The risk of radiation-induced neurocognitive impairment and the impact of sparing the hippocampus during pediatric proton cranial irradiation.

BACKGROUND AND PURPOSE: Hippocampus is a central component for neurocognitive function and memory. We investigated the predicted risk of neurocognitive impairment of craniospinal irradiation (CSI) and the deliverability and effects of hippocampal sparing. The risk estimates were derived from published NTCP models. Specifically, we leveraged the estimated benefit of reduced neurocognitive impairment with the risk of reduced tumor control. MATERIAL AND METHODS: For this dose planning study, a total of 504 hippocampal sparing intensity modulated proton therapy (HS-IMPT) plans were generated for 24 pediatric patients whom had previously received CSI. Plans were evaluated with respect to target coverage and homogeneity index to target volumes, maximum and mean dose to OARs. Paired t-tests were used to compare hippocampal mean doses and normal tissue complication probability estimates. RESULTS: The median mean dose to the hippocampus could be reduced from 31.3 GyRBE to 7.3 GyRBE (p < .001), though 20% of these plans were not considered clinically acceptable as they failed one or more acceptance criterion. Reducing the median mean hippocampus dose to 10.6 GyRBE was possible with all plans considered as clinically acceptable treatment plans. By sparing the hippocampus to the lowest dose level, the risk estimation of neurocognitive impairment could be reduced from 89.6%, 62.1% and 51.1% to 41.0% (p < .001), 20.1% (p < .001) and 29.9% (p < .001) for task efficiency, organization and memory, respectively. Estimated tumor control probability was not adversely affected by HS-IMPT, ranging from 78.5 to 80.5% for all plans. CONCLUSIONS: We present estimates of potential clinical benefit in terms of neurocognitive impairment and demonstrate the possibility of considerably reducing neurocognitive adverse effects, minimally compromising target coverage locally using HS-IMPT.

Volumetric changes of the parotid gland during IMRT based on mid-treatment imaging: implications for parotid stem cell sparing strategies in head and neck cancer.

BACKGROUND: To evaluate the change in parotid glands at mid-treatment during IMRT and the association between radiation dose to the parotid gland stem cell (PGSC) region and patient-reported xerostomia for patients with head and neck cancer (HNC). MATERIAL AND METHODS: Patients who were treated from 2006-2012 at our institution with patient-reported xerostomia outcomes available at least 9 months following RT were included. PG and PGSC regions were delineated and the dose was estimated from the treatment plan dose distribution, using contours from pre- and mid-treatment CT scans. The association between radiation dose and volumetric changes was assessed using linear regression. Univariable logistic regression, logistic dose-response curves, and receiver operating characteristics (ROC) were used to examine the relationship between radiation dose and patient-reported xerostomia. RESULTS: Sixty-three patients were included, most treated with 70 Gy in 33 fractions; 34 patients had mid-treatment CT scans. Both contralateral and ipsilateral PGs had considerable volume reduction from baseline to mid-treatment (25% and 27%, respectively, both p < .001), significantly associated with mean PG dose (-0.44%/Gy, p = .008 and -0.54%/Gy, p < .001, respectively). There was a > 5 Gy difference in mean PG and PGSC dose for 8/34 patients at mid-treatment, with 6/8 (75%) reporting severe xerostomia. Xerostomia prediction based on whole PG or PGSC region dose showed similar performance (ROC AUC 0.754 and 0.749, respectively). The corresponding dose-response models also predicted similar risk of patient-reported xerostomia with mean dose to the contralateral PG (32.5%) or PGSC region (31.4%) at the 20 Gy QUANTEC-recommended sparing level. CONCLUSIONS: The radiation dose to the PGSC region did not show stronger association with patient-reported xerostomia compared to that of whole PG, possibly due to considerable anatomical changes identified at mid-treatment. This shift in the size and position of the PG warrants adaptive planning strategies to evaluate the true benefit of parotid stem cell sparing.

Organ-at-risk dose prediction using a machine learning algorithm: Clinical validation and treatment planning benefit for lung SBRT.

