy; both had favorable histology WT. One patient who was diagnosed with WT on therapy relapsed at 12 months (one of eight [12.5%]) and developed anaplastic histology. CONCLUSIONS: Chemotherapy for patients with DHPLN was effective in preserving kidney function. Five-year OS is excellent, however the ideal type and duration of chemotherapy to prevent WT development remains elusive.

The effects of palbociclib in combination with radiation in preclinical models of aggressive meningioma.

BACKGROUND: Meningiomas are the most common tumor arising within the cranium of adults. Despite surgical resection and radiotherapy, many meningiomas invade the brain, and many recur, often repeatedly. To date, no chemotherapy has proven effective against such tumors. Thus, there is an urgent need for chemotherapeutic options for treating meningiomas, especially those that enhance radiotherapy. Palbociclib is an inhibitor of cyclin-dependent kinases 4 and 6 that has been shown to enhance radiotherapy in preclinical models of other cancers, is well-tolerated in patients, and is used to treat malignancies elsewhere in the body. We, therefore, sought to determine its therapeutic potential in preclinical models of meningioma. METHODS: Patient-derived meningioma cells were tested in vitro and in vivo with combinations of palbociclib and radiation. Outputs included cell viability, apoptosis, clonogenicity, engrafted mouse survival, and analysis of engrafted tumor tissues after therapy. RESULTS: We found that palbociclib was highly potent against p16-deficient, Rb-intact CH157 and IOMM-Lee meningioma cells in vitro, but was ineffective against p16-intact, Rb-deficient SF8295 meningioma cells. Palbociclib also enhanced the in vitro efficacy of radiotherapy when used against p16-deficient meningioma, as indicated by cell viability and clonogenic assays. In vivo, the combination of palbociclib and radiation extended the survival of mice bearing orthotopic p16 deficient meningioma xenografts, relative to each as a monotherapy. CONCLUSIONS: These data suggest that palbociclib could be repurposed to treat patients with p16-deficient, Rb-intact meningiomas, and that a clinical trial in combination with radiation therapy merits consideration.

Practice Patterns of Pediatric Total Body Irradiation Techniques: A Children's Oncology Group Survey.

PURPOSE: The aim of this study was to examine current practice patterns in pediatric total body irradiation (TBI) techniques among COG member institutions. METHODS AND MATERIALS: Between November 2019 and February 2020, a questionnaire containing 52 questions related to the technical aspects of TBI was sent to medical physicists at 152 COG institutions. The questions were designed to obtain technical information on commonly used TBI treatment techniques. Another set of 9 questions related to the clinical management of patients undergoing TBI was sent to 152 COG member radiation oncologists at the same institutions. RESULTS: Twelve institutions were excluded because TBI was not performed in their institutions. A total of 88 physicists from 88 institutions (63% response rate) and 96 radiation oncologists from 96 institutions (69% response rate) responded. The anterior-posterior/posterior-anterior (AP/PA) technique was the most common technique reported (49 institutions [56%]); 44 institutions (50%) used the lateral technique, and 14 (16%) used volumetric modulated arc therapy or tomotherapy. Midplane dose rates of 6 to 15 cGy/min were most commonly used. The most common specification for lung dose was the midlung dose for both AP/PA techniques (71%) and lateral techniques (63%). Almost all physician responders agreed with the need to refine current TBI techniques, and 79% supported the investigation of new TBI techniques to further lower the lung dose. CONCLUSIONS: There was no consistency in the practice patterns, methods for dose measurement, and reporting of TBI doses among COG institutions. The lack of standardization precludes meaningful correlation between TBI doses and clinical outcomes including disease control and normal tissue toxicity. The COG radiation oncology discipline is currently undertaking several steps to standardize the practice and dose reporting of pediatric TBI using detailed questionnaires and phantom-based credentialing for all COG centers.

Impact of the First Generation of Children's Oncology Group Clinical Trials on Clinical Practice for Wilms Tumor.

