Efficiency of the Breslow estimator in semiparametric transformation models.

Semiparametric transformation models for failure time data consist of a parametric regression component and an unspecified cumulative baseline hazard. The nonparametric maximum likelihood estimator (NPMLE) of the cumulative baseline hazard can be summarized in terms of weights introduced into a Breslow-type estimator (Weighted Breslow). At any given time point, the weights invoke an integral over the future of the cumulative baseline hazard, which presents theoretical and computational challenges. A simpler non-MLE Breslow-type estimator (Breslow) was derived earlier from a martingale estimating equation (MEE) setting observed and expected counts of failures equal, conditional on the past history. Despite much successful theoretical and computational development, the simpler Breslow estimator continues to be commonly used as a compromise between simplicity and perceived loss of full efficiency. In this paper we derive the relative efficiency of the Breslow estimator and consider the properties of the two estimators using simulations and real data on prostate cancer survival.

Increase in the Life Expectancy of Patients with Cancer in the United States.

BACKGROUND: Cancer is becoming more of a chronic disease due to improvements in treatment and early detection for multiple cancer sites. To gain insight on increased life expectancy due to these improvements, we quantified trends in the loss in expectation of life (LEL) due to a cancer diagnosis for six cancer sites from 1975 through 2018. METHODS: We focused on patients diagnosed with female breast cancer, chronic myeloid leukemia (CML), colon and rectum cancer, diffuse large B-cell lymphoma (DLBCL), lung cancer, or melanoma between 1975 and 2018 from nine Surveillance, Epidemiology, and End Results cancer registries. Life expectancies for patients with cancer ages 50+ were modeled using flexible parametric survival models. LEL was calculated as the difference between general population life expectancy and life expectancy for patients with cancer. RESULTS: Over 2 million patients were diagnosed with one of the six cancers between 1975 and 2018. Large increases in life expectancy were observed between 1990 and 2010 for female breast, DLBCL, and CML. Patients with colon and rectum cancer and melanoma had more gradual improvements in life expectancy. Lung cancer LEL only began decreasing after 2005. Increases in life expectancy corresponded with decreases in LEL for patients with cancer. CONCLUSIONS: The reported gains in life expectancy largely correspond to progress in the screening, management, and treatment of these six cancers since 1975. IMPACT: LEL provides an important public health perspective on how improvements in treatment and early detection and their impacts on survival translate into changes in cancer patients' life expectancy.

Long-term Cancer Survival Trends by Updated Summary Stage.

BACKGROUND: Stage is the most important prognostic factor for understanding cancer survival trends. Summary stage (SS) classifies cancer based on the extent of spread: In situ, Localized, Regional, or Distant. Continual updating of staging systems poses challenges to stage comparisons over time. We use a consistent summary stage classification and present survival trends for 25 cancer sites using the joinpoint survival (JPSurv) model. METHODS: We developed a modified summary stage variable, Long-Term Site-Specific Summary Stage, based on as consistent a definition as possible and applied it to a maximum number of diagnosis years, 1975-2019. We estimated trends by stage by applying JPSurv to relative survival data for 25 cancer sites in SEER-8, 1975-2018, followed through December 31, 2019. To help interpret survival trends, we report incidence and mortality trends using the joinpoint model. RESULTS: Five-year relative survival improved for nearly all sites and stages. Large improvements were observed for localized pancreatic cancer [4.25 percentage points annually, 2007-2012 (95% confidence interval, 3.40-5.10)], distant skin melanoma [2.15 percentage points annually, 2008-2018 (1.73-2.57)], and localized esophagus cancer [1.18 percentage points annually, 1975-2018 (1.11-1.26)]. CONCLUSIONS: This is the first analysis of survival trends by summary stage for multiple cancer sites. The largest survival increases were seen for cancers with a traditionally poor prognosis and no organized screening, which likely reflects clinical management advances. IMPACT: Our study will be particularly useful for understanding the population-level impact of new treatments and identifying emerging trends in health disparities research.

Estimating the Number of Men Living with Metastatic Prostate Cancer in the United States.