OBJECTIVE: To quantify the clinical performance of a machine learning (ML) algorithm for organ-at-risk (OAR) dose prediction for lung stereotactic body radiation therapy (SBRT) and estimate the treatment planning benefit from having upfront access to these dose predictions. METHODS: ML models were trained using multi-center data consisting of 209 patients previously treated with lung SBRT. Two prescription levels were investigated, 50 Gy in five fractions and 54 Gy in three fractions. Models were generated using a gradient-boosted regression tree algorithm using grid searching with fivefold cross-validation. Twenty patients not included in the training set were used to test OAR dose prediction performance, ten for each prescription. We also performed blinded re-planning based on OAR dose predictions but without access to clinically delivered plans. Differences between predicted and delivered doses were assessed by root-mean square deviation (RMSD), and statistical differences between predicted, delivered, and re-planned doses were evaluated with one-way analysis of variance (ANOVA) tests. RESULTS: ANOVA tests showed no significant differences between predicted, delivered, and replanned OAR doses (all p ≥ 0.36). The RMSD was 2.9, 3.9, 4.3, and 1.7Gy for max dose to the spinal cord, great vessels, heart, and trachea, respectively, for 50 Gy in five fractions. Average improvements of 1.0, 1.4, and 2.0 Gy were seen for spinal cord, esophagus, and trachea max doses in blinded replans compared to clinically delivered plans with 54 Gy in three fractions, and 1.8, 0.7, and 1.5 Gy, respectively, for the esophagus, heart and bronchus max doses with 50 Gy in five fractions. Target coverage was similar with an average PTV V100% of 94.7% for delivered plans compared to 97.3% for blinded re-plans for 50 Gy in five fractions, and respectively 98.4% versus 99.2% for 54 Gy in three fractions. CONCLUSION: This study validated ML-based OAR dose prediction for lung SBRT, showing potential for improved OAR dose sparing and more consistent plan quality using dose predictions for patient-specific planning guidance.

The risk of late effects following pediatric and adult radiotherapy regimens in Hodgkin lymphoma.

PURPOSE: Adolescent young adults (AYA) with Hodgkin lymphoma (HL) are treated according to either pediatric or adult protocols, however, the best strategy has yet to be established. We describe the AYA patients referred for radiotherapy and quantify the risk of radiation-induced late effects and the corresponding life years lost (LYL) following pediatric and adult regimens. METHODS: Patients ≤24 years irradiated for HL were included. For each patient, organs at risk (OARs) were contoured and dosimetric parameters were extracted. Estimated excess hazard ratios of radiation-induced late effects were calculated from dose-response models and LYL attributable to various late effects were estimated. RESULTS: In total, 77 patients were analyzed (pediatric regimen: 15; adult regimen: 62). Age, clinical stage, and the number of patients enrolled in protocols were significantly different between the groups. Pediatric patients had more advanced disease, which resulted in larger target volumes and higher doses to most OARs, despite a lower prescribed dose compared to adult regimens. LYL estimates were all higher with the pediatric regimens. Total LYL with pediatric and adult treatment regimens were 3.2 years and 2.3 years, respectively. Due to the clinical stage variation and heterogeneity in disease location, a direct comparison of the estimated risks of late effects was only exploratory. CONCLUSION: Pediatric regimens selected patients with more advanced disease to radiotherapy resulting in larger target volumes and higher doses to the OARs. Target volume rather than prescribed dose impacted OAR exposure. Consequently, the estimated risk of radiation-induced late effects and corresponding LYL was increased when compared to adult regimens.

Human papillomavirus, radiation dose and survival of patients with anal cancer.

Purpose: To determine if anal cancer patients with HPV positive disease have different overall survival (OS) compared to those with HPV negative disease, and to elucidate differences in the association between radiation dose and OS.Patients and methods: We utilized the National Cancer Database (NCDB) registry to identify a cohort of non-metastatic anal cancer patients treated with curative intent between 2008 and 2014. Propensity score matching was used to account for potential selection bias between patients with HPV positive and negative disease. Multivariable Cox regression was used to determine the association between HPV status and OS. Kaplan-Meier methods were used to compare actuarial survival estimates.Results: We identified 5927 patients with tumor HPV status for this analysis, 3523 (59.4%) had HPV positive disease and 2404 (40.6%) had HPV negative disease. Propensity-matched analysis demonstrated that patients with HPV positive locally advanced (T3-4 or node positive) anal cancer had better OS (HR = 0.81 (95%CI: 0.68-0.96), p=.018). For patients with early stage disease (T1-2 and node negative) there was no difference in OS (HR = 1.11 (95%CI: 0.86-1.43), p=.43). In the unmatched cohort, we found a significant improvement in OS with increasing radiation dose only for patients with locally advanced, HPV negative disease (p<.001). In those patients, significant improvement in OS compared to the group receiving 30-45 Gy was seen for increasing doses up to 55-60 Gy, but not beyond 60 Gy.Conclusion: We found HPV to be a significant prognostic marker in anal tumors, especially for locally advanced disease. We further found that higher radiation dose up to 55-60 Gy was associated with better OS, but only for patients with locally advanced, HPV negative disease.

Optimizing the radiation therapy dose prescription for pediatric medulloblastoma: minimizing the life years lost attributable to failure to control the disease and late complication risk.

