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Background and purposePatients with hepatocellular carcinoma (HCC) commonly have underlying liver dysfunction with variable tolerance to liver stereotactic body radiation therapy (SBRT). We hypothesized that insertion of a 1-month mid-treatment break would allow us to adapt treatment to the individual patient response, thereby reducing toxicity without compromising local control (LC).Materials and methodsWe analyzed HCC patients receiving 3-5 fraction SBRT at our institution from 2005 to 2017. Over this time, patients were offered enrollment on prospective trials assessing individualized adaptive SBRT. Based on normal tissue complication probability and modeling of changes in liver function following a 1-month treatment break between fractions 3 and 4, patients could receive a total of 3 or 5 fractions. Patients not on trial received 3 or 5 fractions without a break. Toxicity was defined as a ≥2 point rise in Child-Pugh (CP) score within 6 months of SBRT.Results178 patients were treated with SBRT to 263 HCCs. Median follow-up was 23 months. 86 treatments had a 1-month break. 1-Year LC was 95.4%; this was not different between patients treated with or without a break (p = 0.14). Controlling for tumor size and dose a break was not associated with inferior LC (HR: 0.58, 95%CI: 0.1-3.34, p = 0.54). 54 patients experienced a ≥2 point rise in CP score. Controlling for the number of prior liver directed therapies and mean liver dose, a treatment break reduced the odds of toxicity (OR: 0.42, 95% CI: 0.17-1.03, p = 0.06).ConclusionA one-month mid-treatment break and reassessment may reduce the odds of treatment related toxicity without compromising LC.

The purpose of this study was to determine the maximum tolerated dose (MTD) of gemcitabine when given concurrently with standard radiotherapy for the treatment of chest wall recurrences, and to compare actuarial rates of local-regional control with those achieved in historical controls. Patients with unresectable chest wall recurrences were enrolled in a phase I trial of concurrent gemcitabine and radiotherapy. Gemcitabine was increased at 150 mg/m2/week increments, starting at 300 mg/m2/ week. Radiotherapy was delivered to the chest wall and regional nodes to a total of 60 to 70 Gy in 2 Gy daily fractions. Treatment toxicity was assessed and a comparison of treatment outcome was performed between study patients and historical groups treated with either radiotherapy alone or excision followed by radiotherapy. The dose-limiting toxicities of neutropenia and thrombocytopenia occurred at the second planned dose of 450 mg/m2/week after accrual of only six patients, resulting in a MTD of 300 mg/m2/ week. Myelosuppression and skin desquamation were commonly observed. Actuarial rates of local-regional control were 100%, 50%, and 90% at 2 years for the gemcitabine with radiotherapy, radiotherapy alone, and excision followed by radiotherapy groups, respectively (p = 0.105).The difference among the Kaplan-Meier curves for overall local-regional control was statistically significant at p = 0.007 in favor of combined gemcitabine and radiotherapy. The MTD of gemcitabine is 300 mg/m2/week when gemcitabine is delivered concurrently with radiotherapy for unresectable chest wall failures. This novel approach suggests excellent local-regional control when compared to historical controls. A phase II trial is warranted. [ABSTRACT FROM AUTHOR]

Purpose: For men with intermediate-risk prostate cancer treated with definitive therapy, the addition of androgen deprivation therapy (ADT) reduces the risk of distant metastasis and cancer-related mortality. However, the absolute benefit of ADT varies by baseline cancer risk. Estimates of prognosis have improved over time, and little is known about ADT decision making in the modern era. We sought to characterize variability and identify factors associated with intended ADT use within the Michigan Radiation Oncology Quality Consoritum (MROQC)., Materials and Methods: Patients with localized prostate cancer undergoing definitive radiation therapy were enrolled from June 9, 2020, to June 26, 2023 (n = 815). Prospective data were collected using standardized patient, physician, and physicist forms. Intended ADT use was prospectively defined and was the primary outcome. Associations with patient, tumor, and practice-related factors were tested with multivariable analyses. Random intercept modeling was used to estimate facility-level variability., Results: Five hundred seventy patients across 26 facilities were enrolled with intermediate-risk disease. ADT was intended for 46% of men (n = 262/570), which differed by National Comprehensive Cancer Network favorable intermediate-risk (23.5%, n = 38/172) versus unfavorable intermediate-risk disease (56.3%, n = 224/398; P < .001). After adjusting for the statewide case mix, the predicted probability of intended ADT use varied significantly across facilities, ranging from 15.4% (95% CI, 5.4%-37.0%) to 71.7% (95% CI, 57.0%-82.9%), with P < .01. Multivariable analyses showed that grade group 3 (OR, 4.60 [3.20-6.67]), ≥50% positive cores (OR, 2.15 [1.43-3.25]), and prostate-specific antigen 10 to 20 (OR, 1.87 [1.24-2.84]) were associated with ADT use. Area under the curve was improved when incorporating MRI adverse features (0.76) or radiation treatment variables (0.76), but there remained significant facility-level heterogeneity in all models evaluated (P < .05)., Conclusions: Within a state-wide consortium, there is substantial facility-level heterogeneity in intended ADT use for men with intermediate-risk prostate cancer. Future efforts are necessary to identify patients who will benefit most from ADT and to develop strategies to standardize appropriate use., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Surveillance, Epidemiology, and End Results (SEER) cancer registries provides information about survival duration and cause of death for cancer patients. Baseline demographic and tumor characteristics such as age, sex, race, year of diagnosis, and tumor stage can inform the expected survival time of patients, but their associations with survival may not be constant over the post-diagnosis period., Methods: Using SEER data, we examined if there were time-varying associations of patient and tumor characteristics on survival, and we assessed how these relationships differed across 14 cancer sites. Standard Cox proportional hazards models were extended to allow for time-varying associations and incorporated into a competing-risks framework, separately modeling cancer-specific and other-cause deaths. For each cancer site and for each of the five factors, we estimated the relative hazard ratio and absolute hazard over time in the presence of competing risks., Results: Our comprehensive consideration of patient and tumor characteristics when estimating time-varying hazards showed that the associations of age, tumor stage at diagnosis, and race/ethnicity with risk of death (cancer-specific and other-cause) change over time for many cancers; characteristics of sex and year of diagnosis exhibit some time-varying patterns as well. Stage at diagnosis had the largest associations with survival., Conclusion: These findings suggest that proportional hazards assumptions are often violated when examining patient characteristics on cancer survival post-diagnosis. We discuss several interesting results where the relative hazards are time-varying and suggest possible interpretations. Based on the time-varying associations of several important covariates on survival after cancer diagnosis using a pan-cancer approach, the likelihood of the proportional hazards assumption being met or corresponding interpretation should be considered in survival analyses, as flawed inference may have implications for cancer care and policy., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Women remain underrepresented in medical physics in the United States, and determinants of persisting disparities remain unclear. Here, we performed a detailed investigation of American Association of Physicists in Medicine (AAPM) membership trajectories to evaluate trends in Full membership with respect to gender, age, and highest degree., Methods and Materials: Membership data, including gender, date of birth, highest degree, membership type, and years of active membership for 1993 to 2023 were obtained from AAPM. Group 1 included Full members who joined AAPM in 1993 or later. A subset of group 1 including only members who joined and left AAPM since 1993 (former members, group 1 F ) was used to calculate age at membership cessation and duration. Results were compared by gender and highest degree. A Kaplan-Meier analysis was also used to evaluate membership "survival" by age and highest degree., Results: Complete data were available for 6647 current and former Full members (group 1), including 2211 former members (group 1 F ). On average, women became Full members at a significantly younger age than men (34.6 vs 37.5 years of age, P < .001) and ended their memberships (if applicable) at a significantly younger age than men (46.1 vs 50.1 years of age, P < .001). The Kaplan-Meier "survival" analysis showed that for a given age, women were at a significantly greater risk of membership cessation than men, and women with master's degrees had the lowest membership survival of any gender/degree subgroup. When analyzing by membership duration, there was no difference in survival by gender alone. Still, women with PhDs were found to have the greatest membership survival among gender/degree subgroups., Conclusions: Both gender and degree type influenced AAPM membership trajectories. Although we have offered a discussion of possible explanations, qualitative data collected from both continuing and departing AAPM members will be critical in the ongoing journey toward gender parity in the profession of medical physics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Treatment for inoperable stage II to III non-small cell lung cancer (NSCLC) involves chemo-radiotherapy (CRT). However, some patients transition to hospice or die early during their treatment course. We present a model to prognosticate early poor outcomes in NSCLC patients treated with curative-intent CRT., Methods and Materials: Across a statewide consortium, data was prospectively collected on stage II to III NSCLC patients who received CRT between 2012 and 2019. Early poor outcomes included hospice enrollment or death within 3 months of completing CRT. Logistic regression models were used to assess predictors in prognostic models. LASSO regression with multiple imputation were used to build a final multivariate model, accounting for missing covariates., Results: Of the 2267 included patients, 128 experienced early poor outcomes. Mean age was 71 years and 59% received concurrent chemotherapy. The best predictive model, created parsimoniously from statistically significant univariate predictors, included age, ECOG, planning target volume (PTV), mean heart dose, pretreatment lack of energy, and cough. The estimated area under the ROC curve for this multivariable model was 0.71, with a negative predictive value of 95%, specificity of 97%, positive predictive value of 23%, and sensitivity of 16% at a predicted risk threshold of 20%., Conclusions: This multivariate model identified a combination of clinical variables and patient reported factors that may identify individuals with inoperable NSCLC undergoing curative intent chemo-radiotherapy who are at higher risk for early poor outcomes., Competing Interests: Disclosure MROQC is financially supported by Blue Cross Blue Shield of Michigan and the Blue Care Network of Michigan as part of the BCBSM Value Partnerships Program., (Published by Elsevier Inc.)