BACKGROUND: Metastatic prostate cancer (MPC) includes metastases detected at diagnosis (de novo) and those occurring after diagnosis with early-stage disease (recurrent). Cancer registries collect data only on de novo MPC, providing a partial picture of the burden of MPC. We use cancer registry data to estimate the number of men living with MPC in the United States including both de novo and recurrent cases. METHODS: We apply a back-calculation method to estimate MPC incidence and prevalence from U.S. prostate cancer mortality and de novo MPC relative survival for cases diagnosed between 2000 and 2017 in 18 Surveillance, Epidemiology, and End Results registries. We hold overall prostate cancer mortality and MPC survival constant for future prevalence projections. RESULTS: On January 1, 2018, we estimated 120,400 U.S. men living with MPC (45% de novo, 55% recurrent). The age-adjusted prevalence in 2018 for Black men was over double that of White men (137.1 vs. 62.2 per 100,000 men). By 2030, 192,500 men are expected to be living with MPC, with the increase being driven by population growth projections. CONCLUSIONS: The number of men living with MPC in the United States exceeds 100,000 and represents a small fraction of the >3 million men living with a prior diagnosis of prostate cancer. IMPACT: Relatively similar fractions of de novo and recurrent MPC among prevalent cases highlight opportunities for management of localized disease in reducing the MPC burden. Changes in diagnostic technologies could lead to greater growth in MPC cases in the United States than projected. See related commentary by Stopsack et al., p. 585.

Cannabis Use in Patients Seen in an Academic Radiation Oncology Department.

PURPOSE: Cannabis use rates are increasing in the United States. Patients with cancer use cannabis for many reasons, even without high-quality supporting data. This study sought to characterize cannabis use among patients seen in radiation oncology in a state that has legalized adult nonmedical use cannabis and to identify key cannabis-related educational topics. METHODS AND MATERIALS: Cannabis history was documented by providers using a structured template at patient visits in an academic radiation oncology practice October 2020 to November 2021. Cannabis use data, including recency/frequency of use, reason, and mode of administration, were summarized, and logistic regression was used to explore associations between patient and disease characteristics and recent cannabis use. A multivariable model employed stepwise variable selection using the Akaike Information Criterion. RESULTS: Of 3143 patients total, 91 (2.9%) declined to answer cannabis use questions, and 343 (10.9%) endorsed recent use (≤1 month ago), 235 (7.5%) noted nonrecent use (>1 month ago), and 2474 (78.7%) denied history of cannabis use. In multivariable analyses, those ≥50 years old (odds ratio [OR], 0.409; 95% confidence interval [CI], 0.294-0.568; P < .001) or with history of prior courses of radiation (OR, 0.748; 95% CI, 0.572-0.979; P = .034) were less likely, and those with a mental health diagnosis not related to substance use (OR, 1.533; 95% CI, 1.171-2.005; P = .002) or who smoked tobacco (OR, 3.003; 95% CI, 2.098-4.299; P < .001) were more likely to endorse recent cannabis use. Patients reported pain, insomnia, and anxiety as the most common reasons for use. Smoking was the most common mode of administration. CONCLUSIONS: Patients are willing to discuss cannabis use with providers and reported recent cannabis use for a variety of reasons. Younger patients new to oncologic care and those with a history of mental illness or tobacco smoking may benefit most from discussions about cannabis given higher rates of cannabis use in these groups.

Estimation of the Number of Individuals Living With Metastatic Cancer in the United States.

BACKGROUND: The purpose of this study was to estimate the number of individuals living with metastatic breast, prostate, lung, colorectal, or bladder cancer or metastatic melanoma in the United States using population-based data. METHODS: A back-calculation method was used to estimate the number of individuals living with metastatic cancer for each cancer type from US cancer mortality and survival statistics from the Surveillance, Epidemiology, and End Results registries. The percentages of those living with metastatic cancer who advanced to metastatic disease from early stage cancer vs who were diagnosed with metastatic cancer de novo were calculated. One- and 5-year relative survival rates for de novo metastatic cancer were compared by year of diagnosis to assess time trends in survival. RESULTS: It is estimated that, in 2018, 623 405 individuals were living with metastatic breast, prostate, lung, colorectal, or bladder cancer, or metastatic melanoma in the United States. This number is expected to increase to 693 452 in 2025. In 2018, the percentage of metastatic cancer survivors who were initially diagnosed with early stage cancer and advanced to metastatic cancer ranged from 30% for lung cancer to 72% for bladder cancer. CONCLUSIONS: This study demonstrates increasing numbers of individuals living with metastatic cancer of the 6 most common cancer types in the United States. This information is critical for informing the allocation of research efforts and healthcare infrastructure needed to address the needs of these individuals.

Cancer treatment and survivorship statistics, 2022.

