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The treatment for favorable-prognosis stage I and II Hodgkin's lymphoma has evolved over the past several years. Studies have attempted to reduce long-term treatment-related side effects, such as second malignancies and cardiac toxicity, through reduced chemotherapy or reduced radiotherapy. Randomized trials have compared radiation therapy alone with combined-modality therapy (chemotherapy followed by involved-field radiotherapy). Recent and ongoing trials have evaluated the optimal regimen and number of cycles of chemotherapy and the optimal radiotherapy dose and field size as part of combined-modality therapy, as well as the elimination of radiation therapy. Combined-modality therapy represents the current standard of care for most patients with favorable-prognosis early-stage Hodgkin's lymphoma. Chemotherapy alone could also be an option for selected patients who are at low risk for relapse and high risk for late effects from radiotherapy. This article reviews recent and ongoing studies on treatment for favorable-prognosis early stage Hodgkin's lymphoma. Representative clinical cases are presented, with treatment recommendations from an expert panel of radiation oncologists and medical oncologists. [ABSTRACT FROM AUTHOR]

Radiotherapy is routinely used for management of limited-stage follicular lymphoma (FL), yet half of patients ultimately relapse. We hypothesized that the presence of specific gene mutations may predict outcomes. We performed targeted sequencing of a 69-gene panel in 117 limited-stage FL patients treated with radiotherapy and identified recurrently mutated genes. CREBBP was most frequently mutated, and mutated CREBBP was associated with inferior progression-free survival, though not after false discovery rate adjustment. This association failed to validate in an independent cohort. We conclude that recurrent gene mutations do not predict outcomes in this setting. Alternative biomarkers may offer better prognostic insight., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: The capacity for machine learning (ML) to facilitate radiation therapy (RT) planning for primary brain tumors has not been described. We evaluated ML-assisted RT planning with regard to clinical acceptability, dosimetric outcomes, and planning efficiency for adults and children with primary brain tumors., Methods and Materials: In this prospective study, children and adults receiving 54 Gy fractionated RT for a primary brain tumor were enrolled. For each patient, one ML-assisted RT plan was created and compared with 1 or 2 plans created using standard ("manual") planning procedures. Plans were evaluated by the treating oncologist, who was blinded to the method of plan creation. The primary endpoint was the proportion of ML plans that were clinically acceptable for treatment. Secondary endpoints included the frequency with which ML plans were selected as preferable for treatment, and dosimetric differences between ML and manual plans., Results: A total of 116 manual plans and 61 ML plans were evaluated across 61 patients. Ninety-four percent of ML plans and 93% of manual plans were judged to be clinically acceptable (P = 1.0). Overall, the quality of ML plans was similar to manual plans. ML plans comprised 34.5% of all plans evaluated and were selected for treatment in 36.1% of cases (P = .82). Similar tumor target coverage was achieved between both planning methods. Normal brain (brain minus planning target volume) received an average of 1 Gy less mean dose with ML plans (compared with manual plans, P < .001). ML plans required an average of 45.8 minutes less time to create, compared with manual plans (P < .001)., Conclusions: ML-assisted automated planning creates high-quality plans for patients with brain tumors, including children. Plans created with ML assistance delivered slightly less dose to normal brain tissues and can be designed in less time., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy., Methods and Materials: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores., Results: The mean dose and dose to 40% of the brain (D40) were 2.7 and 4.1 Gy less among proton-treated patients compared with photon-treated patients (P = .03 and .007, respectively). Mean doses to the left and right hippocampi were 11.2 Gy lower among proton-treated patients (P < .001 for both). Mean doses to the left and right temporal lobes were 6.9 and 7.1 Gy lower with proton treatment, respectively (P < .001 for both). Models of cognition found statistically significant associations between higher mean brain dose and reduced verbal comprehension, increased right temporal lobe D40 with reduced perceptual reasoning, and greater left temporal mean dose with reduced working memory. Higher brain D40 was associated with reduced processing speed and global IQ scores., Conclusions: Proton therapy reduces doses to normal brain structures compared with photon treatment. This leads to reduced cognitive decline after radiation therapy across multiple intellectual endpoints. Proton therapy should be offered to children receiving radiation for medulloblastoma., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Children who require radiation therapy (RT) should ideally be treated awake, without anaesthesia, if possible. Audiovisual distraction is a known method to facilitate awake treatment, but its effectiveness at keeping children from moving during treatment is not known. The aim of this study was to evaluate intrafraction movement of children receiving RT while awake., Methods: In this prospective study, we measured the intrafraction movement of children undergoing treatment with fractionated RT, using pre- and post-RT cone beam CT (CBCT) with image matching on bony anatomy. Study CBCTs were acquired at first fraction, weekly during RT, and at last fraction. The primary endpoint was the magnitude of vector change between the pre- and post-RT scans. Our hypothesis was that 90 % of CBCT acquisitions would have minimal movement, defined as <3 mm for head-and-neck (HN) treatments and <5 mm for non-HN treatments., Results: A total of 65 children were enrolled and had evaluable data across 302 treatments with CBCT acquisitions. Median age was 11 years (range, 2-18; 1st and 3rd quartiles 7 and 14 years, respectively). Minimal movement was observed in 99.4 % of HN treatments and 97.2 % of non-HN treatments. The study hypothesis of >90 % of evaluations having minimal movement was met. Children who were age >11 years moved less at initial evaluation but tended to move more as a course of radiation progressed, as compared to children who were younger., Conclusion: Children receiving RT with audiovisual distraction while awake had small magnitudes of observed intrafraction movement, with minimal movement in >97 % of observed RT fractions. This study validates methods of anaesthesia avoidance using audiovisual distraction for selected children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Importance: Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but also increased the cumulative doxorubicin dose, making overall treatment consequences for late cardiac toxic effects uncertain., Objective: To estimate the risk of cardiac toxic effects associated with treatments used in modern pediatric HL clinical trials., Design, Setting, and Participants: For this cohort study, Fine and Gray models were fitted using survivors in the Childhood Cancer Survivor Study who were diagnosed with HL between January 1, 1970, and December 31, 1999, and were followed for a median of 23.5 (range, 5.0-46.3) years. These models were applied to the exposures in the study population to estimate the 30-year cumulative incidence of cardiac disease. The study population comprised patients with intermediate-risk or high-risk HL treated in 4 consecutive Children's Oncology Group clinical trials from September 2002 to October 2022: AHOD0031, AHOD0831, AHOD1331, and S1826. Data analysis was performed from April 2020 to February 2023., Exposures: All patients received chemotherapy including doxorubicin, and some patients received mediastinal RT, dexrazoxane, or mediastinal RT and dexrazoxane., Main Outcomes and Measures: Estimated 30-year cumulative incidence of grade 3 to 5 cardiac disease., Results: The study cohort comprised 2563 patients, with a median age at diagnosis of 15 (range, 1-22) years. More than half of the patients were male (1357 [52.9%]). All 2563 patients received doxorubicin, 1362 patients (53.1%) received mediastinal RT, and 307 patients (12.0%) received dexrazoxane. Radiation therapy use and the median mean heart dose among patients receiving RT decreased, whereas the planned cumulative dose of doxorubicin and use of dexrazoxane cardioprotection increased. For patients treated at age 15 years, the estimated 30-year cumulative incidence of severe or fatal cardiac disease was 9.6% (95% CI, 4.2%-16.4%) in the AHOD0031 standard treatment group (enrolled 2002-2009), 8.6% (95% CI, 3.8%-14.9%) in the AHOD0831 trial (enrolled 2009-2012), 8.2% (95% CI, 3.6%-14.3%) in the AHOD1331 trial (enrolled 2015-2019), and 6.2% (95% CI, 2.7%-10.9%) in the S1826 trial (enrolled 2019-2022), whereas the expected rate in an untreated population was 5.0% (95% CI, 2.1%-9.3%). Despite the estimated reduction in late cardiac morbidity, the frequency of recommended echocardiographic screening among survivors will increase based on current guidelines., Conclusions and Relevance: In this cohort study of sequential HL trials, reductions in the proportion of children receiving mediastinal RT and increases in dexrazoxane use were estimated to offset the increased doxorubicin dose and produce a net reduction in late cardiac disease. Further studies on dexrazoxane are warranted to confirm whether its role in reducing cardiac toxic effects is maintained long term. These findings suggest that survivorship follow-up guidelines should be refined to align with the risks associated with treatment.