Background: The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy., Methods: We did a retrospective review of five multicentre, randomised trials (NRG/RTOG 9003, 0129, 0234, 0522, and 1016) that tested radiotherapy with or without chemotherapy in patients (aged ≥18 years) with p16-positive localised head or neck squamous-cell carcinomas. Eight intermediate clinical endpoints were considered as potential surrogates for overall survival: freedom from local progression, freedom from regional progression, freedom from distant metastasis, freedom from locoregional progression, freedom from any progression, locoregional progression-free survival, progression-free survival, and distant metastasis-free survival. We used a two-stage meta-analytical framework, which requires high correlation between the intermediate clinical endpoint and overall survival at the patient level (condition 1), and high correlation between the treatment effect on the intermediate clinical endpoint and the treatment effect on overall survival (condition 2). For both, an r 2 greater than 0·7 was used as criteria for clinically relevant surrogacy., Findings: We analysed 1373 patients with oropharyngeal cancer from May 9, 2020, to Nov 22, 2023. 1231 (90%) of patients were men, 142 (10%) were women, and 1207 (88%) were White, with a median age of 57 years (IQR 51-62). Median follow-up was 4·2 years (3·1-5·1). For the first condition, correlating the intermediate clinical endpoints with overall survival at the individual and trial level, the three composite endpoints of locoregional progression-free survival (Kendall's τ 0·91 and r 2 0·72), distant metastasis-free survival (Kendall's τ 0·93 and r 2 0·83), and progression-free survival (Kendall's τ 0·88 and r 2 0·70) were highly correlated with overall survival at the patient level and at the trial-group level. For the second condition, correlating treatment effects of the intermediate clinical endpoints and overall survival, the composite endpoints of locoregional progression-free survival (r 2 0·88), distant metastasis-free survival (r 2 0·96), and progression-free survival (r 2 0·92) remained strong surrogates. Treatment effects on the remaining intermediate clinical endpoints were less strongly correlated with overall survival., Interpretation: We identified locoregional progression-free survival, distant metastasis-free survival, and progression-free survival as surrogates for overall survival in p16-positive oropharyngeal cancers treated with chemotherapy or radiotherapy, which could serve as clinical trial endpoints., Funding: NRG Oncology Operations, NRG Oncology SDMC, the National Cancer Institute, Eli Lilly, Aventis, and the University of Michigan., Competing Interests: Declaration of interests LAG reports grant funding from the PROTEUS Consortium. JAB reports royalties or licenses from Bristol Myers Squibb, Eli Lilly, and Merck Serono; consulting fees from Cel-Sci, Merck Serano, and ICON; payment for lectures or presentations from Bristol Myers Squibb, Eli Lilly, Merck Serano, and Cel-Sci; and support for attending meetings or travel from Bristol Myers Squibb, Eli Lilly, and Merck Serono. MLG reports research funding from Genocea Biosciences, Bristol Myers Squibb, Genentech, Kura, Cullinan Labs, Agenus, LaRoche, NRG Oncology, and the University of Cincinnati; consulting fees from iTeos Therapeutics, Istari Oncology, LLX Solutions, OncLive Intellisphere, Seagen, Sensei Biotherapeutics, Kura Oncology, Coherus Biosciences, Mirati Therapeutics, BioNtech AG, Sensei Biotherapeutics, Caladrius Biosciences, Bristol Myers Squibb, Bicara Therapeutics, Bayer Healthcare Pharmaceutics, Genocea Biosciences, Shattuck Labs, EMD Serono, Debiopharm, Merck & Co, Ipsen Biopharmaceuticals, Gilead Sciences, Nektar Therapeutics, Eisai Medical Research, Roche, Roche Diagnostics, NewLink Genetics, Aspyrian Therapeutics, Amgen, TRM Oncology, AstraZeneca Pharmaceuticals, Celgene, and Exelixis; payment from OncLive and Roche; and support for meetings or travel for presentations from the American Association for Cancer Research, the American Society of Clinical Oncology, and the Society for Immunotherapy of Cancer. SK reports research funding from Merck, Bristol Myers Squibb, Castle Biosciences, and Regeneron; consulting fees from Merck, Bristol Myers Squibb, Regeneron, and Galera Therapeutics; and honorarium from Varian Medical Systems. Q-TL reports a leadership role as RTOG Group Chair for NRG Oncology and support from RTOG Foundation for attending meetings and travel. MM reports clinical trial drug support from Bristol Myers Squbb, and grant funding from the PROTEUS Consortium and Livestrong Foundation, advistory board of Adaptimmune. DLM reports a grant from the National Cancer Institute (3R01CA262388-02S1 NCI Diversity Supplement Award). EM reports a University of Michigan M-Cubed Grant (P30CA046592). JAR reports non-financial interests National Comprehensive Cancer Network Thyroid Cancer Panel and American Thyroid Association Guidelines Task Force. DIR reports payments from Merck to the Scientific Advisory Board for presentations. MJS reports consulting fees from Innovative Analytics. WAS reports a research grant from Georgia Research Alliance. PT-S reports NRG Oncology SDMC Grant from the National Cancer Institute (NCI). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

There is debate about why stereotactic body radiation therapy (SBRT) produces superior control of hepatocellular cancer (HCC) compared to fractionated treatment. Both preclinical and clinical evidence has been presented to support a "classic" biological explanation: the greater BED of SBRT produces more DNA damage and tumor cell kill. More recently, preclinical evidence has supported the concept of a "new biology", particularly radiation-induced vascular collapse, which increases hypoxia and free radical activation. This is hypothesized to cause much greater tumor cell death than was produced by the initial radiation-induced DNA damage to the tumor. We decided to investigate if vascular collapse occurs after standard SBRT for patients with HCC. Eight patients with 10 lesions underwent dynamic contrast enhanced MRI at the time of simulation and either 48 or 96 hours after the first fraction. Only three of 10 tumors showed a decrease in blood flow. These findings suggest that vascular collapse does not typically occur after SBRT for HCC., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Liver-directed radiation therapy is an effective treatment for hepatocellular carcinoma (HCC), but metachronous lesions develop outside the irradiated field in >50% of patients. We hypothesized that irradiation of these new lesions would produce an outcome like that of patients receiving a first course (C1) of treatment., Methods and Materials: We included patients with HCC who received a second course (C2) of radiation therapy >1 month after C1. Toxicity was defined as Child-Pugh score increase ≥2 within 6 months posttreatment (binary model) and as the change in albumin-bilirubin during the year after treatment (longitudinal model). Overall survival (OS) and local failure (LF) were captured at the patient and lesion level, respectively; both were summarized with Kaplan-Meier estimates. Predictors of toxicity and OS were assessed using generalized linear mixed and Cox regression models, respectively., Results: Of 340 patients with HCC, 47 underwent irradiation for metachronous HCC, receiving similar prescription dose in C1/C2. Median follow-up was 17 months after C1 and 15 months after C2. Twenty-two percent of patients experienced toxicity after C1, and 25% experienced toxicity after C2. Worse baseline albumin-bilirubin predicted toxicity in both binary (odds ratio, 2.40; 95% CI, 1.46-3.94; P = .0005) and longitudinal models (P < .005). Two-year LF rate was 11.2% after C1 and 8.3% after C2; tumor dose (hazard ratio [HR], 0.982; 95% CI, 0.969-0.995; P = .007) and tumor size (HR, 1.135; 95% CI, 1.068-1.206; P < .005) predicted LF. Two-year OS was 46.0% after C1 and 42.6% after C2; tumor dose (HR, 0.986; 95% CI, 0.979-0.992; P < .005) and tumor size (HR, 1.049; 95% CI, 1.010-1.088; P = .0124) predicted OS. Reirradiation was not associated with toxicity (P > .7), LF (P = .79), or OS (P = .39)., Conclusions: In this largest series in the Western hemisphere, we demonstrate that irradiation for metachronous HCC offers low rates of LF with acceptable toxicity and OS like that of patients receiving a C1. These findings support judicious selection of patients for reirradiation in metachronous HCC., Competing Interests: Disclosures None., (Copyright © 2023 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: 18 F-Fluorodeoxyglucose positron emission tomography (FDG-PET) parameters are prognostic of oncologic outcomes in human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). We used FDG-PET imaging biomarkers to select patients for de-escalated chemoradiotherapy (CRT), hypothesizing that acute toxicity will be improved with de-escalation., Methods and Materials: This is a planned interim initial feasibility and acute toxicity report from a phase 2, prospective, nonrandomized study, which enrolled patients with stage I-II p16+ OPSCC. All patients started definitive CRT to 70 Gy in 35 fractions, and those who met de-escalation criteria on midtreatment FDG-PET at fraction 10 completed treatment at 54 Gy in 27 fractions. We report the acute toxicity and patient-reported outcomes for 59 patients with a minimum follow-up of 3 months., Results: There were no statistically significant differences between baseline patient characteristics in the standard and de-escalated cohorts. There were 28 of 59 (47.5%) patients who met FDG-PET de-escalation criteria and collectively received 20% to 30% less dose to critical organs at risk known to affect toxicity. At 3 months posttreatment, patients who received de-escalated CRT lost significantly less weight (median, 5.8% vs 13.0%; P < .001), had significantly less change from baseline in penetration-aspiration scale score (median, 0 vs 1; P = .018), and had significantly fewer aspiration events on repeat swallow study (8.0% vs 33.3%, P = .037) compared with patients receiving standard CRT., Conclusions: Approximately half of patients with early-stage p16+ OPSCC are selected for de-escalation of definitive CRT using midtreatment FDG-PET biomarkers, which resulted in significantly improved rates of observed acute toxicity. Further follow-up is ongoing and will be required to determine whether this de-escalation approach preserves the favorable oncologic outcomes for patients with p16+ OPSCC before adoption., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Estimation of the time-integrated activity (TIA) for dosimetry from imaging at a single time point (STP) facilitates the clinical translation of dosimetry-guided radiopharmaceutical therapy. However, the accuracy of the STP methods for TIA estimation varies on the basis of time-point selection. We constructed patient data-driven regression models to reduce the sensitivity to time-point selection and to compare these new models with commonly used STP methods. Methods: SPECT/CT performed at time period (TP) 1 (3-5 h), TP2 (days 1-2), TP3 (days 3-5), and TP4 (days 6-8) after cycle 1 of [ 177 Lu]Lu-DOTATATE therapy involved 27 patients with 100 segmented tumors and 54 kidneys. Influenced by the previous physics-based STP models of Madsen et al. and Hänscheid et al., we constructed an STP prediction expression, TIA = A ( t ) × g ( t ), in a SPECT data-driven way (model 1), in which A ( t ) is the observed activity at imaging time t, and the curve, g ( t ), is estimated with a nonparametric generalized additive model by minimizing the normalized mean square error relative to the TIA derived from 4-time-point SPECT (reference TIA). Furthermore, we fit a generalized additive model that incorporates baseline biomarkers as auxiliary data in addition to the single activity measurement (model 2). Leave-one-out cross validation was performed to evaluate STP models using mean absolute error (MAE) and mean square error between the predicted and reference TIA. Results: At days 3-5, all evaluated STP methods performed very well, with an MAE of less than 7% (between-patient SD of <10%) for both kidneys and tumors. At other TPs, the Madsen method and data-driven models 1 and 2 performed reasonably well (MAEs < 17% for kidneys and < 32% for tumors), whereas the error with the Hänscheid method was substantially higher. The proof of concept of adding baseline biomarkers to the prediction model was demonstrated and showed a moderate enhancement at TP1, especially for estimating kidney TIA (MAE ± SD from 15.6% ± 1.3% to 11.8% ± 1.0%). Evaluations on 500 virtual patients using clinically relevant time-activity simulations showed a similar performance. Conclusion: The performance of the Madsen method and proposed data-driven models is less sensitive to TP selection than is the Hänscheid method. At the earliest TP, which is the most practical, the model incorporating baseline biomarkers outperforms other methods that rely only on the single activity measurement., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: National guidelines on limited-stage small cell lung cancer (LS-SCLC) treatment give preference to a hyperfractionated regimen of 45 Gy in 30 fractions delivered twice daily; however, use of this regimen is uncommon compared with once-daily regimens. The purpose of this study was to characterize the LS-SCLC fractionation regimens used throughout a statewide collaborative, analyze patient and treatment factors associated with these regimens, and describe real-world acute toxicity profiles of once- and twice-daily radiation therapy (RT) regimens., Methods and Materials: Demographic, clinical, and treatment data along with physician-assessed toxicity and patient-reported outcomes were prospectively collected by 29 institutions within the Michigan Radiation Oncology Quality Consortium between 2012 and 2021 for patients with LS-SCLC. We modeled the influence of RT fractionation and other patient-level variables clustered by treatment site on the odds of a treatment break specifically due to toxicity with multilevel logistic regression. National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, incident grade 2 or worse toxicity was longitudinally compared between regimens., Results: There were 78 patients (15.6% overall) treated with twice-daily RT and 421 patients treated with once-daily RT. Patients receiving twice-daily RT were more likely to be married or living with someone (65% vs 51%; P = .019) and to have no major comorbidities (24% vs 10%; P = .017). Once-daily RT fractionation toxicity peaked during RT, and twice-daily toxicity peaked within 1 month after RT. After stratifying by treatment site and adjusting for patient-level variables, once-daily treated patients had 4.11 (95% confidence interval, 1.31-12.87) higher odds of treatment break specifically due to toxicity than twice-daily treated patients., Conclusions: Hyperfractionation for LS-SCLC remains infrequently prescribed despite the lack of evidence demonstrating superior efficacy or lower toxicity of once-daily RT. With peak acute toxicity after RT and lower likelihood of a treatment break with twice-daily fractionation in real-word practice, providers may start using hyperfractionated RT more frequently., (Copyright © 2023 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Patients with pancreatic cancer undergoing chemoradiation therapy may experience acute and chronic side effects. We conducted an exploratory analysis of patients with locally advanced pancreatic cancer (LAPC) undergoing definitive chemoradiation to identify factors influencing the occurrence of gastrointestinal (GI) bleeding, short-term radiation side effects, patterns of failure, and survival., Methods and Materials: Under an institutional review board-approved protocol, we retrospectively studied patients with LAPC treated with chemoradiation. Statistical models were used to test associations between clinical characteristics and outcomes, including upper GI bleeding, radiation treatment breaks, and weight loss during therapy., Results: Between 1999 and 2012, 211 patients were treated with radiation for pancreatic cancer. All patients received concurrent chemotherapy with either gemcitabine (174) or 5-fluorouracil (27), and 67 received intensity modulated radiation therapy (IMRT). Overall, 18 patients experienced an upper GI bleed related to treatment, with 70% of bleeds occurring in the stomach or duodenum, and among those patients, 11 (61%) patients had a pancreatic head tumor and 17 (94%) patients had a metallic biliary stent. IMRT was associated with decreased risk of postradiation nausea (odds ratio, 0.27 [0.11, 0.67], P  = .006) compared with 3-dimensional conformal radiation. Regarding long-term toxicities, patients with a metallic biliary stent at the time of radiation therapy were at a significantly higher risk of developing upper GI bleeding (unadjusted hazard ratio [HR], 15.41 [2.02, 117.42], P  = .008), even after controlling for radiation treatment modality and prescribed radiation dose (adjusted HR, 17.38 [2.26, 133.58], P  = .006). Furthermore, biliary stent placement was associated with a higher risk of death (HR, 1.99 [1.41, 2.83], P < .001) after adjusting for demographic, treatment-related, and patient-related variables., Conclusions: Metallic biliary stents may be associated with an increased risk of upper GI bleeding and mortality. Furthermore, IMRT was associated with less nausea and short-term toxicity compared with 3-dimensional conformal therapy., Competing Interests: 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., (© 2023 The Author(s).)