BACKGROUND: A mathematical framework is presented for simultaneously quantifying and evaluating the trade-off between tumor control and late complications for risk-based radiation therapy (RT) decision-support. To demonstrate this, we estimate life years lost (LYL) attributable to tumor recurrence, late cardiac toxicity and secondary cancers for standard-risk pediatric medulloblastoma (MB) patients and compare the effect of dose re-distribution on a common scale. METHODS: Total LYL were derived, based on the LYL attributable to radiation-induced late complications and the LYL from not controlling the primary disease. We compared the estimated LYL for three different treatments in 10 patients: 1) standard 3D conformal RT; 2) proton therapy; 3) risk-adaptive photon treatment lowering the dose to part of the craniospinal (CS) target volume situated close to critical risk organs. RESULTS: Late toxicity is important, with 0.75 LYL (95% CI 0.60-7.2 years) for standard uniform 24 Gy CS irradiation. However, recurrence risk dominates the total LYL with 14.2 years (95% CI 13.4-16.6 years). Compared to standard treatment, a risk-adapted strategy prescribing 12 Gy to the spinal volume encompassing the 1st-10th thoracic vertebrae (Th1-Th10), and 36 Gy to the remaining CS volume, estimated a LYL reduction of 0.90 years (95% CI -0.18-2.41 years). Proton therapy with 36 Gy to the whole CS volume was associated with significantly fewer LYL compared to the risk-adapted photon strategies, with a mean LYL difference of 0.50 years (95% CI 0.25-2.60 years). CONCLUSIONS: Optimization of RT prescription strategies considering both late complications and the risk of recurrence, an all-cause mortality dose painting approach, was demonstrated. The risk-adapted techniques compared favorably to the standard, and although in this context, the gain is small compared to estimated uncertainty, this study demonstrates a framework for all-cause mortality risk estimation, rather than evaluates direct clinical applicability of risk-adapted strategies.

A treatment planning and delivery comparison of volumetric modulated arc therapy with or without flattening filter for gliomas, brain metastases, prostate, head/neck and early stage lung cancer.

BACKGROUND: Flattening filter-free (FFF) beams are an emerging technology that has not yet been widely implemented as standard practice in radiotherapy centers. To facilitate the clinical implementation of FFF, we attempted to elucidate the difference in plan quality and treatment delivery time compared to flattening filter beams (i.e. standard, STD) for several patient groups. We hypothesize that the treatment plan quality is comparable while the treatment delivery time of volumetric modulated arc therapy (VMAT) is considerably shorter using FFF beams, especially for stereotactic treatments. METHODS: A total of 120 patients treated for head and neck (H&N) tumors, high-grade glioma, prostate cancer, early stage lung cancer and intra-cranial metastatic disease (both single and multiple metastases) were included in the study. For each cohort, 20 consecutive patients were selected. The plans were generated using STD- and FFF-VMAT for both 6 MV and 10 MV, and were compared with respect to plan quality, monitor units and delivery time using Wilcoxon signed rank tests. RESULTS: For H&N and high-grade gliomas, there was a significant difference in homogeneity index in favor for STD-VMAT (p < 0.001). For the stereotactic sites there were no differences in plan conformity. Stereotactic FFF-VMAT plans required significantly shorter delivery time compared to STD-VMAT plans (p < 0.001) for higher dose per fraction, on average 54.5% for 6 MV and 71.4% for 10 MV. FFF-VMAT generally required a higher number of MU/Gy (p < 0.001), on average 7.0% for 6 MV and 8.4% for 10 MV. CONCLUSION: It was generally possible to produce FFF-VMAT plans with the same target dose coverage and doses to organs at risk as STD-VMAT plans. Target dose homogeneity tended to be somewhat inferior for FFF-VMAT for the larger targets investigated. For stereotactic radiotherapy, FFF-VMAT resulted in a considerable time gain while maintaining similar plan quality compared to STD beams.

Risk of Subsequent Neoplasms in Childhood Cancer Survivors After Radiation Therapy: A Comprehensive PENTEC Review.