The number of cancer survivors continues to increase in the United States due to the growth and aging of the population as well as advances in early detection and treatment. To assist the public health community in better serving these individuals, the American Cancer Society and the National Cancer Institute collaborate triennially to estimate cancer prevalence in the United States using incidence and survival data from the Surveillance, Epidemiology, and End Results cancer registries, vital statistics from the Centers for Disease Control and Prevention's National Center for Health Statistics, and population projections from the US Census Bureau. Current treatment patterns based on information in the National Cancer Database are presented for the most prevalent cancer types by race, and cancer-related and treatment-related side-effects are also briefly described. More than 18 million Americans (8.3 million males and 9.7 million females) with a history of cancer were alive on January 1, 2022. The 3 most prevalent cancers are prostate (3,523,230), melanoma of the skin (760,640), and colon and rectum (726,450) among males and breast (4,055,770), uterine corpus (891,560), and thyroid (823,800) among females. More than one-half (53%) of survivors were diagnosed within the past 10 years, and two-thirds (67%) were aged 65 years or older. One of the largest racial disparities in treatment is for rectal cancer, for which 41% of Black patients with stage I disease receive proctectomy or proctocolectomy compared to 66% of White patients. Surgical receipt is also substantially lower among Black patients with non-small cell lung cancer, 49% for stages I-II and 16% for stage III versus 55% and 22% for White patients, respectively. These treatment disparities are exacerbated by the fact that Black patients continue to be less likely to be diagnosed with stage I disease than White patients for most cancers, with some of the largest disparities for female breast (53% vs 68%) and endometrial (59% vs 73%). Although there are a growing number of tools that can assist patients, caregivers, and clinicians in navigating the various phases of cancer survivorship, further evidence-based strategies and equitable access to available resources are needed to mitigate disparities for communities of color and optimize care for people with a history of cancer. CA Cancer J Clin. 2022;72:409-436.

Better Understanding the Timing Of Androgen Deprivation Trial Outcomes: Impacts of Prior Androgen Deprivation Therapy.

BACKGROUND: The Timing Of Androgen Deprivation (TOAD) trial found an overall survival benefit for immediate vs delayed androgen deprivation therapy (ADT) for prostate-specific antigen (PSA)-relapsed or noncurable prostate cancer. However, broad eligibility criteria allowed entry of a heterogeneous participant group, including those with prior ADT exposure, raising concerns about subsequent androgen sensitivity. For these reasons, we completed previously specified subgroup analyses to assess if prior ADT was associated with ADT timing efficacy after PSA relapse. METHODS: We examined TOAD trial patient-level data for participants with PSA relapse after local therapy. We performed Kaplan-Meier analyses for overall survival stratified by prior ADT and randomized treatment arm (immediate or delayed ADT). We compared group characteristics using Mann-Whitney U and Fisher exact tests. All hypothesis tests were 2-sided. RESULTS: We identified 261 patients with PSA relapse, 125 of whom received prior ADT. Patients with prior ADT had higher PSA at presentation (12.1 vs 9.0 ng/mL; P < .001), more cT3 disease (38.4% vs 25.0%; P = .007), and more likely received radiotherapy as local treatment (80.0% vs 47.8%; P < .001) but were otherwise similar to patients without prior ADT exposure. Within this prior ADT group, those who received immediate ADT (n = 56) had improved overall survival compared with those who received delayed ADT (n = 69; P = .02). This benefit was not observed in the group with no prior ADT (P = .98). CONCLUSIONS: The survival benefit demonstrated in the TOAD trial may be driven by patients who received ADT prior to trial entry. We provide possible explanations for this finding with implications for treatment of PSA-relapsed prostate cancer and future study planning.

Pretreatment Levels of Soluble Tumor Necrosis Factor Receptor 1 and Hepatocyte Growth Factor Predict Toxicity and Overall Survival After 90Y Radioembolization: Potential Novel Application of Biomarkers for Personalized Management of Hepatotoxicity.

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 90Y 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 90Y 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 90Y 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.

A Novel Time-Activity Information-Sharing Approach Using Nonlinear Mixed Models for Patient-Specific Dosimetry with Reduced Imaging Time Points: Application in SPECT/CT After 177Lu-DOTATATE.

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 177Lu-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.

TNFR1 and the TNFα axis as a targetable mediator of liver injury from stereotactic body radiation therapy.

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.

Integrated Survival Estimates for Cancer Treatment Delay Among Adults With Cancer During the COVID-19 Pandemic.

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.

Low-Dose Hsp90 Inhibitor Selectively Radiosensitizes HNSCC and Pancreatic Xenografts.