Purpose: Pretreatment predictions of absorbed doses can be especially valuable for patient selection and dosimetry-guided individualization of radiopharmaceutical therapy. Our goal was to build regression models using pretherapy 68Ga-DOTATATE PET uptake data and other baseline clinical factors/biomarkers to predict renal absorbed dose delivered by 177Lu-DOTATATE peptide receptor radionuclide therapy (177Lu-PRRT) for neuroendocrine tumors. We explore the combination of biomarkers and 68Ga PET uptake metrics, hypothesizing that they will improve predictive power over univariable regression., Patients and Methods: Pretherapy 68Ga-DOTATATE PET/CTs were analyzed for 25 patients (50 kidneys) who also underwent quantitative 177Lu SPECT/CT imaging at approximately 4, 24, 96, and 168 hours after cycle 1 of 177Lu-PRRT. Kidneys were contoured on the CT of the PET/CT and SPECT/CT using validated deep learning-based tools. Dosimetry was performed by coupling the multi-time point SPECT/CT images with an in-house Monte Carlo code. Pretherapy renal PET SUV metrics, activity concentration per injected activity (Bq/mL/MBq), and other baseline clinical factors/biomarkers were investigated as predictors of the 177Lu SPECT/CT-derived mean absorbed dose per injected activity to the kidneys using univariable and bivariable models. Leave-one-out cross-validation (LOOCV) was used to estimate model performance using root mean squared error and absolute percent error in predicted renal absorbed dose including mean absolute percent error (MAPE) and associated standard deviation (SD)., Results: The median therapy-delivered renal dose was 0.5 Gy/GBq (range, 0.2-1.0 Gy/GBq). In LOOCV of univariable models, PET uptake (Bq/mL/MBq) performs best with MAPE of 18.0% (SD = 13.3%), and estimated glomerular filtration rate (eGFR) gives an MAPE of 28.5% (SD = 19.2%). Bivariable regression with both PET uptake and eGFR gives LOOCV MAPE of 17.3% (SD = 11.8%), indicating minimal improvement over univariable models., Conclusions: Pretherapy 68Ga-DOTATATE PET renal uptake can be used to predict post-177Lu-PRRT SPECT-derived mean absorbed dose to the kidneys with accuracy within 18%, on average. Compared with PET uptake alone, including eGFR in the same model to account for patient-specific kinetics did not improve predictive power. Following further validation of these preliminary findings in an independent cohort, predictions using renal PET uptake can be used in the clinic for patient selection and individualization of treatment before initiating the first cycle of PRRT., Competing Interests: Conflicts of interest and sources of funding: The authors declare that they have no conflicts of interest. This work was supported by grants R01CA240706 and P30CA046592 from the National Cancer Institute., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

BACKGROUND: The Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group identified metastasis-free survival as a valid surrogate end point for overall survival (OS) for patients with localized prostate cancer. No comparably validated surrogate end points exist in advanced prostate cancer. METHODS: We searched for trials in advanced prostate cancer, defined as node-positive, metastatic castration-sensitive, nonmetastatic, or metastatic castration-resistant prostate cancer. Eligible randomized trials reported OS and one or more intermediate clinical end points, including biochemical failure (BF), clinical failure, biochemical failure–free survival (BFS), progression-free survival (PFS), and radiographic PFS. Candidacy for surrogacy was assessed by using the second condition of the meta-analytic approach; R2 was weighted by the inverse variance of the log intermediate clinical end point hazard ratio and defined as R2>0.70. RESULTS: A total of 143 randomized trials (n=75,601 patients) were included. No candidate end points met the criteria for surrogacy (R2 BF [n=28,922], 0.42 [95% confidence interval (CI), 0.18 to 0.64]; BFS [n=25,741], 0.57 [95% CI, 0.37 to 0.73]; clinical failure [n=22,616], 0.31 [95% CI, 0.075 to 0.56]; PFS [n=52,639], 0.50 [95% CI, 0.35 to 0.63]; and radiographic PFS [n=52,548], 0.50 [95% CI, 0.35 to 0.63]). Within preplanned subgroups according to castration-sensitive or castration-resistant disease or according to treatment type, neither BFS nor PFS consistently met criteria for surrogacy. Sensitivity analyses showed that candidacy for surrogacy of all end points tested did not change over time. CONCLUSIONS: Our aggregate screening method for surrogate end points in advanced prostate cancer showed that commonly used clinical end points are not clear valid surrogate end points for OS. (Funded by the Prostate Cancer Foundation and the National Cancer Institute.)

This work describes a 35.9 kHz ultrasonic transducer that incorporates a magnetic arrangement to apply a static-compressive prestress to a d 32 -mode relaxor ferroelectric single crystal drive-element. The magnetic arrangement produces a 22.5 N static-compressive force, inducing a static compression of ∼630 nm on the drive-element. Operating in air with a continuous-wave 10 V peak drive at ∼35.9 kHz, the measured resonant peak displacement of the transducers head-mass was 127 nm. This is well within the predicted static compression, thus, the drive-element is protected from damaging tensile stress. Under the same drive conditions and at an axial distance of 10 mm from the face of the head-mass, the measured acoustic pressure was ∼12 Pa. Analytical and finite element model predictions and the measured behaviour of a prototype device are presented and show good correlation, demonstrating that magnetic prestressing of the drive-element can be a viable alternative to the traditional bolt-clamp.