The optimal salvage chemotherapy regimen (SC) for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) prior to autologous stem cell transplant remains unclear. Moreover, although chimeric antigen receptor T cell (CAR-T) therapies were recently approved for primary refractory DLBCL, head-to-head comparisons are lacking. We searched MEDLINE, EMBASE and CENTRAL to July 2022, for randomized trials that enrolled adult patients with R/R DLBCL and performed network meta-analyses (NMA) to assess the efficacy of SC and CAR-T therapies. NMA of SC (6 trials, 7 regimens, n  = 1831) indicated that rituximab with gemcitabine, dexamethasone, cisplatin (R-GDP) improved OS and PFS over compared regimens. NMA of 3 CAR-T trials ( n  = 865) indicated that both axi-cel and liso-cel improved PFS over standard of care, with no difference in OS. Our results indicate that R-GDP may be preferred for R/R DLBCL over other SC compared. Longer follow-up is required for ongoing comparative survival analysis as data from CAR-T trials matures.

Purpose/objective: We compared the prognostic value of chest radiograph (CXR)- and computed tomography (CT)-derived definition of large mediastinal adenopathy (LMA) in pediatric Hodgkin lymphoma (HL)., Materials/methods: Total 143 patients treated for stage IIIB/IVB HL on COG AHOD0831 were included in this study. Six definitions of LMA were investigated: (i) mediastinal mass ratio on CXR (MR CXR ) > 1/3; (ii) mediastinal mass ratio on CT (MR CT ) > 1/3; (iii) mediastinal mass volume on CT (MV CT ) > 200 mL; (iv) normalized mediastinal mass volume (MV CT /thoracic diameter [TD]) > 1 mL/mm; (v) mediastinal mass diameter on CT (MD CT ) > 10 cm; and (vi) normalized mediastinal mass diameter (MD CT /TD) > 1/3., Results: Median age at diagnosis was 15.8 years (range: 5.2-21.3 years). In patients with a slow early response (SER) to chemotherapy, MV CT  > 200 mL, MD CT  > 10 cm, and MD CT /TD > 1/3 were associated with worse relapse-free survival (RFS) on MVA, while MR CXR  > 1/3, MR CT  > 1/3, and MV CT /TD > 1 mL/mm trended toward worse RFS; MD CT /TD was the most strongly prognostic for inferior RFS, with a hazard ratio of 6.41 for MD CT /TD > 1/3 versus ≤1/3 on MVA (p = .02)., Conclusion: LMA according to MV CT  > 200 mL, MD CT  > 10 cm, and MD CT /TD > 1/3 is associated with poor prognosis in advanced-stage HL patients with SER. The normalized mediastinal diameter, MD CT /TD > 1/3 appears to be the strongest predictor of inferior RFS., (© 2023 Wiley Periodicals LLC.)

Purpose: We investigated the effects of central review of the interim fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan response (iPET) assessment on treatment allocation in the risk-based, response-adapted, Children's Oncology Group study AHOD1331 (ClinicalTrials.gov identifier: NCT02166463) for pediatric patients with high-risk Hodgkin lymphoma., Methods and Materials: Per protocol, after 2 cycles of systemic therapy, patients underwent iPET, with visual response assessment by 5-point Deauville score (DS) at their treating institution and a real-time central review, with the latter considered the reference standard. An area of disease with a DS of 1 to 3 was considered a rapid-responding lesion, whereas a DS of 4 to 5 was considered a slow-responding lesion (SRL). Patients with 1 or more SRLs were considered iPET positive, whereas patients with only rapid-responding lesions were considered iPET negative. We conducted a predefined exploratory evaluation of concordance in iPET response assessment between institutional and central reviews of 573 patients. The concordance rate was evaluated using the Cohen κ statistic (κ > 0.80 was considered very good agreement and κ > 0.60-0.80, good agreement)., Results: The concordance rate (514 of 573 [89.7%]) had a κ of 0.685 (95% CI, 0.610-0.759), consistent with good agreement. In terms of the direction of discordance, among the 126 patients who were considered iPET positive by institutional review, 38 (30.2%) were categorized as iPET negative by central review, preventing overtreatment with radiation therapy. Conversely, among the 447 patients who were considered iPET negative by institutional review, 21 patients (4.7%) were categorized as iPET positive by the central review and would have been undertreated without radiation therapy., Conclusions: Central review is integral to PET response-adapted clinical trials for children with Hodgkin lymphoma. Continued support of central imaging review and education about DS are needed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Previous efforts to predict absolute risk of treatment-related cardiovascular diseases (CVDs) have mostly focused on childhood cancer survivors. We aimed to develop prediction models for risk of coronary heart disease (CHD) and heart failure (HF) for survivors of adolescent/adult Hodgkin lymphoma (HL)., Methods: For model development, we used a multicenter cohort including 1,433 5-year HL survivors treated between 1965 and 2000 and age 18-50 years at HL diagnosis, with complete data on administered chemotherapy regimens, radiotherapy volumes and doses, and cardiovascular follow-up. Using cause-specific hazard models, covariate-adjusted cumulative incidences for CHD and HF were estimated in the presence of competing risks of death because of other causes than CHD and HF. Age at HL diagnosis, sex, smoking status, radiotherapy, and anthracycline treatment were included as predictors. External validation for the CHD model was performed using a Canadian cohort of 708 HL survivors treated between 1988 and 2004 and age 18-50 years at HL diagnosis., Results: After a median follow-up of 24 years, 341 survivors had developed CHD and 102 had HF. We were able to predict CHD and HF risk at 20 and 30 years after treatment with moderate to good overall calibration and moderate discrimination (areas under the curve: 0.68-0.74), which was confirmed by external validation for the CHD model (areas under the curve: 0.73-0.74). On the basis of our model including prescribed mediastinal radiation dose, 30-year risks ranged from 4% to 78% for CHD and 3% to 46% for HF, depending on risk factors., Conclusion: We developed and validated prediction models for CHD and HF with good overall calibration and moderate discrimination. These models can be used to identify HL survivors who might benefit from targeted screening for CVD and early treatment for CVD risk factors.