PURPOSE: A Pediatric Normal Tissue Effects in the Clinic (PENTEC) analysis of published investigations of central nervous system (CNS) subsequent neoplasms (SNs), subsequent sarcomas, and subsequent lung cancers in childhood cancer survivors who received radiation therapy (RT) was performed to estimate the effect of RT dose on the risk of SNs and the modification of this risk by host and treatment factors. METHODS AND MATERIALS: A systematic literature review was performed to identify data published from 1975 to 2022 on SNs after prior RT in childhood cancer survivors. After abstract review, usable quantitative and qualitative data were extracted from 83 studies for CNS SNs, 118 for subsequent sarcomas, and 10 for lung SNs with 4 additional studies (3 for CNS SNs and 1 for lung SNs) later added. The incidences of SNs, RT dose, age, sex, primary cancer diagnosis, chemotherapy exposure, and latent time from primary diagnosis to SNs were extracted to assess the factors influencing risk for SNs. The excess relative ratio (ERR) for developing SNs as a function of dose was analyzed using inverse-variance weighted linear regression, and the ERR/Gy was estimated. Excess absolute risks were also calculated. RESULTS: The ERR/Gy for subsequent meningiomas was estimated at 0.44 (95% CI, 0.19-0.68); for malignant CNS neoplasms, 0.15 (95% CI, 0.11-0.18); for sarcomas, 0.045 (95% CI, 0.023-0.067); and for lung cancer, 0.068 (95% CI, 0.03-0.11). Younger age at time of primary diagnosis was associated with higher risk of subsequent meningioma and sarcoma, whereas no significant effect was observed for age at exposure for risk of malignant CNS neoplasm, and insufficient data were available regarding age for lung cancer. Females had a higher risk of subsequent meningioma (odds ratio, 1.46; 95% CI, 1.22-1.76; P < .0001) relative to males, whereas no statistically significant sex difference was seen in risk of malignant CNS neoplasms, sarcoma SNs, or lung SNs. There was an association between chemotherapy receipt (specifically alkylating agents and anthracyclines) and subsequent sarcoma risk, whereas there was no clear association between specific chemotherapeutic agents and risk of CNS SNs and lung SNs. CONCLUSIONS: This PENTEC systematic review shows a significant radiation dose-response relationship for CNS SNs, sarcomas, and lung SNs. Given the linear dose response, improved conformality around the target volume that limits the high dose volume might be a promising strategy for reducing the risk of SNs after RT. Other host- and treatment-related factors such as age and chemotherapy play a significant contributory role in the development of SNs and should be considered when estimating the risk of SNs after RT among childhood cancer survivors.

Life years lost--comparing potentially fatal late complications after radiotherapy for pediatric medulloblastoma on a common scale.

BACKGROUND: The authors developed a framework for estimating and comparing the risks of various long-term complications on a common scale and applied it to 3 different techniques for craniospinal irradiation in patients with pediatric medulloblastoma. METHODS: Radiation dose-response parameters related to excess hazard ratios for secondary breast, lung, stomach, and thyroid cancer; heart failure, and myocardial infarction were derived from large published clinical series. Combined with age-specific and sex-specific hazards in the US general population, the dose-response analysis yielded excess hazards of complications for a cancer survivor as a function of attained age. After adjusting for competing risks of death, life years lost (LYL) were estimated based on excess hazard and prognosis of a complication for 3-dimensional conformal radiotherapy (3D CRT), volumetric modulated arc therapy (VMAT), and intensity-modulated proton therapy (IMPT). RESULTS: Lung cancer contributed most to the estimated LYL, followed by myocardial infarction, and stomach cancer. The estimates of breast or thyroid cancer incidence were higher than those for lung and stomach cancer incidence, but LYL were lower because of the relatively good prognosis. Estimated LYL ranged between 1.90 years for 3D CRT to 0.28 years for IMPT. In a paired comparison, IMPT was associated with significantly fewer LYL than both photon techniques. CONCLUSIONS: Estimating the risk of late complications is associated with considerable uncertainty, but including prognosis and attained age at an event to obtain the more informative LYL estimate added relatively little to this uncertainty.

Fatigue in Patients With Head and Neck Cancer Treated With Radiation Therapy: A Prospective Study of Patient-Reported Outcomes and Their Association With Radiation Dose to the Cerebellum.

Purpose: Although fatigue is a known side effect in patients with head and neck cancer (HNC) receiving radiation therapy, knowledge regarding long-term fatigue and dose-response relationships to organs at risk is scarce. The aim of this prospective study was to analyze patient-reported fatigue in patients with HNC receiving radiation therapy and to explore any possible association with organ-at-risk doses. Methods and Materials: Patients with HNC referred for curative radiation therapy were eligible for inclusion in the study. To assess patient-reported fatigue, quality of life questionnaires (European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-FA12) were distributed before treatment and 1, 3, 6, 12, 24, and 60 months after the start of treatment. Mean dose (Dmean) and near maximum dose (D2%) of the cerebellum and brain stem were evaluated in relation to baseline-adjusted fatigue scores at 3 months. Results: One hundred twenty-six patients treated with intensity modulated radiation therapy between 2008 and 2010 were available for final analysis. Female sex and age <60 years were associated with higher fatigue at baseline, whereas patients also treated with chemotherapy had reduced physical and emotional fatigue at 6 months. Physical fatigue (QLQ-FA12 scale) increased from baseline up to 3 months (29 vs 59; P < .0001) but showed no difference compared with baseline from 1 to 5 years. Emotional fatigue was significantly lower at 5 years compared with baseline (14 vs 28; P < .0001). Patients with cerebellum Dmean > 3.5 Gy had higher mean physical fatigue scores at 3 months (38 vs 27; P = .036). Conclusions: Although there is a significant increase in fatigue scores for patients with HNC up to 1 year after radiation therapy, this study showed a return to baseline levels at 5 years. A possible association was found between physical fatigue and a higher mean dose to the cerebellum.