Purpose: The aim was to quantify inter- and intra-observer variability in manually delineated hepatocellular carcinoma (HCC) lesion contours and the resulting impact on radioembolization (RE) dosimetry., Methods: Ten patients with HCC lesions treated with Y-90 RE and imaged with post-therapy Y-90 PET/CT were selected for retrospective analysis. Three radiologists contoured 20 lesions manually on baseline multiphase contrast-enhanced MRIs, and two of the radiologists re-contoured at two additional sessions. Contours were transferred to co-registered PET/CT-based Y-90 dose maps. Volume-dependent recovery coefficients were applied for partial volume correction (PVC) when reporting mean absorbed dose. To understand how uncertainty varies with tumor size, we fit power models regressing relative uncertainty in volume and in mean absorbed dose on contour volume. Finally, we determined effects of segmentation uncertainty on tumor control probability (TCP), as calculated using logistic models developed in a previous RE study., Results: The average lesion volume ranged from 1.8 to 194.5 mL, and the mean absorbed dose ranged from 23.4 to 1629.0 Gy. The mean inter-observer Dice coefficient for lesion contours was significantly less than the mean intra-observer Dice coefficient (0.79 vs. 0.85, p < 0.001). Uncertainty in segmented volume, as measured by the Coefficient of Variation (CV), ranged from 4.2 to 34.7% with an average of 17.2%. The CV in mean absorbed dose had an average value of 5.4% (range 1.2-13.1%) without PVC while it was 15.1% (range 1.5-55.2%) with PVC. Using the fitted models for uncertainty as a function of volume on our prior data, the mean change in TCP due to segmentation uncertainty alone was estimated as 16.2% (maximum 48.5%)., Conclusions: Though we find relatively high inter- and intra-observer reliability overall, uncertainty in tumor contouring propagates into non-negligible uncertainty in dose metrics and outcome prediction for individual cases that should be considered in dosimetry-guided treatment., (© 2022. The Author(s).)

Background: Sustained viral response (SVR) improves survival for patients with hepatitis C (HCV) and hepatocellular carcinoma (HCC) after curative treatment; however, the benefit of SVR in those with active HCC with a significant competing risk of mortality is unknown. This study aimed to evaluate the association between SVR and outcomes in patients with active HCC., Methods: The authors performed a multicenter, retrospective cohort study including consecutive adults with HCV cirrhosis and treatment-naive HCC diagnosed between 2014 and 2018. Patients were stratified into two groups: active viremia (n = 431) and SVR before HCC diagnosis (n = 135). All patients underwent nonsurgical therapy as their initial treatment and were followed until liver transplantation, last follow-up, or death. The primary outcome was incident or worsening hepatic decompensation within 6 months and the secondary outcome was overall survival. All analyses used inverse probability of treatment weights (IPTW) to account for differences between the nonrandomized cohorts., Results: Post-SVR patients had significantly lower odds of hepatic decompensation compared to viremic patients (odds ratio [OR], 0.18; 95% confidence interval [CI], 0.06-0.59). Results were consistent among subgroups of patients with Child Pugh A cirrhosis (OR, 0.22; 95% CI, 0.04-0.77), Barcelona Clinic Liver Cancer stage B/C HCC (OR, 0.20; 95% CI, 0.04-0.65), and those receiving nonablative HCC therapies (OR, 0.21; 95% CI, 0.07-0.67). However, in IPTW multivariable Cox regression, SVR was not associated with improved survival (hazard ratio, 0.79; 95% CI, 0.56-1.12)., Conclusions: Patients with HCV-related HCC and SVR are less likely to experience hepatic decompensation than viremic patients, suggesting patients with HCC who are undergoing nonsurgical therapies may benefit from DAA treatment., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Objective: To develop and validate an accurate, usable prediction model for other-cause mortality (OCM) in patients with prostate cancer diagnosed in the United States., Materials and Methods: Model training was performed using the National Health and Nutrition Examination Survey 1999-2010 including men aged >40 years with follow-up to the year 2014. The model was validated in the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial prostate cancer cohort, which enrolled patients between 1993 and 2001 with follow-up to the year 2015. Time-dependent area under the curve (AUC) and calibration were assessed in the validation cohort. Analyses were performed to assess algorithmic bias., Results: The 2420 patient training cohort had 459 deaths over a median follow-up of 8.8 years among survivors. The final model included eight predictors: age; education; marital status; diabetes; hypertension; stroke; body mass index; and smoking. It had an AUC of 0.75 at 10 years for predicting OCM in the validation cohort of 8220 patients. The final model significantly outperformed the Social Security Administration life tables and showed adequate predictive performance across race, educational attainment, and marital status subgroups. There is evidence of major variability in life expectancy that is not captured by age, with life expectancy predictions differing by 10 or more years among patients of the same age., Conclusion: Using two national cohorts, we have developed and validated a simple and useful prediction model for OCM for patients with prostate cancer treated in the United States, which will allow for more personalized treatment in accordance with guidelines., (© 2022 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Purpose: Current radiation therapy (RT) treatment planning relies mainly on pre-defined dose-based objectives and constraints to develop plans that aim to control disease while limiting damage to normal tissues during treatment. These objectives and constraints are generally population-based, in that they are developed from the aggregate response of a broad patient population to radiation. However, correlations of new biologic markers and patient-specific factors to treatment efficacy and toxicity provide the opportunity to further stratify patient populations and develop a more individualized approach to RT planning. We introduce a novel intensity-modulated radiation therapy (IMRT) optimization strategy that directly incorporates patient-specific dose response models into the planning process. In this strategy, we integrate the concept of utility-based planning where the optimization objective is to maximize the predicted value of overall treatment utility, defined by the probability of efficacy (e.g., local control) minus the weighted sum of toxicity probabilities. To demonstrate the feasibility of the approach, we apply the strategy to treatment planning for non-small cell lung cancer (NSCLC) patients., Methods and Materials: We developed a prioritized approach to patient-specific IMRT planning. Using a commercial treatment planning system (TPS), we calculate dose based on an influence matrix of beamlet-dose contributions to regions-of-interest. Then, outside of the TPS, we hierarchically solve two optimization problems to generate optimal beamlet weights that can then be imported back to the TPS. The first optimization problem maximizes a patient's overall plan utility subject to typical clinical dose constraints. In this process, we facilitate direct optimization of efficacy and toxicity trade-off based on individualized dose-response models. After optimal utility is determined, we solve a secondary optimization problem that minimizes a conventional dose-based objective subject to the same clinical dose constraints as the first stage but with the addition of a constraint to maintain the optimal utility from the first optimization solution. We tested this method by retrospectively generating plans for five previously treated NSCLC patients and comparing the prioritized utility plans to conventional plans optimized with only dose metric objectives. To define a plan utility function for each patient, we utilized previously published correlations of dose to local control and grade 3-5 toxicities that include patient age, stage, microRNA levels, and cytokine levels, among other clinical factors., Results: The proposed optimization approach successfully generated RT plans for five NSCLC patients that improve overall plan utility based on personalized efficacy and toxicity models while accounting for clinical dose constraints. Prioritized utility plans demonstrated the largest average improvement in local control (16.6%) when compared to plans generated with conventional planning objectives. However, for some patients, the utility-based plans resulted in similar local control estimates with decreased estimated toxicity., Conclusion: The proposed optimization approach, where the maximization of a patient's RT plan utility is prioritized over the minimization of standardized dose metrics, has the potential to improve treatment outcomes by directly accounting for variability within a patient population. The implementation of the utility-based objective function offers an intuitive, humanized approach to biological optimization in which planning trade-offs are explicitly optimized., (© 2022 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: Metastasis-free survival (MFS), but not event-free survival, is a validated surrogate end point for overall survival (OS) in men treated for localized prostate cancer. It remains unknown if this holds true in biochemically recurrent disease after radical prostatectomy. Leveraging NRG/RTOG 9601, we aimed to determine the performance of intermediate clinical end points (ICEs) as surrogate end points for OS in recurrent prostate cancer., Materials and Methods: NRG/RTOG 9601 randomly assigned 760 men with recurrence after prostatectomy to salvage radiation therapy with 2 years of placebo versus bicalutamide 150 mg daily. ICEs assessed were biochemical failure (BF) per NRG/RTOG 9601 (prostate-specific antigen nadir + 0.3-0.5 ng/mL or initiation of salvage hormone therapy; [BF1]) and NRG/RTOG 0534 (prostate-specific antigen nadir+2 ng/mL; [BF2]), distant metastasis (DM), and MFS (DM or death). Surrogacy was assessed by the Prentice criteria and a two-stage meta-analytic approach (condition one assessed at the patient level with Kendall's τ and condition two assessed by randomly dividing the entire trial cohort into 10 pseudo trial centers and calculating the average R 2 between treatment hazard ratios for ICE and OS)., Results: BF1, BF2, DM, and MFS satisfied the four Prentice criteria. However, with the two-condition meta-analytic approach, there was strong correlation between MFS and OS (τ = 0.86), moderate correlation between DM and OS (τ = 0.66), and weaker correlation between BF1 (τ = 0.25) or BF2 (τ = 0.40) and OS. Similarly, for condition two, the treatment effect of antiandrogen therapy on MFS and OS were correlated ( R 2 = 0.67), but this was not true for BF1 ( R 2 = 0.09), BF2 ( R 2 = 0.12), or DM ( R 2 = 0.18) and OS., Conclusion: MFS is also a strong surrogate for OS in men receiving salvage radiation therapy for recurrence after prostatectomy. Caution should be used when inferring survival benefit from effects on BF in biochemically recurrent prostate cancer. Lack of comorbidity data did not allow us to assess whether BF in men with no/minimal comorbidity could serve as a surrogate for OS.