Purpose: The Children's Oncology Group protocol AHOD0831, for pediatric patients with high-risk classical Hodgkin lymphoma (cHL), used response-adapted radiation fields, rather than larger involved-field radiation therapy (IFRT) that were historically used. This retrospective analysis of patterns of relapse among patients enrolled in the study was conducted to study the potential effect of a reduction in RT exposure., Methods and Materials: From December 2009 to January 2012, 164 eligible patients under 22 years old with stage IIIB (43%) and stage IVB (57%) enrolled on AHOD0831. All patients received 4 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). Those patients with a slow early response (SER) after the first 2 ABVE-PC courses were nonrandomly assigned to 2 intensification cycles with ifosfamide/vinorelbine before the final 2 ABVE-PC cycles. Response-adapted RT (21 Gy) was prescribed to initial areas of bulky disease and SER sites. Rapid early response (RER) sites without bulk were not targeted. Imaging studies at the time of progression or relapse were reviewed centrally for this retrospective analysis. Relapses were characterized with respect to site (initial, new, or both; and initial bulk or initial nonbulk), initial chemotherapy response, and radiation field (in-field, out-of-field, or both)., Results: Of the entire cohort, 140 patients were evaluable for the patterns of failure analyses. To investigate the pattern of failure, this analysis focuses on 23 patients who followed protocol treatment and suffered relapses at a median 1.05 years with 7.97-year median follow-up time. These 23 patients (11 RER and 12 SER) experienced a relapse in 105 total sites (median, 4; range, 1-11). Of the 105 relapsed sites, 67 sites (64%) occurred within an initial site of involvement, with 12 of these 67 sites (18%) at an initial site of bulky disease and 63 of these 67 relapses (94%) occurring in sites that were not fluorodeoxyglucose (FDG)-avid after 2 cycles of ABVE-PC (PET2-negative). Of the 105 relapsed sites, 34 sites (32%) occurred in a new site of disease (that would not have been covered by RT); and, overall, only 4 of 140 patients (2.8%) (occurring in 3 RER and 1 SER) experienced isolated out-of-field relapses that would have been covered by historical IFRT., Conclusions: For a cohort of high-risk patients with cHL patients, most failures occurred in nonbulky, initially involved sites, largely due to response-based consolidation RT delivered to patients with bulky disease. In this analysis, we discovered low rates of failures outside of these modern risk-adapted radiation treatment volumes. Also, FDG uptake on PET2 did not identify most relapse sites., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: High-quality radiotherapy (RT) planning for children and young adults with primary brain tumours is essential to minimize the risk of late treatment effects. The feasibility of using automated machine-learning (ML) to aid RT planning in this population has not previously been studied., Methods and Materials: We developed a ML model that identifies learned relationships between image features and expected dose in a training set of 95 patients with a primary brain tumour treated with focal radiotherapy to a dose of 54 Gy in 30 fractions. This ML method was then used to create predicted dose distributions for 15 previously-treated brain tumour patients across two institutions, as a testing set. Dosimetry to target volumes and organs-at-risk (OARs) were compared between the clinically-delivered (human-generated) plans versus the ML plans., Results: The ML method was able to create deliverable plans in all 15 patients in the testing set. All ML plans were generated within 30 min of initiating planning. Planning target volume coverage with 95% of the prescription dose was attained in all plans. OAR doses were similar across most structures evaluated; mean doses to brain and left temporal lobe were lower in ML plans than manual plans (mean difference to left temporal, - 2.3 Gy, p = 0.006; mean differences to brain, - 1.3 Gy, p = 0.017), whereas mean doses to right cochlea and lenses were higher in ML plans (+ 1.6-2.2 Gy, p < 0.05 for each)., Conclusions: Use of an automated ML method to aid RT planning for children and young adults with primary brain tumours is dosimetrically feasible and can be successfully used to create high-quality 54 Gy RT plans. Further evaluation after clinical implementation is planned., (© 2022. The Author(s).)

Childhood cancer survivors are known to be at risk of chronic co-morbidities, although their risk of COVID-19 infection remains uncertain. Understanding the risk of COVID-19 in this population is necessary to counsel survivors and inform potential mitigation strategies. The objective of this study was to determine whether the rates of COVID-19 infection differed between childhood cancer survivors and the general population. Administrative health care data from a population-based registry of children and adolescents diagnosed with cancer in Ontario, Canada, were linked with a universal health insurance registry and a repository of laboratory data. Rates of COVID-19 testing, test positivity and infection between March 1, 2020 and March 31, 2021 among childhood cancer survivors ( n = 10 242) were compared to matched controls from the general population ( n = 49 068). Compared to the general population, childhood cancer survivors were more likely to have COVID-19 testing (35.9% [95% CI, 34.5-37.4%] vs. 32.0% [95% CI, 31.4-32.6%]), but had a lower likelihood of positive COVID-19 result among those tested (4.3% [95% CI, 3.6-4.9%] vs. 5.5% [95% CI, 5.1-5.8%]) and a similar rate of infection among all subjects at risk (1.5% [95% CI, 1.3-1.8%] vs. 1.7% [95% CI, 1.6-1.9%]). These findings can inform counseling of survivors and clinician recommendations for this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Agha, Leung, Moineddin, Bradley, Gibson and Hodgson.)

The successful integration of clinical trials into pediatric oncology has led to steady improvement in the 5-year survival rate for children diagnosed with Hodgkin lymphoma (HL). It is estimated that >95% of children newly diagnosed with HL will become long-term survivors. Despite these successes, survival can come at a cost. Historically, long-term survivors of HL have a high risk of late-occurring adverse health effects and increased risk of nonrelapse mortality compared with the general population. The recognition of late-occurring events paired with the decades of life remaining for children cured of HL have made paramount the need to develop effective treatments that minimize the risk of late toxicity. Toward this goal, multiple, dose-intense, risk- and response-based regimens that use lower cumulative doses of chemotherapy and radiation have been developed. Appropriate frontline treatment selection requires a level of familiarity with the efficacy, acute toxicity, convenience, and late effects of treatments that may be impractical for providers who infrequently treat children with HL. There is an increasing need for guideline developers to begin to merge considerations from both frontline treatment and survivorship guidelines into practical documents that integrate potential long-term health risks. Herein, we take the first steps toward doing so by aligning cumulative treatment exposures, anticipated risks of late toxicity, and suggested surveillance recommendations for NCCN-endorsed Pediatric HL Guidelines. Future studies that integrate simulation modeling will strengthen this integrated approach and allow for opportunities to incorporate regimen-specific risks, health-related quality of life, and cost-effectiveness into decision tools to optimize HL therapy.