PURPOSE: Treatment approaches using Hsp90 inhibitors at their maximum tolerated doses (MTDs) have not produced selective tumor toxicity. Inhibition of Hsp90 activity causes degradation of client proteins including those involved in recognizing and repairing DNA lesions. We hypothesized that if DNA repair proteins were degraded by concentrations of an Hsp90 inhibitor below those required to cause nonspecific cytotoxicity, significant tumor-selective radiosensitization might be achieved. EXPERIMENTAL DESIGN: Tandem mass tagged-mass spectrometry was performed to determine the effect of a subcytotoxic concentration of the Hsp90 inhibitor, AT13387 (onalespib), on global protein abundance. The effect of AT13387 on in vitro radiosensitization was assessed using a clonogenic assay. Pharmacokinetics profiling was performed in mice bearing xenografts. Finally, the effect of low-dose AT13387 on the radiosensitization of three tumor models was assessed. RESULTS: A subcytotoxic concentration of AT13387 reduced levels of DNA repair proteins, without affecting the majority of Hsp90 clients. The pharmacokinetics study using one-third of the MTD showed 40-fold higher levels of AT13387 in tumors compared with plasma. This low dose enhanced Hsp70 expression in peripheral blood mononuclear cells (PBMCs), which is a biomarker of Hsp90 inhibition. Low dose monotherapy was ineffective, but when combined with radiotherapy, produced significant tumor growth inhibition. CONCLUSIONS: This study shows that a significant therapeutic ratio can be achieved by a low dose of Hsp90 inhibitor in combination with radiotherapy. Hsp90 inhibition, even at a low dose, can be monitored by measuring Hsp70 expression in PBMCs in human studies.

Natural history of hepatocellular carcinoma after stereotactic body radiation therapy.

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.

BRAINSTORM: A Multi-Institutional Phase 1/2 Study of RRx-001 in Combination With Whole Brain Radiation Therapy for Patients With Brain Metastases.

PURPOSE: To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response. METHODS AND MATERIALS: Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, 27.5 mg/m2). Dose escalation was managed by the time-to-event continual reassessment method algorithm. Linear mixed models were used to correlate change in 24-hour T1, Ktrans (capillary permeability), and fractional plasma volume with change in tumor volume. RESULTS: Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The most common tumor types were melanoma (59%) and non-small cell lung cancer (18%). No dose limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2 of 29). The median intracranial response rate was 46% (95% confidence interval, 24-68) and median overall survival was 5.2 months (95% confidence interval, 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing dynamic contrast-enhanced MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (P ≤ .01). CONCLUSIONS: The addition of RRx-001 to WBRT is well tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, the recommended phase 2 dose is 10 mg twice weekly. A reduction in fractional plasma volume on dynamic contrast-enhanced MRI 24 hours after RRx-001 suggests antiangiogenic activity associated with longer-term tumor response.

Prediction of Tumor Control in 90Y Radioembolization by Logit Models with PET/CT-Based Dose Metrics.

The aim of this work was to develop models for tumor control probability (TCP) in radioembolization with 90Y PET/CT-derived radiobiologic dose metrics. Methods: Patients with primary liver cancer or liver metastases who underwent radioembolization with glass microspheres were imaged with 90Y PET/CT for voxel-level dosimetry to determine lesion absorbed dose (AD) metrics, biological effective dose (BED) metrics, equivalent uniform dose, and equivalent uniform BED for 28 treatments (89 lesions). The lesion dose-shrinkage correlation was assessed on the basis of RECIST and, when available, modified RECIST (mRECIST) at first follow-up. For a subset with mRECIST, logit regression TCP models were fit via maximum likelihood to relate lesion-level binary response to the dose metrics. As an exploratory analysis, the nontumoral liver dose-toxicity relationship was also evaluated. Results: Lesion dose-shrinkage analysis showed that there were no significant differences between model parameters for primary and metastatic subgroups and that correlation coefficients were superior with mRECIST. Therefore, subsequent TCP analysis was performed for the combined group using mRECIST only. The overall lesion-level mRECIST response rate was 57%. The AD and BED metrics yielding 50% TCP were 292 and 441 Gy, respectively. All dose metrics considered for TCP modeling, including mean AD, were significantly associated with the probability of response, with high areas under the curve (0.87-0.90, P < 0.0001) and high sensitivity (>0.75) and specificity (>0.83) calculated using a threshold corresponding to 50% TCP. Because nonuniform AD deposition by microspheres cannot be determined by PET at a microscopic scale, radiosensitivity values extracted here by fitting models to clinical response data were substantially lower than reported for in vitro cell cultures or for external-beam radiotherapy clinical studies. There was no correlation between nontumoral liver AD and toxicity measures. Conclusion: Despite the heterogeneous patient cohort, logistic regression TCP models showed a strong association between various dose metrics and the probability of response. The performance of mean AD was comparable to that of radiobiologic dose metrics that involve more complex calculations. These results demonstrate the importance of considering TCP in treatment planning for radioembolization.