The goal in personalized medicine is to individualize treatment using patient characteristics and improve health outcomes. Selection of optimal dose must balance the effect of dose on both treatment efficacy and toxicity outcomes. We consider a setting with one binary efficacy and one binary toxicity outcome. The goal is to find the optimal dose for each patient using clinical features and biomarkers from available dataset. We propose to use flexible machine learning methods such as random forest and Gaussian process models to build models for efficacy and toxicity depending on dose and biomarkers. A copula is used to model the joint distribution of the two outcomes and the estimates are constrained to have non-decreasing dose-efficacy and dose-toxicity relationships. Numerical utilities are elicited from clinicians for each potential bivariate outcome. For each patient, the optimal dose is chosen to maximize the posterior mean of the utility function. We also propose alternative approaches to optimal dose selection by adding additional toxicity based constraints and an approach taking into account the uncertainty in the estimation of the utility function. The proposed methods are evaluated in a simulation study to compare expected utility outcomes under various estimated optimal dose rules. Gaussian process models tended to have better performance than random forest. Enforcing monotonicity during modeling provided small benefits. Whether and how, correlation between efficacy and toxicity, was modeled, had little effect on performance. The proposed methods are illustrated with a study of patients with liver cancer treated with stereotactic body radiation therapy., (© 2022 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Grade 2 and higher radiation pneumonitis (RP2) is a potentially fatal toxicity that limits efficacy of radiation therapy (RT). We wished to identify a combined biomarker signature of circulating miRNAs and cytokines which, along with radiobiological and clinical parameters, may better predict a targetable RP2 pathway. In a prospective clinical trial of response-adapted RT for patients (n = 39) with locally advanced non-small cell lung cancer, we analyzed patients' plasma, collected pre- and during RT, for microRNAs (miRNAs) and cytokines using array and multiplex enzyme linked immunosorbent assay (ELISA), respectively. Interactions between candidate biomarkers, radiobiological, and clinical parameters were analyzed using data-driven Bayesian network (DD-BN) analysis. We identified alterations in specific miRNAs (miR-532, -99b and -495, let-7c, -451 and -139-3p) correlating with lung toxicity. High levels of soluble tumor necrosis factor alpha receptor 1 (sTNFR1) were detected in a majority of lung cancer patients. However, among RP patients, within 2 weeks of RT initiation, we noted a trend of temporary decline in sTNFR1 (a physiological scavenger of TNFα) and ADAM17 (a shedding protease that cleaves both membrane-bound TNFα and TNFR1) levels. Cytokine signature identified activation of inflammatory pathway. Using DD-BN we combined miRNA and cytokine data along with generalized equivalent uniform dose (gEUD) to identify pathways with better accuracy of predicting RP2 as compared to either miRNA or cytokines alone. This signature suggests that activation of the TNFα-NFκB inflammatory pathway plays a key role in RP which could be specifically ameliorated by etanercept rather than current therapy of non-specific leukotoxic corticosteroids., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: Historical racial disparities in lung cancer surgery rates resulted in lower survival in Black patients. Our objective was to examine racial differences in thoracic radiation treatments and toxicities in patients with non-small-cell lung cancer., Methods and Materials: A large institutional review board-approved statewide patient-level database of patients with stage II-III non-small-cell lung cancer who received definitive thoracic radiation from March 2012 to November 2019 was analyzed to assess associations between race and other variables. Race (White or Black) was defined by patient self-report. Provider-reported toxicity was defined by Common Terminology Criteria for Adverse Events version 4.0. Patient-reported toxicity was determined by the Functional Assessment of Cancer Therapy-Lung quality-of-life instrument. Univariable and multivariable regression models were fitted to assess relationships between race and variables of interest. Spearman rank-correlation coefficients were calculated between provider-reported toxicity and similar patient-reported outcomes., Results: One thousand four hundred forty-one patients from 24 institutions with mean age 68 years (range, 38-94 years) were evaluated. Race was not significantly associated with radiation or chemotherapy approach. There was significantly increased patient-reported general pain in Black patients at the preradiation and end-of-radiation time points. Black patients were significantly less likely to have provider-reported grade 2+ pneumonitis (odds ratio 0.36, P = .03), even after controlling for known patient and treatment factors. Correlation coefficients between provider- and patient-reported toxicities were generally similar across race groups except for a stronger correlation between patient- and provider-reported esophagitis in White patients., Conclusion: In this large multi-institutional study, we found no evidence of racial differences in radiation treatment or chemotherapy approaches. We did, however, unexpectedly find that Black race was associated with lower odds of provider-reported grade 2+ radiation pneumonitis. The stronger correlation between patient- and provider-reported esophagitis and swallowing symptoms for White patients also suggests possible under-recognition of symptoms in Black patients. Further research is needed to study the implications for Black patients., Competing Interests: Anna Mary Brown LaucisPatents, Royalties, Other Intellectual Property: Patent pending Matthew J. SchipperConsulting or Advisory Role: Innovative Analytics Peter A. PaximadisTravel, Accommodations, Expenses: Zeiss Thomas P. BoikeEmployment: MHP Radiation Oncology InstituteConsulting or Advisory Role: Blue Earth DiagnosticsSpeakers' Bureau: Boston Scientific Benjamin MovsasResearch Funding: Varian Medical Systems (Inst), Philips Healthcare (Inst), ViewRay (Inst)Patents, Royalties, Other Intellectual Property: Lung phantom for image guidance, MR-CT imaging–related patent for radiation oncologyTravel, Accommodations, Expenses: Varian Medical Systems Daniel E. SprattHonoraria: Varian Medical SystemsConsulting or Advisory Role: Janssen Oncology, AstraZeneca, Boston Scientific, Bayer, Blue Earth Diagnostics, Varian Medical SystemsResearch Funding: Janssen (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/869226 Michael M. DominelloResearch Funding: Novocure Martha M. MatuszakConsulting or Advisory Role: Varian Medical SystemsResearch Funding: Varian Medical SystemsOther Relationship: Blue Cross Blue Shield of Michigan Reshma JagsiThis author is a member of the Journal of Oncology Practice Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Employment: University of MichiganStock and Other Ownership Interests: Equity QuotientResearch Funding: Genentech (Inst)Expert Testimony: Baptist Health/Dressman Benziger Lavalle Law, Kleinbard, LLC, Sherinian and HassoTravel, Accommodations, Expenses: AmgenOther Relationship: JAMA OncologyOpen Payments Link: https://openpaymentsdata.cms.gov/physician/373670/summary Lori J. PierceStock and Other Ownership Interests: PFS GenomicsPatents, Royalties, Other Intellectual Property: UpToDate, PFS GenomicsUncompensated Relationships: Bristol Myers Squibb, Exact SciencesOpen Payments Link: https://openpaymentsdata.cms.gov/physician/1250431/summary Shruti JollyHonoraria: Varian Medical SystemsConsulting or Advisory Role: AstraZeneca, Varian Medical SystemsNo other potential conflicts of interest were reported.

Liver function may be negatively affected by radiation for treatment of hepatic malignancy. Pretreatment blood cytokine levels are biomarkers for prediction of toxicity and survival after external-beam radiation therapy. We hypothesized that cytokines may also predict outcomes after radioembolization, enabling a biomarker-driven personalized approach to treatment. Methods: Pretherapy blood samples from patients enrolled on a prospective protocol evaluating 90 Y radioembolization for management of intrahepatic malignancy were analyzed for 2 cytokines selected on the basis of prior studies in stereotactic body radiotherapy, soluble tumor necrosis factor receptor 1 (sTNFR1) and hepatocyte growth factor (HGF), via enzyme-linked immunosorbent assay, and key dosimetric parameters were derived from posttreatment 90 Y PET/CT imaging. Toxicity was defined as a change in albumin-bilirubin score from baseline to follow-up (3-6 mo after treatment). Associations of cytokine levels, dose metrics, and baseline liver function with toxicity and overall survival were assessed. Results: Data from 43 patients treated with 90 Y radioembolization for primary (48.8% [21/43]) or secondary (51.2% [22/43]) malignancy were assessed. Examined dose metrics and baseline liver function were not associated with liver toxicity; however, levels of sTNFR1 ( P = 0.045) and HGF ( P = 0.005) were associated with liver toxicity in univariate models. Cytokines were the only predictors of toxicity in multivariable models including dose metrics and prior liver-directed therapy. sTNFR1 (hazard ratio, 12.3; 95% CI, 3.5-42.5, P < 0.001) and HGF (hazard ratio, 7.5; 95% CI, 2.4-23.1, P < 0.001) predicted overall survival, and findings were similar when models were controlled for absorbed dose and presence of metastatic disease. Conclusion: Pretreatment cytokine levels predict liver toxicity and overall survival. These pathways can be targeted with available drugs, an advantage over previously studied dose metrics and liver function tests. Interventions directed at the TNFα-axis should be considered in future studies for prevention of liver toxicity, and HGF should be explored further to determine whether its elevation drives toxicity or indicates ongoing liver regeneration after prior injury., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Parametric response mapping (PRM) of high-resolution, paired inspiration and expiration computed tomography (CT) scans is a promising analytical imaging technique that is currently used in diagnostic applications and offers the ability to characterize and quantify certain pulmonary pathologies on a patient-specific basis. As one of the first studies to implement such a technique in the radiation oncology clinic, the goal of this work was to assess the feasibility for PRM analysis to identify pulmonary abnormalities in patients with lung cancer before radiation therapy (RT)., Methods and Materials: High-resolution, paired inspiration and expiration CT scans were acquired from 23 patients with lung cancer as part of routine treatment planning CT acquisition. When applied to the paired CT scans, PRM analysis classifies lung parenchyma, on a voxel-wise basis, as normal, small airways disease (SAD), emphysema, or parenchymal disease (PD). PRM classifications were quantified as a percent of total lung volume and were evaluated globally and regionally within the lung., Results: PRM analysis of pre-RT CT scans was successfully implemented using a workflow that produced patient-specific maps and quantified specific phenotypes of pulmonary abnormalities. Through this study, a large prevalence of SAD and PD was demonstrated in this lung cancer patient population, with global averages of 10% and 17%, respectively. Moreover, PRM-classified normal and SAD in the region with primary tumor involvement were found to be significantly different from global lung values. When present, elevated levels of PD and SAD abnormalities tended to be pervasive in multiple regions of the lung, indicating a large burden of underlying disease., Conclusions: Pulmonary abnormalities, as detected by PRM, were characterized in patients with lung cancer scheduled for RT. Although further study is needed, PRM is a highly accessible CT-based imaging technique that has the potential to identify local lung abnormalities associated with chronic obstructive pulmonary disease and interstitial lung disease. Further investigation in the radiation oncology setting may provide strategies for tailoring RT planning and risk assessment based on pre-existing PRM-based pathology., (© 2022 The Authors.)