Background: The objective of this study was to evaluate the contribution of radiation dose to different intracranial structures on changes in intellectual function for children with brain tumors., Methods: We evaluated children with brain tumors treated in 2005-2017 who had longitudinal neuropsychological assessments and available photon dosimetric data (if radiation therapy [RT] given). Full Scale Intelligence Quotient (FSIQ) and index scores were evaluated (perceptual reasoning index [PRI], processing speed index [PSI], verbal comprehension index [VCI], and working memory index [WMI]). Multivariable linear mixed effects models were used to model endpoints, with age at RT and dose to different brain regions as fixed effects and patient-specific random intercepts. P-values (P*) were adjusted for multiple comparisons., Results: Sixty-nine patients were included, 56 of whom received RT. Median neuropsychological follow-up was 3.2 years. Right temporal lobe mean dose was strongly associated with decline in FSIQ (P* = 0.005); with each gray increase in mean dose, there was a decrease of 0.052 FSIQ points per year. Dose to 50% (D50) of the supratentorial brain was associated with decline in PSI (P* = 0.006) and WMI (P* = 0.001). Right and left hippocampus D50 were individually strongly associated with declines in VCI (P* = 0.009 for each). Presence of a ventriculoperitoneal shunt decreased FSIQ by 10 points., Conclusions: We reported associations between dosimetry to specific brain regions and intellectual outcomes, with suggested avoidance structures during RT planning. These models can help clinicians anticipate changes in neurocognition post-RT and guide selection of an optimal RT plan., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

To study radiotherapy-related adverse effects, detailed dose information (3D distribution) is needed for accurate dose-effect modeling. For childhood cancer survivors who underwent radiotherapy in the pre-CT era, only 2D radiographs were acquired, thus 3D dose distributions must be reconstructed from limited information. State-of-the-art methods achieve this by using 3D surrogate anatomies. These can however lack personalization and lead to coarse reconstructions. We present and validate a surrogate-free dose reconstruction method based on Machine Learning (ML). Abdominal planning CTs (n = 142) of recently-treated childhood cancer patients were gathered, their organs at risk were segmented, and 300 artificial Wilms' tumor plans were sampled automatically. Each artificial plan was automatically emulated on the 142 CTs, resulting in 42,600 3D dose distributions from which dose-volume metrics were derived. Anatomical features were extracted from digitally reconstructed radiographs simulated from the CTs to resemble historical radiographs. Further, patient and radiotherapy plan features typically available from historical treatment records were collected. An evolutionary ML algorithm was then used to link features to dose-volume metrics. Besides 5-fold cross validation, a further evaluation was done on an independent dataset of five CTs each associated with two clinical plans. Cross-validation resulted in mean absolute errors ≤ 0.6 Gy for organs completely inside or outside the field. For organs positioned at the edge of the field, mean absolute errors ≤ 1.7 Gy for [Formula: see text], ≤ 2.9 Gy for [Formula: see text], and ≤ 13% for [Formula: see text] and [Formula: see text], were obtained, without systematic bias. Similar results were found for the independent dataset. To conclude, we proposed a novel organ dose reconstruction method that uses ML models to predict dose-volume metric values given patient and plan features. Our approach is not only accurate, but also efficient, as the setup of a surrogate is no longer needed.

Background and Purpose: Radiation-related heart disease (RRHD) can occur many decades after thoracic radiotherapy for Hodgkin lymphoma (HL) or childhood cancer (CC). To quantify the likely risk of RRHD for patients treated today, dose-response relationships derived from patients treated in previous decades are used. Publications presenting these dose-response relationships usually include estimates of uncertainties in the risks but ignore the effect of uncertainties in the reconstructed cardiac doses., Materials/methods: We assessed the systematic and random uncertainties in the reconstructed doses for published dose-response relationships for RRHD risk in survivors of HL or CC. Using the same reconstruction methods as were used in the original publications, we reconstructed mean heart doses and, wherever possible, mean left-ventricular doses for an independent case-series of test patients. These patients had known, CT-based, cardiac doses which were compared with the reconstructed doses to estimate the magnitude of the uncertainties and their effect on the dose-response relationships., Results: For all five reconstruction methods the relationship between reconstructed and CT-based doses was linear. For all but the simplest reconstruction method, the dose uncertainties were moderate, the effect of the systematic uncertainty on the dose-response relationships was less than 10%, and the effects of random uncertainty were small except at the highest doses., Conclusions: These results increase confidence in the published dose-response relationships for the risk of RRHD in HL and CC survivors. This may encourage doctors to use these dose-response relationships when estimating individualised risks for patients-an important aspect of personalising radiotherapy treatments today., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

This report by the Radiation Oncology Discipline of Children's Oncology Group (COG) describes the practice patterns of pediatric image-guided radiotherapy (IGRT) based on a member survey and provides practice recommendations accordingly. The survey comprised of 11 vignettes asking clinicians about their recommended treatment modalities, IGRT preferences, and frequency of in-room verification. Technical questions asked physicists about imaging protocols, dose reduction, setup correction, and adaptive therapy. In this report, the COG Radiation Oncology Discipline provides an IGRT modality/frequency decision tree and the expert guidelines for the practice of ionizing image guidance in pediatric radiotherapy patients., (© 2020 Wiley Periodicals LLC.)

Purpose: At our institution, a multifaceted approach is used to reduce general anesthetic (GA) use for children receiving photon radiation therapy (RT) as standard-of-care treatment. The purpose of this study was to evaluate the effectiveness of our methods., Methods and Materials: Patients treated as part of the pediatric radiation therapy program from 2010 to 2018 were retrospectively reviewed. GA use was defined as need for intravenous propofol or inhaled gaseous anesthetic for at least 1 simulation or RT session. Methods to reduce GA use included presence of a dedicated pediatric nurse for procedural preparation, audiovisual distraction (television during RT), and 2-way audio communication with caregivers., Results: There were 779 unique patients who received RT over 14 163 fractions of radiation. GA utilization was 90% in those under age 3, 28% in those age 3 to 6, 1% in those age 7 to 11, and <1% in those ≥12 years of age. Four years of age is a cutoff age at which the majority of patients switch from needing GA (56.6% for those aged 3) to not needing GA (29.8% for those aged 4). Younger age, use of total body irradiation, and craniospinal irradiation were independently associated with requiring GA., Conclusions: Using methods designed to reduce GA use, most children aged 4 years or older were able receive RT awake. Our GA rates compare favorably to other literature reports; thus, pediatric RT centers should consider adopting specific interventions to reduce GA use., (Copyright © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: Childhood cancer survivors (CCS) are at increased risk of developing colorectal cancer (CRC) compared to the general population, especially those previously exposed to abdominal or pelvic radiation therapy (APRT). However, the benefits and costs of CRC screening in CCS are unclear. In this study, we evaluated the cost-effectiveness of early-initiated colonoscopy screening in CCS., Methods: We adjusted a previously validated model of CRC screening in the US population (MISCAN-Colon) to reflect CRC and other-cause mortality risk in CCS. We evaluated 91 colonoscopy screening strategies varying in screening interval, age to start, and age to stop screening for all CCS combined and for those treated with or without APRT. Primary outcomes were CRC deaths averted (compared to no screening) and incremental cost-effectiveness ratios (ICERs). A willingness-to-pay threshold of $100 000 per life-years gained (LYG) was used to determine the optimal screening strategy., Results: Compared to no screening, the US Preventive Services Task Force's average risk screening schedule prevented up to 73.2% of CRC deaths in CCS. The optimal strategy of screening every 10 years from age 40 to 60 years averted 79.2% of deaths, with ICER of $67 000/LYG. Among CCS treated with APRT, colonoscopy every 10 years from age 35 to 65 years was optimal (CRC deaths averted: 82.3%; ICER: $92 000/LYG), whereas among those not previously treated with APRT, screening from age 45 to 55 years every 10 years was optimal (CRC deaths averted: 72.7%; ICER: $57 000/LYG)., Conclusions: Early initiation of colonoscopy screening for CCS is cost-effective, especially among those treated with APRT., (© The Author(s) 2019. Published by Oxford University Press.)