Case Report: Can Targeted Intraoperative Radiotherapy in Patients With Breast Cancer and Pacemakers be the New Standard of Care?

Background: Partial breast irradiation with Intra-operative radiotherapy (IORT) has become a popular management option as opposed to whole breast radiation using external beam radiotherapy for breast cancer patients. While previous studies have highlighted the use of IORT in breast cancer patients, there is a scarcity of literature on the use of IORT in those who also have ipsilateral pacemakers. Thus, the aim of our case report is to highlight the applicability of IORT in breast cancer patients who also have a pacemaker. Case Reports: Two female patients with an implanted dual-chamber pacemaker presented with a diagnosis of left-sided invasive ductal carcinoma on mammogram. Mammography of the left breast revealed a 10 mm and 7 mm spiculated mass, respectively, further confirmed with an ultrasound-guided core biopsy that was conclusive of clinical Stage I T1 N0 grade 2, ER +, PR + Her2 - invasive ductal carcinoma. They met our eligibility criteria for IORT, which is being performed as a registry trial. These patients underwent a wide excision lumpectomy along with IORT. Conclusion: Our findings underscore the successful use of targeted IORT for breast-conserving surgery in a patient with invasive ductal carcinoma and pacemaker, hence eliminating the necessity for relocating pacemaker surgeries in these patients. Furthermore, no device failure or malfunction for the pacemaker was recorded before, during, or after the surgery, demonstrating the safety of using IORT in patients with preinstalled pacemaker despite a lack of evidence on safe radiation dosage or manufacturer guidelines. Nonetheless, the effects of IORT on pacemaker < 10 cm were not studied in our patients and further clinical studies are recommended to reinforce the applicability and safe distance of IORT in breast cancer patients with pacemaker.

Improving Adjuvant Liver-Directed Treatment Recommendations for Unresectable Hepatocellular Carcinoma: An Artificial Intelligence-Based Decision-Making Tool.

PURPOSE: Liver-directed therapy after transarterial chemoembolization (TACE) can lead to improvement in survival for selected patients with unresectable hepatocellular carcinoma (HCC). However, there is uncertainty in the appropriate application and modality of therapy in current clinical practice guidelines. The aim of this study was to develop a proof-of-concept, machine learning (ML) model for treatment recommendation in patients previously treated with TACE and select patients who might benefit from additional treatment with combination stereotactic body radiotherapy (SBRT) or radiofrequency ablation (RFA). METHODS: This retrospective observational study was based on data from an urban, academic hospital system selecting for patients diagnosed with stage I-III HCC from January 1, 2008, to December 31, 2018, treated with TACE, followed by adjuvant RFA, SBRT, or no additional liver-directed modality. A feedforward, ML ensemble model provided a treatment recommendation on the basis of pairwise assessments evaluating each potential treatment option and estimated benefit in survival. RESULTS: Two hundred thirty-seven patients met inclusion criteria, of whom 54 (23%) and 49 (21%) received combination of TACE and SBRT or TACE and RFA, respectively. The ML model suggested a different consolidative modality in 32.7% of cases among patients who had previously received combination treatment. Patients treated in concordance with model recommendations had significant improvement in progression-free survival (hazard ratio 0.5; P = .007). The most important features for model prediction were cause of cirrhosis, stage of disease, and albumin-bilirubin grade (a measure of liver function). CONCLUSION: In this proof-of-concept study, an ensemble ML model was able to provide treatment recommendations for HCC who had undergone prior TACE. Additional treatment in line with model recommendations was associated with significant improvement in progression-free survival, suggesting a potential benefit for ML-guided medical decision making.

A positron emission tomography radiomic signature for distant metastases risk in oropharyngeal cancer patients treated with definitive chemoradiotherapy.