Objectives: The addition of adjuvant durvalumab improves overall survival in locally advanced nonsmall-cell lung cancer (NSCLC) patients treated with definitive chemoradiation, but the real-world uptake of adjuvant durvalumab is unknown., Materials and Methods: We identified patients with stage III NSCLC treated with definitive concurrent chemoradiation from January 2018 to October 2020 from a statewide radiation oncology quality consortium, representing a mix of community (n=22 centers) and academic (n=5) across the state of Michigan. Use of adjuvant durvalumab was ascertained at the time of routine 3-month or 6-month follow-up after completion of chemoradiation., Results: Of 421 patients with stage III NSCLC who completed chemoradiation, 322 (76.5%) initiated adjuvant durvalumab. The percentage of patients initiating adjuvant durvalumab increased over time from 66% early in the study period to 92% at the end of the study period. There was substantial heterogeneity by treatment center, ranging from 53% to 90%. In multivariable logistic regression, independent predictors of durvalumab initiation included more recent month (odds ratio [OR]: 1.05 per month, 95% confidence interval [CI]: 1.02-1.08, P=0.003), lower Eastern Cooperative Oncology Group score (OR: 4.02 for ECOG 0 vs. 2+, 95% CI: 1.67-9.64, P=0.002), and a trend toward significance for female sex (OR: 1.66, 95% CI: 0.98-2.82, P=0.06)., Conclusion: Adjuvant durvalumab for stage III NSCLC treated with definitive chemoradiation was rapidly and successfully incorporated into clinical care across a range of community and academic settings in the state of Michigan, with over 90% of potentially eligible patients starting durvalumab in more recent months., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Little data have been reported about the patient experience during curative radiation therapy (RT) for lung cancer in routine clinical practice or how this relates to treatment toxicity as reported by clinicians. The purpose of this study was to compare clinician-reported adverse events (AEs) with patient-reported outcomes (PROs), including both specific symptoms/side effects, as well as overall quality of life (QoL) during and after definitive RT for locally advanced lung cancer (LALC) in a large statewide cohort., Methods and Materials: PROs were prospectively collected from patients treated with definitive RT for LALC at 24 institutions within the Michigan Radiation Oncology Quality Consortium between 2012 and 2018 using the Functional Assessment of Cancer Therapy trial outcome index. Physicians prospectively recorded AEs using the Common Terminology Criteria for Adverse Events, version 4.0. Patient-reported QoL changes from baseline were assessed during and after RT using the Functional Assessment of Cancer Therapy trial outcome index. Spearman correlation coefficients were calculated for AEs and similar PROs, and a multivariable analysis was used to assess associations with QoL., Results: A total 1361 patients were included in the study, and 53% of respondents reported clinically meaningful declines in QoL at the end of RT. The correlation between clinician-reported esophagitis and patient-reported trouble swallowing was moderate (R = .67), but correlations between clinician-reported pneumonitis and patient-reported shortness of breath (R = .13) and cough (R = .09) were weak. Clinician-reported AEs were significantly associated with clinically meaningful declines in patient-reported QoL (R = - .46 for summary AE score). QoL was more strongly associated with fatigue (R = - .41) than lung-specific AEs., Conclusions: AEs are associated with clinically meaningful declines in QoL during and after RT for LALC, but associations between AEs and QoL are only modest. This highlights the importance of PRO data, and future research should assess whether earlier detection of PRO changes could allow for interventions that reduce the frequency of treatment-related clinically meaningful declines in QoL., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Radiation therapy (RT) can increase the risk of cardiac events in patients with breast cancer (BC), but biomarkers predicting risk for developing RT-induced cardiac disease are currently lacking. We report results from a prospective clinical trial evaluating early magnetic resonance imaging (MRI) and serum biomarker changes as predictors of cardiac injury and risk of subsequent cardiac events after RT for left-sided disease., Methods: Women with node-negative and node-positive (N-/+) left-sided BC were enrolled on 2 institutional review board (IRB)-approved protocols at 2 institutions. MRI was conducted pretreatment (within 1 week of starting radiation), at the end of treatment (last day of treatment ±1 week), and 3 months after the last day of treatment (±2 weeks) to quantify left and right ventricular volumes and function, myocardial fibrosis, and edema. Perfusion changes during regadenoson stress perfusion were also assessed on a subset of patients (n = 28). Serum was collected at the same time points. Whole heart and cardiac substructures were contoured using CT and MRI. Models were constructed using baseline cardiac and clinical risk factors. Associations between MRI-measured changes and dose were evaluated., Results: Among 51 women enrolled, mean heart dose ranged from 0.80 to 4.7 Gy and mean left ventricular (LV) dose from 1.1 to 8.2 Gy, with mean heart dose 2.0 Gy. T1 time, a marker of fibrosis, and right ventricular (RV) ejection fraction (EF) significantly changed with treatment; these were not dose dependent. T2 (marker of edema) and LV EF did not significantly change. No risk factors were associated with baseline global perfusion. Prior receipt of doxorubicin was marginally associated with decreased myocardial perfusion after RT (P = .059), and mean MHD was not associated with perfusion changes. A significant correlation between baseline IL-6 and mean heart dose (MHD) at the end of RT (ρ 0.44, P = .007) and a strong trend between troponin I and MHD at 3 months post-treatment (ρ 0.33, P = .07) were observed. No other significant correlations were identified., Conclusions: In this prospective study of women with left-sided breast cancer treated with contemporary treatment planning, cardiac radiation doses were very low relative to historical doses reported by Darby et al. Although we observed significant changes in T1 and RV EF shortly after RT, these changes were not correlated with whole heart or substructure doses. Serum biomarker analysis of cardiac injury demonstrates an interesting trend between markers and MHD that warrants further investigation., (Published by Elsevier Inc.)

Purpose: Our individualized functional response adaptive approach to liver stereotactic body radiation therapy (SBRT) with assessment of indocyanine green (ICG) retention at baseline and midtreatment to detect subclinical changes in liver function, permitting dose adjustment, has decreased toxicity while preserving efficacy. We hypothesized that assessment of the albumin-bilirubin (ALBI) score at baseline and midtreatment would allow for more practical identification of patients at risk for treatment-related toxicity (TRT)., Methods and Materials: Patients with hepatocellular carcinoma were treated on 3 prospective institutional review board-approved trials using baseline and midtreatment ICG to deliver individualized functional response adaptive liver SBRT. Patients received 3 or 5 fractions, with fraction 3 followed by a 1-month treatment break. TRT was a ≥2-point rise in Child-Pugh score within 6 months of SBRT. Logistic regression was used to estimate odds ratios (ORs) and confidence intervals (CIs) for assessment of TRT. Area under the receiver operating curve was used to compare predictive ability across models., Results: In total, 151 patients underwent 166 treatments. Baseline Child-Pugh class and ALBI grade were A (66.9%), B (31.3%), or C (1.8%) and 1 (25.9%), 2 (65.7%), or 3 (8.4%), respectively. Thirty-five patients (20.3%) experienced TRT. On univariate analysis, baseline ALBI (OR, 1.8; 95% CI, 1.24-2.62; P = .02), baseline ICG (OR, 1.66; 95% CI, 1.17-2.35; P = .04), and change in ALBI (OR, 3.07; 95% CI, 1.29-7.32; P = .003) were associated with increased odds of TRT. ALBI-centric models performed similarly to ICG-centric models on multivariate analyses predicting toxicity (area under the receiver operating curve of 0.79 for both). In a model incorporating baseline and midtreatment change in ALBI and ICG, both ALBI values were statistically significantly associated with toxicity, whereas ICG values were not., Conclusions: Incorporation of midtreatment change in ALBI in addition to baseline ALBI improves the ability to predict TRT in patients with hepatocellular carcinoma receiving SBRT. Our findings suggest that functional response adaptive treatment could be implemented in a practical manner because the ALBI score is easily obtained from standard laboratory values., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Optimal surveillance paradigms for survivors of early stage human papillomavirus (HPV)-related oropharyngeal cancer are not well defined. This study aimed to characterize patient interest in and factors associated with an altered surveillance paradigm., Materials and Methods: We surveyed patients with Stage I or II HPV-related oropharyngeal cancer treated at a tertiary care institution from 2016 to 2019. Primary outcomes were descriptive assessment of patient knowledge, interest in altered surveillance, burdens of in-person appointments, and priorities for surveillance visits. Ordinal regression was used to identify correlates of interest in altered surveillance., Results: Sixty-seven patients completed surveys from February to April 2020 at a median of 21 months since completing definitive treatment. A majority (61%) of patients were interested in a surveillance approach that decreased in-person clinic visits. Patients who self-identified as medical maximizers, had higher worry of cancer recurrence, or were in long-term relationships were less likely to be interested. Patients reported significant burdens associated with surveillance visits, including driving distance, time off work, and nonmedical costs. Patients were most concerned with discussing cancer recurrence (76%), physical quality of life (70%), mortality (61%), and mental quality of life (52%) with their providers at follow-up visits., Conclusion: Patients with early stage HPV-related oropharyngeal cancers are interested in altered surveillance approaches, experience significant burdens related to surveillance visits, and have concerns that are not well addressed with current surveillance approaches, including physical and mental quality of life. Optimized surveillance approaches should incorporate patient priorities and minimize associated burdens., Implications for Practice: The number of patients with HPV-related oropharyngeal cancers is increasing, and numerous clinical trials are investigating novel approaches to treating these good-prognosis patients. There has been limited work assessing optimal surveillance paradigms in these patients. Patients experience significant appointment-related burdens and have concerns such as physical and mental quality of life. Additionally, patients with early stage HPV-related oropharyngeal cancers express interest in altered surveillance approaches that decrease in-person clinic visits. Optimization of surveillance paradigms to promote broader survivorship care in clinical practice is needed., (© 2021 AlphaMed Press.)

Multiple-time-point SPECT/CT imaging for dosimetry is burdensome for patients and lacks statistical efficiency. A novel method for joint kidney time-activity estimation based on a statistical mixed model, a prior cohort of patients with complete time-activity data, and only 1 or 2 imaging points for new patients was compared with previously proposed single-time-point methods in virtual and clinical patient data. Methods: Data were available for 10 patients with neuroendocrine tumors treated with 177 Lu-DOTATATE and imaged up to 4 times between days 0 and 7 using SPECT/CT. Mixed models using 1 or 2 time points were evaluated retrospectively in the clinical cohort, using the multiple-time-point fit as the reference. Time-activity data for 250 virtual patients were generated using parameter values from the clinical cohort. Mixed models were fit using 1 (∼96 h) and 2 (4 h, ∼96 h) time points for each virtual patient combined with complete data for the other patients in each dataset. Time-integrated activities (TIAs) calculated from mixed model fits and other reduced-time-point methods were compared with known values. Results : All mixed models and single-time-point methods performed well overall, achieving mean bias < 7% in the virtual cohort. Mixed models exhibited lower bias, greater precision, and substantially fewer outliers than did single-time-point methods. For clinical patients, 1- and 2-time-point mixed models resulted in more accurate TIA estimates for 94% (17/18) and 72% (13/18) of kidneys, respectively. In virtual patients, mixed models resulted in more than a 2-fold reduction in the proportion of kidneys with |bias| > 10% (6% vs. 15%). Conclusion: Mixed models based on a historical cohort of patients with complete time-activity data and new patients with only 1 or 2 SPECT/CT scans demonstrate less bias on average and significantly fewer outliers when estimating kidney TIA, compared with popular reduced-time-point methods. Use of mixed models allows for reduction of the imaging burden while maintaining accuracy, which is crucial for clinical implementation of dosimetry-based treatment., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

In medical research, the Brier score (BS) and the area under the receiver operating characteristic (ROC) curves (AUC) are two common metrics used to evaluate prediction models of a binary outcome, such as using biomarkers to predict the risk of developing a disease in the future. The assessment of an existing prediction models using data with missing covariate values is challenging. In this article, we propose inverse probability weighted (IPW) and augmented inverse probability weighted (AIPW) estimates of AUC and BS to handle the missing data. An alternative approach uses multiple imputation (MI), which requires a model for the distribution of the missing variable. We evaluated the performance of IPW and AIPW in comparison with MI in simulation studies under missing completely at random, missing at random, and missing not at random scenarios. When there are missing observations in the data, MI and IPW can be used to obtain unbiased estimates of BS and AUC if the imputation model for the missing variable or the model for the missingness is correctly specified. MI is more efficient than IPW. Our simulation results suggest that AIPW can be more efficient than IPW, and also achieves double robustness from miss-specification of either the missingness model or the imputation model. The outcome variable should be included in the model for the missing variable under all scenarios, while it only needs to be included in missingness model if the missingness depends on the outcome. We illustrate these methods using an example from prostate cancer., (© 2021 John Wiley & Sons Ltd.)