Purpose: Children with recurrent medulloblastoma have a poor prognosis. Re-irradiation is an option for some patients, but has not been well-studied in the era of molecular characterization for pediatric medulloblastoma., Methods: This was a retrospective cohort study of 14 children age 18 years and younger at initial diagnosis with recurrent medulloblastoma, who received two or more courses of radiation therapy (RT). Molecular subgrouping was performed using nanoString and was available for nine patients. The primary study endpoint was overall survival., Results: Re-irradiation (RT2) was directed at the supratentorial brain in six patients, infratentorial brain in one patient, and spine in seven patients. In addition, six patients received stem cell transplant as part of salvage therapy. Median OS for all patients was 12.4 months. One patient with recurrent Wnt-activated medulloblastoma remains alive with 154 months' survival; median survival was not reached for four patients with Group 4 disease, while three with Shh-activated disease had median survival of 2.2 months. A single patient with Group 3 disease died 4.3 months after RT2. Patients treated with RT2 to the spine for diffuse disease had poorer OS (p = 0.02), as compared to focal RT2 for intracranial recurrence. Distant failure, outside RT2 volumes, was the predominant pattern of recurrence after RT2., Conclusions: Re-irradiation for recurrent pediatric medulloblastoma can offer some patients disease control, particularly those with focally recurrent disease in the brain. Prospective studies are needed to confirm subgroups of patients who may benefit most from RT2.

The AHOD0831 study for paediatric patients with high risk Hodgkin lymphoma tested a response-based approach designed to limit cumulative alkylator exposure and reduce radiation volumes. Patients (Stage IIIB/IVB) received two cycles of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide). Rapid early responders [RER, no positron emission tomography (PET) activity above mediastinal blood pool] were consolidated with 2 cycles of ABVE-PC. Slow early responders (SER) received 2 cycles of ifosfamide/vinorelbine and 2 cycles of ABVE-PC. Radiotherapy was administered to sites of initial bulk and/or SER. By intent-to-treat analysis, 4-year second event-free survival (EFS; freedom from second relapse or malignancy) was 91·9% [95% confidence interval (CI): 86·1-95·3%], below the projected baseline of 95% (P = 0·038). Five-year first EFS and overall survival (OS) rates are 79·1% (95% CI: 71·5-84·8%) and 95% (95% CI: 88·8-97·8%). Eight of 11 SER patients with persistent PET positive lesions at the end of chemotherapy had clinical evidence of active disease (3 biopsy-proven, 5 with progressive disease or later relapses). Although this response-directed approach did not reach the ambitiously high pre-specified target for second EFS, EFS and OS rates are comparable with results of recent trials despite the reduction in radiotherapy volumes from historical involved fields. Persistent PET at end of chemotherapy identifies a cohort at an especially high risk for relapse/early progression., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Radiation-induced meningioma is a known late effect of cranial radiation therapy. Cranial magnetic resonance imaging (MRI) can detect small meningiomas, but its potential value as a screening tool is unknown., Methods and Materials: MRI was used to screen asymptomatic survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy ≥10 years previously. The incidence of radiation-induced meningioma and outcomes of this group were compared with a historical cohort of survivors with the same exposure who underwent imaging only to investigate clinical signs or symptoms., Results: One hundred seventy-six childhood leukemia survivors were included in this study: 70 in the screening group and 106 unscreened. Screening MRI was performed a median of 25 years after radiation therapy and detected meningioma in 15 (21.4%). In the unscreened group, 17 patients (16.0%) had neurologic symptoms leading to an MRI a median interval of 24 years after radiation therapy, 9 of whom (8.5%) were diagnosed with meningioma. There was no significant difference between screened versus unscreened patients in the size of meningioma (mean diameter, 1.6 cm vs 2.6 cm; P = .13), meningioma incidence (7.4% vs 4.0% at 25 years; P = .19), or extent of resection. Three patients had persistent neurologic symptoms in the unscreened group versus none among screened patients (P = .28)., Conclusions: Screening MRI was able to detect small meningiomas that were not clinically apparent; however, we could not demonstrate a significant improvement in the chance of total resection or a significant decrease in morbidity. A larger sample could clarify potential reduction in neurologic sequelae associated with screening., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: We previously reported that ∼30% of patients with localized follicular lymphoma (FL) staged by 18 F-fluorodeoxyglucose positron emission tomography-computed tomography receiving primary radiation therapy (RT) will relapse within 5 years. We sought to report outcomes for those who relapsed., Methods and Materials: We conducted a multicenter, retrospective study of patients aged ≥18 years who received RT ≥ 24 Gy for stage I to II, grade 1 to 3A FL, staged with 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography-computed tomography. Observation was defined as >6 months without treatment from relapse. Overall survival (OS) and freedom from progression (FFP) were estimated with Kaplan-Meier analysis and univariable and multivariable analyses with Cox regression., Results: Of 512 patients with median follow-up of 52 months, 149 (29.1%) developed recurrent lymphoma at a median of 23 months (range, 1-143) after primary RT. Median follow-up was 33 months after relapse. Three-year OS was 91.4% after recurrence. OS was significantly worse for those with relapse ≤12 months from date of diagnosis versus all others-88.7% versus 97.6%, respectively (P = .01)-and remained significantly worse on multivariable analyses (follicular lymphoma international prognostic index-adjusted hazard ratio, 3.61; P = .009). Histology at relapse included 93 indolent (grade 1-3A), 3 FL grade 3B/not otherwise specified, and 18 diffuse large B-cell lymphoma; 35 patients did not undergo biopsy. Of those with follow-up ≥3 months who underwent biopsy (n = 74) or had presumed (n = 23) indolent recurrence, 58 patients (59.8%) were observed, 19 (19.6%) had systemic therapy, 16 (16.5%) had RT, and 4 (4.1%) had systemic therapy + RT. For patients with indolent recurrences that were observed, 3-year FFP or freedom from treatment was 56.6% (median, 48 months). For all patients with biopsied/presumed indolent recurrence receiving salvage treatment (n = 59, including 20 initially observed) 3-year FFP was 73.9%., Conclusions: Prognosis for patients with relapsed FL after primary radiation therapy is excellent, supporting the role of primary radiation in the management of early stage disease. Patients with localized FL treated with primary RT who experience early relapse (<12 months) have inferior survival compared with those with longer disease-free interval., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose To determine the relationship of PET/CT staging to the management and outcomes of participants with apparent limited-stage (LS) Hodgkin lymphoma (HL) or aggressive non-HL (ANHL) treated with curative intent. Materials and Methods This prospective multicenter registry included 850 participants (467 men and 383 women; median age, 54.1 years) from nine centers who had LS HL or ANHL on the basis of clinical data and CT, or with equivocal CT for advanced stage, who were considered for curative-intent first-line therapy. Participants were recruited between May 1, 2013, and December 31, 2015. Pre-PET/CT treatment plan was compared with treatment provided. Survival and second-line therapy initiation were compared with an historical control pool staged by using CT alone. Administrative data sources were used to control for baseline characteristics. Outcomes were assessed by using adjusted Cox proportional hazards regression and propensity score matching. Results PET/CT helped to upstage 150 of 850 participants (17.6%). There was a change in planned therapy in 224 of 580 (38.6%) of participants after PET/CT. There was a lower 1-year mortality for participants with ANHL in the PET/CT versus CT cohort (hazard ratio, 0.63; 95% confidence interval: 0.40, 1.0; P < .05) and for those with LS at PET/CT compared with those with LS at CT (hazard ratio, 0.40; 95% confidence interval: 0.21, 0.74; P = .004). For participants with HL, no 1-year outcome difference was found (P = .16). Conclusion PET/CT helped to upstage approximately 18% of participants and planned management was frequently altered. Participants with aggressive non-Hodgkin lymphoma whose first-line therapy was guided by PET/CT had significantly better survival compared with participants whose treatment was guided by CT. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Scott in this issue.

Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40 to 50%. As 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography with computerized tomography (PET-CT) upstages 10 to 60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study under the direction of the International Lymphoma Radiation Oncology Group (ILROG). Inclusion criteria were: RT alone for untreated stage I to II FL (grade 1-3A) with dose equivalent ≥24 Gy, staged by PET-CT, age ≥18 years, and follow-up ≥3 months. End points were freedom from progression (FFP), local control, and overall survival (OS). A total of 512 patients treated between 2000 and 2017 at 16 centers were eligible for analysis; median age was 58 years (range, 20-90); 410 patients (80.1%) had stage I disease; median RT dose was 30 Gy (24-52); and median follow-up was 52 months (3.2-174.6). Five-year FFP and OS were 68.9% and 95.7%. For stage I, FFP was 74.1% vs 49.1% for stage II ( P < .0001). Eight patients relapsed in-field (1.6%). Four had marginal recurrences (0.8%) resulting in local control rate of 97.6%. On multivariable analysis, stage II (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.44-3.10) and BCL2 expression (HR, 1.62; 95% CI, 1.07-2.47) were significantly associated with less favorable FFP. Outcome after RT in PET-CT staged patients appears to be better than in earlier series, particularly in stage I disease, suggesting that the curative potential of RT for truly localized FL has been underestimated., (© 2019 by The American Society of Hematology.)

Subsequent malignant neoplasms (SMNs) in childhood cancer survivors cause substantial morbidity and mortality. This review summarizes recent literature on SMN epidemiology, risk factors, surveillance, and interventions. Survivors of childhood cancer experience long-term increased SMN risk compared with the general population, with a greater than twofold increased solid tumor risk extending beyond age 40 years. There is a dose-dependent increased risk for solid tumors after radiotherapy, with the highest risks for tumors occurring in or near the treatment field (eg, greater than fivefold increased risk for breast, brain, thyroid, skin, bone, and soft tissue malignancies). Alkylating and anthracycline chemotherapies increase the risk for development of several solid malignancies in addition to acute leukemia/myelodysplasia, and these risks may be modified by other patient characteristics, such as age at exposure and, potentially, inherited genetic susceptibility. Strategies for identifying survivors at risk and initiating long-term surveillance have improved and interventions are underway to improve knowledge about late-treatment effects among survivors and caregivers. Better understanding of treatment-related risk factors and genetic susceptibility holds promise for refining surveillance strategies and, ultimately, upfront cancer therapies.

We developed a novel simulation model integrating multiple data sets to project long-term outcomes with contemporary therapy for early-stage Hodgkin lymphoma (ESHL), namely combined modality therapy (CMT) versus chemotherapy alone (CA) via 18 F-fluorodeoxyglucose positron emission tomography response-adaption. The model incorporated 3-year progression-free survival (PFS), probability of cure with/without relapse, frequency of severe late effects (LEs), and 35-year probability of LEs. Furthermore, we generated estimates for quality-adjusted life years (QALYs) and unadjusted survival (life years, LY) and used model projections to compare outcomes for CMTversusCA for two index patients. Patient 1: a 25-year-old male with favourable ESHL (stage IA); Patient 2: a 25-year-old female with unfavourable ESHL (stage IIB). Sensitivity analyses assessed the impact of alternative assumptions for LE probabilities. For Patient 1, CMT was superior to CA (CMT incremental gain = 0·11 QALYs, 0·21 LYs). For Patient 2, CA was superior to CMT (CA incremental gain = 0·37 QALYs, 0·92 LYs). For Patient 1, the advantage of CMT changed minimally when the proportion of severe LEs was reduced from 20% to 5% (0·15 QALYs, 0·43 LYs), whereas increasing the severity proportion for Patient 2's LEs from 20% to 80% enhanced the advantage of CA (1·1 QALYs, 6·5 LYs). Collectively, this detailed simulation model quantified the long-term impact that varied host factors and alternative contemporary treatments have in ESHL., (© 2018 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd and British Society for Haematology.)

Relapsed and refractory Hodgkin lymphoma (HL) challenges clinicians to devise treatment strategies that are effective and safe. This problem is particularly prominent in an era when de-escalation trials are designed to minimize therapeutic toxicities in both early- and advanced-stage disease. Radiation therapy is the single most effective treatment modality for HL, and its integration into salvage regimens, or its independent use in select patients, must be understood to maximize our success in treating these patients. The complexity of treating relapsed or refractory HL derives from the spectrum of primary treatment approaches currently in use that creates heterogeneity in both treatment exposure and the potential toxicities of salvage therapy. Patients can have relapsed or refractory disease after limited or aggressive primary therapy (with or without radiation therapy), at early or delayed time points, with limited or extensive disease volumes, and with varying degrees of residual morbidity from primary therapy. Their response to salvage systemic therapy can be partial or complete, and the use of consolidative stem cell transplantation is variably applied. New biologics and immunotherapeutic approaches have broadened but also complicated salvage treatment approaches. Through all of this, radiation therapy remains an integral component of treatment for many patients, but it must be used effectively and judiciously. The purpose of this review is to describe the different treatment scenarios and provide guidance for radiation dose, volume, and timing in patients with relapsed or refractory HL., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Histologic prognostic factors have been described for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). This study examines histologic and immunophenotypic variants in a clinical trial for pediatric NLPHL., Procedure: One hundred sixty-eight cases of localized NLPHL were examined for histologic variants, CD30 and immunoglobulin D (IgD) expression, and outcome. Histologic types were scored categorically as 0 = 0, 1 ≤ 25%, and 2 > 25% of the sample., Results: Fifty-eight (35.1%) cases showed only typical nodular with or without serpiginous histology (types A and B). The remainder showed mixtures of histologies. The numbers of patients with score 2 are 85 (50.6%) type A, 21 (12.5%) type B, 46 (27.4%) with extranodular large B cells (type C), 3 with T-cell-rich nodular pattern (type D), 55 (32.7%) with diffuse T-cell-rich (type E) pattern, and 2 (1.2%) with diffuse B-cell pattern (type F). Higher level of types C (P = 0.048) and D (P = 0.033) resulted in lower event-free survival (EFS). Cytoplasmic IgD was found in 65 of 130 tested (50%), did not significantly associate with EFS but positively correlated with types C and E histology (P < 0.0001) and negatively correlated with types A (P = 0.0003) and B (P = 0.006). Seventeen (10%) expressed CD30, with no adverse effect., Conclusions: Variant histology is common in pediatric NLPHL, especially types C and E, which are associated with IgD expression. Type C variant histology and possibly type D are associated with decreased EFS, but neither IgD nor CD30 are adverse features. Variant histology may warrant increased surveillance, but did not affect overall survival., (© 2017 Wiley Periodicals, Inc.)