BACKGROUND AND PURPOSE: Disease recurrence and distant metastases (DM) are major concerns for oropharyngeal cancer (OPC) patients receiving definitive chemo-radiotherapy. Here, we investigated whether pre-treatment primary tumor positron emission tomography (PET) features could predict progression-free survival (PFS) or DM. METHODS AND MATERIALS: Primary tumors were delineated on pre-treatment PET scans for patients treated between 2005 and 2018 using gradient-based segmentation. Radiomic image features were extracted, along with SUV metrics. Features with zero variance and strong correlation to tumor volume, stage, p16 status, age or smoking were excluded. A random forest model was used to identify features associated with PFS. Kaplan-Meier methods, Cox regression and logistic regression with receiver operating characteristics (ROC) and 5-fold cross-validated areas-under-the-curve (CV-AUCs) were used. RESULTS: A total of 114 patients were included. With median follow-up 40 months (range: 3-138 months), 14 patients had local recurrence, 21 had DM and 38 died. Two-year actuarial local control, distant control, PFS and overall survival was 89%, 84%, 70% and 84%, respectively. The wavelet_LHL_GLDZM_LILDE feature slightly improved PFS prediction compared to clinical features alone (CV-AUC 0.73 vs. 0.71). Age > 65 years (HR = 2.64 (95%CI: 1.36-5.2), p = 0.004) and p16-negative disease (HR = 3.38 (95%CI: 1.72-6.66), p < 0.001) were associated with poor PFS. A binary radiomic classifier strongly predicted DM with multivariable HR = 3.27 (95%CI: 1.15-9.31), p = 0.027, specifically for patients with p16-negative disease with 2-year DM-free survival 83% for low-risk vs. 38% for high-risk patients (p = 0.004). CONCLUSIONS: A radiomics signature strongly associated with DM risk could provide a tool for improved risk stratification, potentially adding adjuvant immunotherapy for high-risk patients.

Orthovoltage X-Rays Exhibit Increased Efficacy Compared with γ-Rays in Preclinical Irradiation.

Radionuclide irradiators (137Cs and 60Co) are commonly used in preclinical studies ranging from cancer therapy to stem cell biology. Amidst concerns of radiological terrorism, there are institutional initiatives to replace radionuclide sources with lower energy X-ray sources. As researchers transition, questions remain regarding whether the biological effects of γ-rays may be recapitulated with orthovoltage X-rays because different energies may induce divergent biological effects. We therefore sought to compare the effects of orthovoltage X-rays with 1-mm Cu or Thoraeus filtration and 137Cs γ-rays using mouse models of acute radiation syndrome. Following whole-body irradiation, 30-day overall survival was assessed, and the lethal dose to provoke 50% mortality within 30-days (LD50) was calculated by logistic regression. LD50 doses were 6.7 Gy, 7.4 Gy, and 8.1 Gy with 1-mm Cu-filtered X-rays, Thoraeus-filtered X-rays, and 137Cs γ-rays, respectively. Comparison of bone marrow, spleen, and intestinal tissue from mice irradiated with equivalent doses indicated that injury was most severe with 1-mm Cu-filtered X-rays, which resulted in the greatest reduction in bone marrow cellularity, hematopoietic stem and progenitor populations, intestinal crypts, and OLFM4+ intestinal stem cells. Thoraeus-filtered X-rays provoked an intermediate phenotype, with 137Cs showing the least damage. This study reveals a dichotomy between physical dose and biological effect as researchers transition to orthovoltage X-rays. With decreasing energy, there is increasing hematopoietic and intestinal injury, necessitating dose reduction to achieve comparable biological effects. SIGNIFICANCE: Understanding the significance of physical dose delivered using energetically different methods of radiation treatment will aid the transition from radionuclide γ-irradiators to orthovoltage X-irradiators.

Radiobiological risk estimates of adverse events and secondary cancer for proton and photon radiation therapy of pediatric medulloblastoma.

INTRODUCTION: The aim of this model study was to estimate and compare the risk of radiation-induced adverse late effects in pediatric patients with medulloblastoma (MB) treated with either three-dimensional conformal radiotherapy (3D CRT), inversely-optimized arc therapy (RapidArc(®) (RA)) or spot-scanned intensity-modulated proton therapy (IMPT). The aim was also to find dose-volume toxicity parameters relevant to children undergoing RT to be used in the inverse planning of RA and IMPT, and to use in the risk estimations. MATERIAL AND METHODS: Treatment plans were created for all three techniques on 10 pediatric patients that have been treated with craniospinal irradiation (CSI) at our institution in 2007-2009. Plans were generated for two prescription CSI doses, 23.4 Gy and 36 Gy. Risk estimates were based on childhood cancer survivor data when available and secondary cancer (SC) risks were estimated as a function of age at exposure and attained age according to the organ-equivalent dose (OED) concept. RESULTS: Estimates of SC risk was higher for the RA plans and differentiable from the estimates for 3D CRT at attained ages above 40 years. The risk of developing heart failure, hearing loss, hypothyroidism and xerostomia was highest for the 3D CRT plans. The risks of all adverse effects were estimated as lowest for the IMPT plans, even when including secondary neutron (SN) irradiation with high values of the neutron radiation weighting factors (WR(neutron)). CONCLUSIONS: When comparing RA and 3D CRT treatment for pediatric MB it is a matter of comparing higher SC risk against higher risks of non-cancer adverse events. Considering time until onset of the different complications is necessary to fully assess patient benefit in such a comparison. The IMPT plans, including SN dose contribution, compared favorably to the photon techniques in terms of all radiobiological risk estimates.