Refinements in surgery, radiation therapy, and chemotherapy since the mid-20th century have resulted in a survival rate exceeding 90% for patients with Wilms tumor (WT). Although this figure is remarkable, a significant proportion of patients continue to have event-free survival (EFS) estimates of <75%, and nearly 25% of survivors experience severe chronic medical conditions. The first-generation Children's Oncology Group (COG) renal tumor trials (AREN '0'), which opened to enrollment in 2006, focused on augmenting treatment regimens for WT subgroups with predicted EFS <75% to 80%, including those with the adverse prognostic marker of combined loss of heterozygosity (LOH) at chromosomes 1p/16q, pulmonary metastasis with incomplete lung nodule response after 6 weeks of chemotherapy, bilateral disease, and anaplastic histology. Conversely, therapy was reduced for patient subgroups with good outcomes and potential for long-term toxicity, such as those with lung metastasis with complete lung nodule response after 6 weeks of chemotherapy. This article summarizes the key findings of the first-generation COG renal tumor studies and their implications for clinical practice.

Adaptability and Resilience of Academic Radiation Oncology Personnel and Procedures during COVID-19 Pandemic.

BACKGROUND: A comprehensive response to the unprecedented SARS-CoV-2 (COVID-19) challenges for public health and its impact on radiation oncology patients and personnel for resilience and adaptability is presented. METHODS: The general recommendations included working remotely when feasible, implementation of screening/safety and personal protective equipment (PPE) guidelines, social distancing, regular cleaning of treatment environment, and testing for high-risk patients/procedures. All teaching conferences, tumor boards, and weekly chart rounds were conducted using a virtual platform. Additionally, specific recommendations were given to each section to ensure proper patient treatments. The impact of these measures, especially adaptability and resilience, were evaluated through specific questionnaire surveys. RESULTS: These comprehensive COVID-19-related measures resulted in most staff expressing a consistent level of satisfaction in regard to personal safety, maintaining a safe work environment, continuing quality patient care, and continuing educational activities during the pandemic. There was a significant reduction in patient treatments and on-site patient visits with an appreciable increase in the number of telemedicine e-visits. CONCLUSIONS: Survey results demonstrated substantial adaptability and resilience, including in the rapid recovery of departmental activities during the reactivation phase. In the event of a future public health emergency, the measures implemented may be adopted with good outcomes by radiation oncology departments across the globe.

Palliative radiation therapy for children with cancer.

Radiation therapy (RT) is often used as a palliative treatment for children with recurrent malignant disease to ameliorate or prevent symptoms. However, no guidelines exist regarding the clinical indications or dose fractionation for palliative RT. The goal of this report is to provide guidelines for the use of palliative RT in children with cancer. In this guideline, appropriate indications for palliative RT, recommended dose-fractionation schedules, relevant toxicities, and avenues for future research are explored. RT is an effective palliative treatment for bone, brain, liver, lung, abdominopelvic and head-and-neck metastases, spinal cord compression, superior vena cava syndrome, and bleeding. Single-fraction regimens (8 Gy in one fraction) for children with short life expectancy are recommended for simple, uncomplicated bone metastases and can be considered for some patients with lung or liver metastases. A short, hypofractionated regimen (20 Gy in five fractions) may be used for other indications to minimize overall burden of therapy. There are little data supporting use of more prolonged fractionation regimens, though they may be considered for patients with very good performance status. Future research should focus on response and outcomes data collection, and to rigorously evaluate the role of stereotactic body RT in well-designed, prospective studies.

Radiation therapy and molecular-targeted agents in preclinical testing for immunotherapy, brain tumors, and sarcomas: Opportunities and challenges.

Despite radiation therapy (RT) being an integral part of the treatment of most pediatric cancers and the recent discovery of novel molecular-targeted agents (MTAs) in this era of precision medicine with the potential to improve the therapeutic ratio of modern chemoradiotherapy regimens, there are only a few preclinical trials being conducted to discover novel radiosensitizers and radioprotectors. This has resulted in a paucity of translational clinical trials combining RT and novel MTAs. This report describes the opportunities and challenges of investigating RT together with MTAs in preclinical testing for immunotherapy, brain tumors, and sarcomas in pediatric oncology. We discuss the need for improving the collaboration between radiation oncologists, biologists, and physicists to improve the reliability, reproducibility, and translational potential of RT-based preclinical research. Current translational clinical trials using RT and MTAs for immunotherapy, brain tumors, and sarcomas are described. The technologic advances in experimental RT, availability of novel experimental tumor models, advances in immunology and tumor biology, and the discovery of novel MTAs together hold considerable promise for good quality preclinical and clinical multimodality research to improve the current rates of survival and toxicity in children afflicted with cancer.