As proton radiotherapy (RT) remains a limited resource, predictive estimates of the potential reduction in adverse treatment-related outcomes compared to photon RT could potentially help improve treatment selection. The aim of this study was to predict the magnitude of the neurocognitive and hearing deficits associated with proton and photon RT for children with brain tumors. The existing RT plans for 50 children treated with photon intensity modulated RT were compared with generated intensity modulated proton RT plans. The proton and photon RT dose distribution was used to estimate the Full Scale Intelligence Quotient (IQ) via a Monte Carlo model and the probability of hearing loss per ear, based on previously published dose-risk relationships. Compared to photon plans, the mean brain dose was found to be reduced in all proton plans, translating into a gain of [Formula: see text] IQ points for the whole cohort at 5 years post-RT for dose regimens of 54 Gy, or [Formula: see text] IQ points for dose regimens of 59.4 Gy, where the errors shown represent statistical and systematic uncertainties. The probability of hearing loss ≥20 dB per ear was less for proton versus photon RT: overall (9 ± 4) versus (17 ± 6)%, respectively, based on dose regimens of 54 Gy, and (13 ± 5) versus (23 ± 9)% for dose regimens of 59.4 Gy. Proton RT is thus expected to reduce the detrimental effect of RT upon IQ and hearing as compared to photon RT for pediatric brain tumors.

Background: As cure rates for breast cancer improve, there is increasing evidence that late effects of treatment-and impaired fertility in particular-are emerging as important concerns among young breast cancer survivors. Older reports have evaluated the occurrence of amenorrhea after treatment, but few data have been reported about the incidence of biochemical evidence for impaired ovarian function in patients who do not become overtly menopausal., Methods: We conducted a cross-sectional study evaluating anti-Müllerian hormone (amh) in premenopausal chemotherapy-treated breast cancer survivors and control patients. Random serum levels of amh and other relevant clinical data were collected for 100 premenopausal chemotherapy-treated breast cancer survivors and 76 control subjects. Subgroup analyses were performed for women with regular menstrual cycles at the time of amh testing., Results: After adjustment for age, amh was significantly lower in the overall group of patients receiving chemotherapy ( p = 0.002) and in the subgroup reporting normal cycles ( p = 0.03). Cyclophosphamide produced a significant dose-dependent reduction in amh ( p < 0.001); trastuzumab was associated with increased amh in survivors with normal cycles. Overall, serum amh in survivors was roughly equivalent to that measured in control patients 12 years older., Conclusions: Young breast cancer survivors often experience significant impairment of ovarian function despite having normal menstrual cycles after treatment. Those results have important implications for patient counselling and the timing of possible referral to a fertility specialist.

This paper offers best practice recommendations for the maintenance and retention of radiotherapy health records and technical information for cancer programmes. The recommendations are based on a review of the published and grey literature, feedback from key informants from seven countries and expert consensus. Ideally, complete health records should be retained for 5 years beyond the patient's lifetime, regardless of where they are created and maintained. Technical information constituting the radiotherapy plan should also be retained beyond the patient's lifetime for 5 years, including the primary images, contours of delineated targets and critical organs, dose distributions and other radiotherapy plan objects. There have been increased data storage and access requirements to support modern image-guided radiotherapy. Therefore, the proposed recommendations represent an ideal state of radiotherapy record retention to facilitate ongoing safe and effective care for patients as well as meaningful and informed retrospective research and policy development., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objective: Cancer survivors treated with abdominal/pelvic radiation therapy (ART) have increased the risks of colorectal cancer (CRC), although evidence supporting early CRC screening for these patients is lacking. We sought to determine whether there is an elevated prevalence of adenomatous colorectal polyps in young survivors prior to the age when screening would be routinely recommended., Design: We conducted a prospective study of early colonoscopic screening in cancer survivors aged 35-49 who had received ART ≥10 years previously. The planned sample size was based on prior studies reporting a prevalence of adenomatous polyps of approximately 20% among the average-risk population ≥50 years of age, in contrast to ≤10% among those average-risk people aged 40-50 years, for whom screening is not routinely recommended., Results: Colonoscopy was performed in 54 survivors, at a median age of 45 years (range 36-49) and after median interval from radiation treatment of 19 years (10.6-43.5). Forty-nine polyps were detected in 24 patients, with 15 patients (27.8%; 95% CI 17.6% to 40.9%) having potentially precancerous polyps. Fifty-three per cent of polyps were within or at the edge of the prior ART fields., Conclusions: Young survivors treated with ART have a polyp prevalence comparable with the average-risk population aged ≥50 years and substantially higher than previously reported for the average-risk population aged 40-50 years. These findings lend support to the early initiation of screening in these survivors., Clinical Trial Registration Number: NCT00982059; results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: To measure the clinical impact of pretreatment fludeoxyglucose positron emission tomography/computed tomography (PET/CT) on the staging and management of apparent limited stage indolent lymphoma being considered for curative radiation therapy., Methods: We conducted a prospective multicenter registry study that included 197 patients accrued between May 1, 2012, and December 31, 2015. Pre-PET/CT stage, determined by clinical and CT data, was documented. If pre-PET/CT stage was indeterminate, a stage was assigned to the patient by the referring oncologist according to best clinical judgment and treatment intent. After PET/CT, revised stage and planned management were recorded and compared with data on actual treatment received available through provincial databases (n = 155)., Results: PET/CT resulted in the upstaging of 47 (23.9%) patients with presumed limited stage disease (stage I-II) to advanced stage disease (stage III-IV) (P < .0001). Ten (5.1%) patients were downstaged by PET/CT, 4 of whom migrated from advanced to limited stage disease. Twenty-eight (14.2%) patients with a specific pre-PET/CT stage had equivocal PET/CT findings that required further evaluation to confirm disease extent. After PET/CT, 95 (61.3%) patients were planned to receive active treatment. Of the 59 patients planned for radiotherapy alone post-PET/CT, 34 (57.6%) received this treatment (P = .002), and nearly 80% of them (n = 27) had confirmed limited stage disease., Conclusion: PET/CT has a significant impact on staging and management in patients with apparent limited stage indolent lymphoma who are being considered for curative radiotherapy. PET/CT should be routinely incorporated into the workup of these patients. Cancer 2017;123:2860-66. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