Validating the SumMean 18F-FDG PET Textural Feature as a Prognostic Marker in an Independent Cohort of Locally Advanced Non-Small Cell Lung Cancer Patients Undergoing Concurrent Chemoradiation Therapy.

PURPOSE: Analyses from the ACRIN6668/RTOG0235 trial data identified the SumMean textural feature, calculated from 18-fluorodeoxyglucose positron emission tomography for tumors with a metabolic tumor volume >93 cm3, as a predictor of overall survival (OS) for patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiation therapy. Here, we validated that finding in a completely independent patient cohort from a single institution. METHODS AND MATERIALS: We identified patients with LA-NSCLC who underwent staging 18-fluorodeoxyglucose positron emission tomography and received definitive chemoradiation therapy at our institution between 2007 and 2018. Primary tumors were segmented semiautomatically, and SumMean score was calculated for each tumor and categorized according to the previously proposed cutoff of 0.018. In patients with metabolic tumor volume >93 cm3, SumMean was evaluated as a predictor of progression-free survival (PFS) and OS using log rank and Cox proportional hazards testing. RESULTS: One hundred forty-eight patients met inclusion criteria, and 34 had large tumors (>93 cm3). Twelve (35%) had high SumMean, and 22 (65%) had low SumMean. SumMean was not significantly associated with other clinical variables. Median PFS for patients with large tumors and low SumMean was 5.8 months, compared with 41.1 months for patients with large tumors and high SumMean (log rank P = .022). Median OS for patients with large tumors and low SumMean was 15.0 months; median OS was not reached for patients with large tumors and high SumMean (log rank P = .014). In multivariable analysis, high SumMean was an independent predictor of improved OS (hazard ratio, 0.26; 95% confidence interval, 0.07-0.94; P = .041) and PFS (hazard ratio, 0.30; 95% confidence interval, 0.10-0.86; P = .026). CONCLUSIONS: We externally validated SumMean as a prognostic marker for patients with LA-NSCLC treated with chemoradiation therapy in an independent patient cohort. Future studies will explore potential mechanisms for this association and how textural features may help guide treatment decisions.

Individualized quality of life benefit and cost-effectiveness estimates of proton therapy for patients with oropharyngeal cancer.

BACKGROUND: Proton therapy is a promising advancement in radiation oncology especially in terms of reducing normal tissue toxicity, although it is currently expensive and of limited availability. Here we estimated the individual quality of life benefit and cost-effectiveness of proton therapy in patients with oropharyngeal cancer treated with definitive radiation therapy (RT), as a decision-making tool for treatment individualization. METHODS AND MATERIALS: Normal tissue complication probability models were used to estimate the risk of dysphagia, esophagitis, hypothyroidism, xerostomia and oral mucositis for 33 patients, comparing delivered photon intensity-modulated RT (IMRT) plans to intensity-modulated proton therapy (IMPT) plans. Quality-adjusted life years (QALYs) lost were calculated for each complication while accounting for patient-specific conditional survival probability and assigning quality-adjustment factors based on complication severity. Cost-effectiveness was modeled based on upfront costs of IMPT and IMRT, and the cost of acute and/or long-term management of treatment complications. Uncertainties in all model parameters and sensitivity analyses were included through Monte Carlo sampling. RESULTS: The incremental cost-effectiveness ratios (ICERs) showed considerable variability in the cost of QALYs spared between patients, with median $361,405/QALY for all patients, varying from $54,477/QALY to $1,508,845/QALY between individual patients. Proton therapy was more likely to be cost-effective for patients with p16-positive tumors ($234,201/QALY), compared to p16-negative tumors ($516,297/QALY). For patients with p16-positive tumors treated with comprehensive nodal irradiation, proton therapy is estimated to be cost-effective in ≥ 50% of sampled cases for 8/9 patients at $500,000/QALY, compared to 6/24 patients who either have p16-negative tumors or receive unilateral neck irradiation. CONCLUSIONS: Proton therapy cost-effectiveness varies greatly among oropharyngeal cancer patients, and highlights the importance of individualized decision-making. Although the upfront cost, societal willingness to pay and healthcare administration can vary greatly among different countries, identifying patients for whom proton therapy will have the greatest benefit can optimize resource allocation and inform prospective clinical trial design.

Using Statistical Measures and Density Maps Generated From Chest Computed Tomography Scans to Identify and Monitor COVID-19 Cases in Radiation Oncology Rapidly.