Purpose: Predicting individual patient sensitivity to radiation therapy (RT) for tumor control or normal tissue toxicity is necessary to individualize treatment planning. In head and neck cancer, radiation doses are limited by many nearby critical structures, including structures involved in swallowing. Previous efforts showed that imaging parameters correlate with RT dose; here, we investigate the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) blood volume (BV) changes in predicting dysphagia., Methods and Materials: This study included 32 patients with locally advanced oropharyngeal squamous cell carcinoma treated with definitive chemoradiation on an institutional protocol incorporating baseline and early midtreatment DCE-MRI. BV maps of the pharyngeal constrictor muscles (PCM) were created, and BV increases midtreatment were correlated with the following parameters at 3 and 12 months post-RT: RT dose, Dynamic Imaging Grade of Swallowing Toxicity swallow score, aspiration frequency, European Organisation for Research and Treatment of Cancer HN35 patient-reported outcomes, physician-reported dysphagia, and feeding tube (FT) dependence., Results: The mean BV to the PCMs increased from baseline to fraction 10, which was significant for the superior PCM (P = .006) and middle PCM (P < .001), with a trend in the inferior PCM where lower mean doses were seen (P = .077). The factors associated with FT dependence at 3 months included BV increases in the total PCM (correlation, 0.48; P = .006) and middle PCM (correlation, 0.50; P = .004). A post-RT increase in aspiration was associated with a BV increase in the superior PCM (correlation, 0.44; P = .013),and the increase in the total PCMs was marginally significant (correlation, 0.34; P = .06). The best-performing models of FT dependence (area under the receiver operating curve [AUC] = 0.84) and aspiration increases (AUC = 0.78) included BV increases as well as a mean RT dose to middle PCM., Conclusions: Our results suggest that midtreatment BV increases derived from DCE-MRI are an early predictor of dysphagia. Further investigation of these promising imaging markers to assess individual patient sensitivity to treatment and the patient's subsequent risk of toxicities is warranted to improve personalization of RT planning., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity., Methods: We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches., Results: Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose., Conclusion: Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

Background: The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer., Methods: For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R 2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R 2 was 0·7 or greater., Findings: 75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7-10·6). Biochemical failure (R 2 0·38 [95% CI 0·11-0·64]), biochemical failure-free survival (R 2 0·12 [0·0030-0·33]), biochemical failure and clinical failure (R 2 0·28 [0·0045-0·65]), and local failure (R 2 0·085 [0·00-0·37]) correlated poorly with overall survival. Progression-free survival (R 2 0·46 [95% CI 0·22-0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R 2 0·78 [0·59-0·89]) correlated strongly., Interpretation: Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date., Funding: Prostate Cancer Foundation and National Institutes of Health., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Dose to normal lung has commonly been linked with radiation-induced lung toxicity (RILT) risk, but incorporating functional lung metrics in treatment planning may help further optimize dose delivery and reduce RILT incidence. The purpose of this study was to investigate the impact of the dose delivered to functional lung regions by analyzing perfusion (Q), ventilation (V), and combined V/Q single-photon-emission computed tomography (SPECT) dose-function metrics with regard to RILT risk in patients with non-small cell lung cancer (NSCLC) patients who received radiation therapy (RT)., Methods and Materials: SPECT images acquired from 88 patients with locally advanced NSCLC before undergoing conventionally fractionated RT were retrospectively analyzed. Dose was converted to the nominal dose equivalent per 2 Gy fraction, and SPECT intensities were normalized. Regional lung segments were defined, and the average dose delivered to each lung region was quantified. Three functional categorizations were defined to represent low-, normal-, and high-functioning lungs. The percent of functional lung category receiving ≥20 Gy and mean functional intensity receiving ≥20 Gy (iV 20 ) were calculated. RILT was defined as grade 2+ radiation pneumonitis and/or clinical radiation fibrosis. A logistic regression was used to evaluate the association between dose-function metrics and risk of RILT., Results: By analyzing V/Q normalized intensities and functional distributions across the population, a wide range in functional capability (especially in the ipsilateral lung) was observed in patients with NSCLC before RT. Through multivariable regression models, global lung average dose to the lower lung was found to be significantly associated with RILT, and Q and V iV 20 were correlated with RILT when using ipsilateral lung metrics. Through a receiver operating characteristic analysis, combined V/Q low-function receiving ≥20 Gy (low-functioning V/Q 20 ) in the ipsilateral lung was found to be the best predictor (area under the curce: 0.79) of RILT risk., Conclusions: Irradiation of the inferior lung appears to be a locational sensitivity for RILT risk. The multivariable correlation between ipsilateral lung iV 20 and RILT, as well as the association of low-functioning V/Q 20 and RILT, suggest that irradiating low-functioning regions in the lung may lead to higher toxicity rates., (© 2021 The Authors.)

Small sample, sequential, multiple assignment, randomized trials (snSMARTs) are multistage trials with the overall goal of determining the best treatment after a fixed amount of time. In snSMART trials, patients are first randomized to one of three treatments and a binary (e.g. response/nonresponse) outcome is measured at the end of the first stage. Responders to first stage treatment continue their treatment. Nonresponders to first stage treatment are rerandomized to one of the remaining treatments. The same binary outcome is measured at the end of the first and second stages, and data from both stages are pooled together to find the best first stage treatment. However, in many settings the primary endpoint may be continuous, and dichotomizing this continuous variable may reduce statistical efficiency. In this article, we extend the snSMART design and methods to allow for continuous outcomes. Instead of requiring a binary outcome at the first stage for rerandomization, the probability of staying on the same treatment or switching treatment is a function of the first stage outcome. Rerandomization based on a mapping function of a continuous outcome allows for snSMART designs without requiring a binary outcome. We perform simulation studies to compare the proposed design with continuous outcomes to standard snSMART designs with binary outcomes. The proposed design results in more efficient treatment effect estimates and similar outcomes for trial patients., (© 2020 John Wiley & Sons, Ltd.)

Purpose: There remains a lack of clarity regarding the influence of sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) on outcomes in prostate cancer (PCa). Herein, we evaluate the optimal sequencing of ADT with prostate-directed RT in localized PCa., Methods: MEDLINE (1966-2018), Embase (1982-2018), ClinicalTrials.gov, and conference proceedings (1990-2018) were searched to identify randomized trials evaluating the sequencing, but not duration, of ADT with RT. Two randomized phase III trials were identified, and individual patient data were obtained: Ottawa 0101 and NRG Oncology's Radiation Therapy Oncology Group 9413. Ottawa 0101 randomly assigned patients to neoadjuvant or concurrent versus concurrent or adjuvant short-term ADT. Radiation Therapy Oncology Group 9413, a 2 × 2 factorial trial, included a random assignment of neoadjuvant or concurrent versus adjuvant short-term ADT. The neoadjuvant or concurrent ADT arms of both trials were combined into the neoadjuvant group, and the arms receiving adjuvant ADT were combined into the adjuvant group. The primary end point of this meta-analysis was progression-free survival (PFS)., Results: The median follow-up was 14.9 years. Overall, 1,065 patients were included (531 neoadjuvant and 534 adjuvant). PFS was significantly improved in the adjuvant group (15-year PFS, 29% v 36%, hazard ratio [HR], 1.25 [95% CI, 1.07 to 1.47], P = .01). Biochemical failure (subdistribution HR [sHR], 1.37 [95% CI, 1.12 to 1.68], P = .002), distant metastasis (sHR, 1.40 [95% CI, 1.00 to 1.95], P = .04), and metastasis-free survival (HR, 1.17 [95% CI, 1.00 to 1.37], P = .050) were all significantly improved in the adjuvant group. There were no differences in late grade ≥ 3 gastrointestinal (2% v 3%, P = .33) or genitourinary toxicity (5% v 5%, P = .76) between groups., Conclusion: The sequencing of ADT with prostate-directed RT has significant association with long-term PFS and MFS in localized PCa. Our findings favor use of an adjuvant over a neoadjuvant approach, without any increase in long-term toxicity.