To further understand the risk of stomach cancer after fractionated high-dose radiotherapy, we pooled individual-level data from three recent stomach cancer case-control studies. These studies were nested in cohorts of five-year survivors of first primary Hodgkin lymphoma (HL), testicular cancer (TC) or cervical cancer (CX) from seven countries. Detailed data were abstracted from patient records and radiation doses were reconstructed to the site of the stomach cancer for cases and to the corresponding sites for matched controls. Among 327 cases and 678 controls, mean doses to the stomach were 15.3 Gy, 24.7 Gy and 1.9 Gy, respectively, for Hodgkin lymphoma, testicular cancer and cervical cancer survivors, with an overall mean dose of 10.3 Gy. Risk increased with increasing radiation dose to the stomach cancer site (P < 0.001) with no evidence of nonlinearity or of a downturn at the highest doses (≥35 Gy). The pooled excess odds ratio per Gy (EOR/Gy) was 0.091 [95% confidence interval (CI): 0.036-0.20] with estimates of 0.049 (95% CI: 0.007-0.16) for Hodgkin lymphoma, 0.27 (95% CI: 0.054-1.44) for testicular cancer and 0.096 (95% CI: -0.002-0.39) for cervical cancer (P homogeneity = 0.25). The EOR/Gy increased with time since exposure (P trend = 0.004), with an EOR/Gy of 0.38 (95% CI: 0.12-1.04) for stomach cancer occurring ≥20 years postirradiation corresponding to odds ratios of 4.8 and 10.5 at radiation doses to the stomach of 10 and 25 Gy, respectively. Of 111 stomach cancers occurring ≥20 years after radiotherapy, 63.8 (57%) could be attributed to radiotherapy. Our findings differ from those based on Japanese atomic-bomb survivors, where the overall EOR/Gy was higher and where there was no evidence of an increase with time since exposure. By pooling data from three studies, we demonstrated a clear increase in stomach cancer risk over a wide range of doses from fractionated radiotherapy with the highest risks occurring many years after exposure. These findings highlight the need to directly evaluate the health effects of high-dose fractionated radiotherapy rather than relying on the data of persons exposed at low and moderate acute doses.

Purpose: To evaluate whether clinical risk factors could further distinguish children with intermediate-risk Hodgkin lymphoma (HL) with rapid early and complete anatomic response (RER/CR) who benefit significantly from involved-field RT (IFRT) from those who do not, and thereby aid refinement of treatment selection., Methods and Materials: Children with intermediate-risk HL treated on the Children's Oncology Group AHOD 0031 trial who achieved RER/CR with 4 cycles of chemotherapy, and who were randomized to 21-Gy IFRT or no additional therapy (n=716) were the subject of this study. Recursive partitioning analysis was used to identify factors associated with clinically and statistically significant improvement in event-free survival (EFS) after randomization to IFRT. Bootstrap sampling was used to evaluate the robustness of the findings., Result: Although most RER/CR patients did not benefit significantly from IFRT, those with a combination of anemia and bulky limited-stage disease (n=190) had significantly better 4-year EFS with the addition of IFRT (89.3% vs 77.9% without IFRT; P=.019); this benefit was consistently reproduced in bootstrap analyses and after adjusting for other prognostic factors., Conclusion: Although most patients achieving RER/CR had favorable outcomes with 4 cycles of chemotherapy alone, those children with initial bulky stage I/II disease and anemia had significantly better EFS with the addition of IFRT as part of combined-modality therapy. Further work evaluating the interaction of clinical and biologic factors and imaging response is needed to further optimize and refine treatment selection., (Copyright © 2016. Published by Elsevier Inc.)

These guidelines review the historical evolution of treatment for early-stage Hodgkin lymphoma (HL) with current standards that rely on prognostic factors to risk stratify and direct current treatment schemes that includes differentiation of favorable and unfavorable presentations. The major clinical trials for unfavorable early-stage HL are reviewed. Patients in this heterogenous subgroup of classic HL are best managed with sequential chemotherapy and radiotherapy. The role of imaging response assessment as a means to modify therapy is a strategy under investigation. Tailoring the radiation treatment volume and radiation dose prescription along with selective use of modern conformal techniques is expected to help reduce long-term toxicities. Many patients are well served receiving involved-site radiotherapy to 30 Gy after appropriate systemic therapy intensity; but, there are nuances for which some variations in the chemotherapy and radiotherapy specifics are appropriately individualized. Following a discussion of the current evidence-based treatment algorithms, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Purpose: Children's Oncology Group study AHOD03P1 was designed to determine whether excellent outcomes can be maintained for patients with low-risk, pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) with a strategy of resection alone or minimal chemotherapy., Patients and Methods: Patients with stage IA LPHL in a single node that was completely resected were observed without further therapy; recurrences were treated with three cycles of doxorubicin/vincristine/prednisone/cyclophosphamide (AV-PC). Patients with unresected stage IA or stage IIA LPHL were treated with three cycles of AV-PC. Patients with less than a complete response (CR) to AV-PC received 21-Gy involved-field radiation therapy (IFRT)., Results: A total of 183 eligible patients were enrolled; 178 were evaluable. Of these, 52 patients underwent complete resection of a single node. There were 13 relapses at a median of 11.5 months; 5-year event-free survival (EFS) was 77% (range, 62% to 87%). A total of 135 patients received AV-PC; 126 were treated at diagnosis and nine at relapse after surgery alone. Eleven patients receiving AV-PC had less than CR and received IFRT. Fourteen first events occurred among 135 patients (12 relapses and two second malignancies). Two relapses occurred in patients who had received IFRT. Five-year EFS was 88.8% (95% CI, 81.8% to 93.2%). Five-year EFS for the entire cohort was 85.5% (95% CI, 79.2% to 90.1%); overall survival was 100%., Conclusion: Some 75% of highly selected pediatric patients with LPHL may be spared chemotherapy after surgical resection alone. Pediatric LPHL has excellent EFS with chemotherapy that is less intensive than standard regimens; > 90% of patients can avoid radiation therapy. The salvage rate for the few relapses is high, with 100% survival overall., (© 2016 by American Society of Clinical Oncology.)

Purpose: Survivors of pediatric Hodgkin lymphoma (HL) are recognized to have an increased risk of delayed adverse health outcomes related to radiation therapy (RT). However, the necessary latency required to observe these late effects means that the estimated risks apply to outdated treatments. We sought to compare the normal tissue dose received by children treated for HL and enrolled in the Childhood Cancer Survivor Study (CCSS) (diagnosed 1970-1986) with that of patients treated in recent Children's Oncology Group (COG) trials (enrolled 2002-2012)., Methods and Materials: RT planning data were obtained for 50 HL survivors randomly sampled from the CCSS cohort and applied to computed tomography planning data sets to reconstruct the normal tissue dosimetry. For comparison, the normal tissue dosimetry data were obtained for all 191 patients with full computed tomography-based volumetric RT planning on COG protocols AHOD0031 and AHOD0831., Results: For early-stage patients, the mean female breast dose in the COG patients was on average 83.5% lower than that for CCSS patients, with an absolute reduction of 15.5 Gy. For advanced-stage patients, the mean breast dose was decreased on average by 70% (11.6 Gy average absolute dose reduction). The mean heart dose decreased on average by 22.9 Gy (68.6%) and 17.6 Gy (56.8%) for early- and advanced-stage patients, respectively. All dose comparisons for breast, heart, lung, and thyroid were significantly lower for patients in the COG trials than for the CCSS participants. Reductions in the prescribed dose were a major contributor to these dose reductions., Conclusions: These are the first data quantifying the significant reduction in the normal tissue dose using actual, rather than hypothetical, treatment plans for children with HL. These findings provide useful information when counseling families regarding the risks of contemporary RT., (Copyright © 2016 Elsevier Inc. All rights reserved.)