Objectives This study aimed to evaluate quantitative and qualitative screening measures for anomalous computed tomography (CT) scans in cancer patients with potential coronavirus disease 2019 (COVID-19) as an automated detection tool in a radiation oncology treatment setting. Methods We identified a non-COVID-19 cohort and patients with suspected COVID-19 with chest CT scans from February 1, 2020 to June 30, 2020. Lungs were segmented, and a mean normal Hounsfield Unit (HU) histogram was generated for the non-COVID-19 CT scans; these were used to define thresholds for designating the COVID-19-suspected histograms as normal or abnormal. Statistical measures were computed and compared to the threshold levels, and density maps were generated to examine the difference between lungs with and without COVID-19 qualitatively. Results The non-COVID-19 cohort consisted of 70 patients with 70 CT scans, and the cohort of suspected COVID-19 patients consisted of 59 patients with 80 CT scans. Sixty-two patients were positive for COVID-19. The mean HUs and skewness of the intensity histogram discriminated between COVID-19 positive and negative cases, with an area under the curve of 0.948 for positive and 0.944 for negative cases. Skewness correctly identified 57 of 62 positive cases, whereas mean HUs correctly identified 17 of 18 negative cases. Density maps allowed for visualization of the temporal evolution of COVID-19 disease. Conclusions The statistical measures and density maps evaluated here could be employed in an automated screening algorithm for COVID-19 infection. The accuracy is high enough for a simple and rapid screening tool for early identification of suspected infection in patients treated with chemotherapy and radiation therapy already receiving CT scans as part of clinical care. This screening tool could also identify other infections that present critical risks for patients undergoing chemotherapy and radiation therapy, such as pneumonitis.

Using CT-guided stereotactic prostate radiation therapy (CT-SPRT) to assess sustained murine prostate ablation.

The prostate is a hormone-responsive organ where testicular androgens drive the proliferation and survival of prostatic cells, ensuring the development and functioning of this gland throughout life. Androgen deprivation therapy leads to apoptosis of prostatic cells and organ regression, and is a cornerstone of prostate cancer and benign prostatic hypertrophy treatment. For several decades, androgen deprivation has been used as an adjuvant to external beam radiotherapy, however, emerging data suggests that the low rates of epithelial proliferation in the castrated prostate imparts radio-resistance. As proliferating cells exhibit increased sensitivity to radiation, we hypothesized that short bursts of synchronized epithelial proliferation, which can be achieved by exogeneous testosterone supplementation prior to targeted high-dose radiation, would maximize sustained prostate ablation, while minimizing damage to surrounding tissues. To test this hypothesis, we designed a novel computed-tomography (CT)-guided stereotactic prostate radiation therapy (CT-SPRT) technique to deliver a single high-dose 25 Gy fraction of X-ray radiation. Sustained prostatic cell ablation was assessed post CT-SPRT by measuring prostate weight, epithelial cell number, and relative contributions of luminal and basal epithelial populations in control and testosterone-pretreated glands. CT-SPRT was safely delivered with no observed damage to surrounding rectal and bladder tissues. Importantly, castrated mice that received a pulse of testosterone to induce synchronous cell proliferation prior to CT-SPRT exhibited significant sustained gland ablation compared to control mice. These results provide new insights in stereotactic radiotherapy sensitivity to maximize prostatic cell ablation and improve our understanding of prostate gland regeneration that can potentially lead to improved non-invasive therapies for benign prostatic hypertrophy and prostate cancer.

Neurocognitive Effects and Necrosis in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review.

PURPOSE: A PENTEC review of childhood cancer survivors who received brain radiation therapy (RT) was performed to develop models that aid in developing dose constraints for RT-associated central nervous system (CNS) morbidities. METHODS AND MATERIALS: A comprehensive literature search, through the PENTEC initiative, was performed to identify published data pertaining to 6 specific CNS toxicities in children treated with brain RT. Treatment and outcome data on survivors were extracted and used to generate normal tissue complication probability (NTCP) models. RESULTS: The search identified investigations pertaining to 2 of the 6 predefined CNS outcomes: neurocognition and brain necrosis. For neurocognition, models for 2 post-RT outcomes were developed to (1) calculate the risk for a below-average intelligence quotient (IQ) (IQ <85) and (2) estimate the expected IQ value. The models suggest that there is a 5% risk of a subsequent IQ <85 when 10%, 20%, 50%, or 100% of the brain is irradiated to 35.7, 29.1, 22.2, or 18.1 Gy, respectively (all at 2 Gy/fraction and without methotrexate). Methotrexate (MTX) increased the risk for an IQ <85 similar to a generalized uniform brain dose of 5.9 Gy. The model for predicting expected IQ also includes the effect of dose, age, and MTX. Each of these factors has an independent, but probably cumulative effect on IQ. The necrosis model estimates a 5% risk of necrosis for children after 58.9 Gy or 59.9 Gy (2 Gy/fraction) to any part of the brain if delivered as primary RT or reirradiation, respectively. CONCLUSIONS: This PENTEC comprehensive review establishes objective relationships between patient age, RT dose, RT volume, and MTX to subsequent risks of neurocognitive injury and necrosis. A lack of consistent RT data and outcome reporting in the published literature hindered investigation of the other predefined CNS morbidity endpoints.