Purpose: Previous reports of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) suggest unacceptably high rates of toxicity in patients with Child-Turcotte-Pugh (CTP) B liver disease. We hypothesized that an individualized adaptive treatment approach based on midtreatment liver function would maintain good local control while limiting toxicity in this population., Methods and Materials: Patients with CTP-B liver disease and HCC were treated on prospective trials of individualized adaptive SBRT between 2006 and 2018. Patients underwent pre- and midtreatment liver function assessments using indocyanine green. Treatment-related toxicity was defined as a ≥2-point increase in CTP score from pretreatment within 6 months of treatment. In addition, we performed analyses with a longitudinal model to assess changes in CTP score over 12 months after SBRT., Results: Eighty patients with CTP-B (median tumor size, 2.5 cm) were treated: 37 patients were CTP-B-7, 28 were CTP-B-8, and 15 were CTP-B-9. The median treatment dose was 36 Gy in 3 fractions. One-year local control was 92%. In a multivariate model controlling for tumor size, treatment dose, and baseline CTP score, higher treatment dose was associated with improved freedom from local progression (hazard ratio: 0.97; 95% confidence interval, 0.94-1.00; P = .04). Eighteen patients (24%) had a ≥2-point increase in CTP score within 6 months of SBRT. In a longitudinal model assessing changes in CTP score over 12 months after SBRT, controlling for baseline CTP and tumor size, increasing mean liver dose was associated with larger increases in CTP score (P = .04)., Conclusions: An individualized adaptive treatment approach allows for acceptable toxicity and effective local control in patients with HCC and CTP-B liver disease. Because increasing dose may increase both local control and toxicity, further work is needed to optimize treatment in patients with compromised liver function., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Radiation therapy for the management of intrahepatic malignancies can adversely affect liver function. Liver damage has been associated with increased levels of inflammatory cytokines, including tumor necrosis factor alpha (TNFα). We hypothesized that an inflammatory state, characterized by increased soluble TNFα receptor (sTNFR1), mediates sensitivity of the liver to radiation., Materials/methods: Plasma samples collected during 3 trials of liver radiation for liver malignancies were assayed for sTNFR1 level via enzyme-linked immunosorbent assay (ELISA). Univariate and multivariate logistic regression and longitudinal models were used to characterize associations between liver toxicity (defined as a ≥2-point increase in Child-Pugh [CP] score within 6 months of radiation treatment) and sTNFR1 levels, ALBI score, biocorrected mean liver dose (MLD), age, and baseline laboratory values., Results: Samples from 78 patients given liver stereotactic body radiation therapy [SBRT] (92%) or hypofractionated radiation were examined. There was a significant association between liver toxicity and sTNFR1 levels, and higher values were associated with increased toxicity over a range of mean liver doses. When ALBI score and biocorrected dose were included in the model with sTNFR1, baseline ALBI score and change in ALBI (ΔALBI) were significantly associated with toxicity, but sTNFR1 was not. Baseline aminotransferase levels also predicted toxicity but not independently of ALBI score., Conclusions: Elevated plasma sTNFR1 levels are associated with liver injury after liver radiation, suggesting that elevated inflammatory cytokine activity is a predictor of radiation-induced liver dysfunction. Future studies should determine whether administration of agents that decrease inflammation prior to treatment is warranted., Competing Interests: Declaration of Competing Interest Dr. Parikh reports personal fees from Bristol Myers-Squibb, personal fees from Eisai, personal fees from Exelixis, grants and personal fees from Exact Sciences, grants and personal fees from Bayer, personal fees from Freenome, personal fees from Eli Lilly, and personal fees from Wako/Fujifilm, outside the submitted work. Dr. Schipper reports personal fees from Innovative Analytics, outside the submitted work. Dr. Ten Haken reports grants from NIH, during the conduct of the study; non-financial support from Varian Medical Systems, outside the submitted work. The other 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 © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: In 2016, the American Joint Committee on Cancer (AJCC) established criteria to evaluate prediction models for staging. No localized prostate cancer models were endorsed by the Precision Medicine Core committee, and 8th edition staging was based on expert consensus., Objective: To develop and validate a pretreatment clinical prognostic stage group system for nonmetastatic prostate cancer., Design, Setting, and Participants: This multinational cohort study included 7 centers from the United States, Canada, and Europe, the Shared Equal Access Regional Cancer Hospital (SEARCH) Veterans Affairs Medical Centers collaborative (5 centers), and the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (43 centers) (the STAR-CAP cohort). Patients with cT1-4N0-1M0 prostate adenocarcinoma treated from January 1, 1992, to December 31, 2013 (follow-up completed December 31, 2017). The STAR-CAP cohort was randomly divided into training and validation data sets; statisticians were blinded to the validation data until the model was locked. A Surveillance, Epidemiology, and End Results (SEER) cohort was used as a second validation set. Analysis was performed from January 1, 2018, to November 30, 2019., Exposures: Curative intent radical prostatectomy (RP) or radiotherapy with or without androgen deprivation therapy., Main Outcomes and Measures: Prostate cancer-specific mortality (PCSM). Based on a competing-risk regression model, a points-based Score staging system was developed. Model discrimination (C index), calibration, and overall performance were assessed in the validation cohorts., Results: Of 19 684 patients included in the analysis (median age, 64.0 [interquartile range (IQR), 59.0-70.0] years), 12 421 were treated with RP and 7263 with radiotherapy. Median follow-up was 71.8 (IQR, 34.3-124.3) months; 4078 (20.7%) were followed up for at least 10 years. Age, T category, N category, Gleason grade, pretreatment serum prostate-specific antigen level, and the percentage of positive core biopsy results among biopsies performed were included as variables. In the validation set, predicted 10-year PCSM for the 9 Score groups ranged from 0.3% to 40.0%. The 10-year C index (0.796; 95% CI, 0.760-0.828) exceeded that of the AJCC 8th edition (0.757; 95% CI, 0.719-0.792), which was improved across age, race, and treatment modality and within the SEER validation cohort. The Score system performed similarly to individualized random survival forest and interaction models and outperformed National Comprehensive Cancer Network (NCCN) and Cancer of the Prostate Risk Assessment (CAPRA) risk grouping 3- and 4-tier classification systems (10-year C index for NCCN 3-tier, 0.729; for NCCN 4-tier, 0.746; for Score, 0.794) as well as CAPRA (10-year C index for CAPRA, 0.760; for Score, 0.782)., Conclusions and Relevance: Using a large, diverse international cohort treated with standard curative treatment options, a proposed AJCC-compliant clinical prognostic stage group system for prostate cancer has been developed. This system may allow consistency of reporting and interpretation of results and clinical trial design.

Objectives: Improved prognosis for p16+ oropharyngeal squamous cell carcinoma (OPSCC) has led to efforts to mitigate long-term complications of treatment, which remains poorly defined in late survivors. Here we characterize very late dysphagia in OPSCC., Materials and Methods: Long-term review of 93 p16+ OPSCC patients treated with chemoradiation was performed. We scored videofluoroscopic swallow studies (VFSS) according to the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale. Very late dysphagia was defined >2.5 years from end of treatment. Fine-Gray regression models were used to assess dysphagia with competing risk of death., Results: Median follow up was 10.5 years. 402 total VFSS were assessed (median 4 per patient, range 0-8). 15.1% of patients had a DIGEST score ≥2 very late after treatment. Very late DIGEST score ≥2 correlated with T-stage (HR 1.7, p = 0.049), second cancer (HR 6.5, p = 0.004), superior pharyngeal constrictor dose (HR 1.11, p = 0.050), total tongue dose (HR 1.07, p = 0.045), but not hypoglossal nerve dose (p > 0.2). Seven patients (7.5%) had late progressive dysphagia, defined as DIGEST score that increased by ≥2 beyond one year after treatment, and this correlated with higher ipsilateral hypoglossal nerve D1cc dose (75 vs 72 Gy, p = 0.037)., Conclusion: In p16+ OPSCC patients treated with definitive chemoradiation, at least 7.5% developed late progressive dysphagia, and 15.1% experienced moderate dysphagia >2.5 years from treatment. Our study suggests that dose to tongue musculature may be associated with very late dysphagia, and hypoglossal nerve dose may be associated with late progressive dysphagia. More intensive long-term dysphagia survivorship monitoring is suggested., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Importance: Cancer treatment delay has been reported to variably impact cancer-specific survival and coronavirus disease 2019 (COVID-19)-specific mortality during the severe acute respiratory syndrome coronavirus 2 pandemic. During the pandemic, treatment delay is being recommended in a nonquantitative, nonobjective, and nonpersonalized manner, and this approach may be associated with suboptimal outcomes. Quantitative integration of cancer mortality estimates and data on the consequences of treatment delay is needed to aid treatment decisions and improve patient outcomes., Objective: To obtain quantitative integration of cancer-specific and COVID-19-specific mortality estimates that can be used to make optimal decisions for individual patients and optimize resource allocation., Design, Setting, and Participants: In this decision analytical model, age-specific and stage-specific estimates of overall survival pre-COVID-19 were adjusted by the probability of COVID-19 (individualized by county, treatment-specific variables, hospital exposure frequency, and COVID-19 infectivity estimates), COVID-19 mortality (individualized by age-specific, comorbidity-specific, and treatment-specific variables), and delay of cancer treatment (impact and duration). These model estimates were integrated into a web application (OncCOVID) to calculate estimates of the cumulative overall survival and restricted mean survival time of patients who received immediate vs delayed cancer treatment. Using currently available information about COVID-19, a susceptible-infected-recovered model that accounted for the increased risk among patients at health care treatment centers was developed. This model integrated the data on cancer mortality and the consequences of treatment delay to aid treatment decisions. Age-specific and cancer stage-specific estimates of overall survival pre-COVID-19 were extracted from the Surveillance, Epidemiology, and End Results database for 691 854 individuals with 25 cancer types who received cancer diagnoses in 2005 to 2006. Data from 5 436 896 individuals in the National Cancer Database were used to estimate the independent impact of treatment delay by cancer type and stage. In addition, data from 275 patients in a nested case-control study were used to estimate the COVID-19 mortality rate by age group and number of comorbidities. Data were analyzed from March 17 to May 21, 2020., Exposures: COVID-19 and cancer., Main Outcomes and Measures: Estimates of restricted mean survival time after the receipt of immediate vs delayed cancer treatment., Results: At the time of the study, the OncCOVID web application allowed for the selection of up to 47 individualized variables to assess net survival for an individual patient with cancer. Substantial heterogeneity was found regarding the association between delayed cancer treatment and net survival among patients with a given cancer type and stage, and these 2 variables were insufficient to discriminate the net impact of immediate vs delayed treatment. Individualized overall survival estimates were associated with patient age, number of comorbidities, treatment received, and specific local community estimates of COVID-19 risk., Conclusions and Relevance: This decision analytical modeling study found that the OncCOVID web-based application can quantitatively aid in the resource allocation of individualized treatment for patients with cancer during the COVID-19 global pandemic.

Purpose: To determine the long-term natural history of size change in SBRT-treated HCC to identify an imaging biomarker to help assess treatment response., Methods: This was a retrospective cohort study of consecutive HCCs treated with SBRT from January 2008 to December 2016 with either 2 years post-treatment MRI follow-up or post-treatment resection histology. Size, major features for HCC, and mRECIST and LI-RADS v.2018 treatment response criteria were assessed at each post-treatment MRI. Local progression, distant progression, and survival were modeled with Kaplan Meier analyses., Results: 56 HCCs met inclusion criteria. Mean baseline HCC diameter was 30 mm (range: 9-105 mm). At 3 months, 76% (N = 43) of treated HCCs decreased in size (mean reduction: 8 mm, range: 5-99 mm) and 0% (N = 0) increased in size. By 24 months, 11% (N = 5) had increased in size and were considered local progression. APHE remained in 77% (43/56) at 3 months, 38% (19/50) at 12 months, and 23% (11/47) at 24 months. mRECIST-defined viable disease was observed in 77% (43/56) at 3 months and 20% (9/47) at 24 months. LI-RADS v.2018 criteria identified viable or equivocal disease in 0% at 3 months and 10% (5/47) at 24 months., Conclusion: Gradual loss of APHE and slow decrease in size are normal findings in HCCs treated with SBRT, and persistent APHE does not indicate viable disease. mRECIST is not accurate in the assessment of HCC after SBRT due to an overreliance on APHE to define viable disease. Increasing mass size or new nodular APHE at the treatment site may indicate local progression.