Dose Escalation Trial of the Wee1 Inhibitor Adavosertib (AZD1775) in Combination With Gemcitabine and Radiation for Patients With Locally Advanced Pancreatic Cancer.

PURPOSE: AZD1775 (adavosertib) is an inhibitor of the Wee1 kinase. In this study, we built on our preclinical studies to evaluate the safety and efficacy of AZD1775 in combination with gemcitabine and radiation in patients with newly diagnosed locally advanced pancreatic cancer. PATIENTS AND METHODS: Thirty-four patients with locally advanced pancreatic cancer were enrolled with the intention to receive four 21-day cycles of gemcitabine (1,000 mg/m2 days 1 and 8) with AZD1775 (once daily on days 1, 2, 8, and 9). Cycles 2 and 3 were administered concurrently with radiation, and cycles 5 to 8 were optional. AZD1775 was dose escalated using a time-to-event continual reassessment method on the basis of the rate of dose-limiting toxicities within the first 15 weeks of therapy. The primary objective was to determine the maximum tolerated dose of AZD1775 given in conjunction with gemcitabine and radiation. Secondary objectives were to estimate overall and progression-free survival and determine pharmacodynamic activity of AZD1775 in surrogate tissues. RESULTS: The recommended phase II dose of AZD1775 was 150 mg/d. Eight patients (24%) experienced a dose-limiting toxicity, most commonly anorexia, nausea, or fatigue. The median overall survival for all patients was 21.7 months (90% CI, 16.7 to 24.8 months), and the median progression-free survival was 9.4 months (90% CI, 8.0 to 9.9 months). Hair follicle biopsy samples demonstrated evidence of Wee1 inhibition with decreased phosphorylation of cyclin-dependent kinase 1 staining by immunohistochemistry after AZD1775 administration at the recommended phase II dose. CONCLUSION: AZD1775 in combination with gemcitabine and radiation therapy was well tolerated at a dose that produced target engagement in a surrogate tissue. The overall survival is substantially higher than prior results combining gemcitabine with radiation therapy and warrants additional investigation.

Serum Levels of Hepatocyte Growth Factor and CD40 Ligand Predict Radiation-Induced Liver Injury.

BACKGROUND: Declining liver function is a concerning side effect associated with radiation therapy. Biomarkers of liver toxicity would be useful in personalizing therapy. METHODS: As part of two prospective clinical trials examining adaptive radiation therapy, we collected serum samples from patients receiving liver radiation. We performed a screen of 22 cytokines using a multiplex assay then used ELISA to quantify the cytokines of greatest interest. Subjects were split into screening and validation cohorts. Toxicity was defined as an increase in Child-Pugh score of 2 points or greater within 6 months. Logistic regression models were used to estimate the relationship between our toxicity endpoint and serum cytokine concentrations. RESULTS: Our initial screen (46 subjects, 11 events) identified hepatocyte growth factor (HGF), CD40L (CD154), and eotaxin (CCL11) as potentially predictive of toxicity. We then tested these markers in an expanded patient cohort (104 subjects, 18 events) with a batch correction due to varying age of the samples which confirmed that high HGF and low CD40L were associated with a subsequent decline in liver function following radiation therapy. Multivariate analysis factoring in baseline Child-Pugh score and mean liver radiation dose demonstrated that HGF and CD40L were potentially predictive of toxicity (HGF OR 4.3, P = .009; CD40L OR 0.5 P = .06). Additionally, higher than median baseline HGF levels (1.4 ng/ml) were significantly associated with decreased survival following liver radiation (27.1 vs 14.5 months, P = .03). CONCLUSIONS: Our study identifies high HGF and low CD40L as potential markers of liver toxicity following radiation therapy.

Impact of 90Y PET gradient-based tumor segmentation on voxel-level dosimetry in liver radioembolization.

BACKGROUND: The purpose was to validate 90Y PET gradient-based tumor segmentation in phantoms and to evaluate the impact of the segmentation method on reported tumor absorbed dose (AD) and biological effective dose (BED) in 90Y microsphere radioembolization (RE) patients. A semi-automated gradient-based method was applied to phantoms and patient tumors on the 90Y PET with the initial bounding volume for gradient detection determined from a registered diagnostic CT or MR; this PET-based segmentation (PS) was compared with radiologist-defined morphologic segmentation (MS) on CT or MRI. AD and BED volume histogram metrics (D90, D70, mean) were calculated using both segmentations and concordance/correlations were investigated. Spatial concordance was assessed using Dice similarity coefficient (DSC) and mean distance to agreement (MDA). PS was repeated to assess intra-observer variability. RESULTS: In phantoms, PS demonstrated high accuracy in lesion volumes (within 15%), AD metrics (within 11%), high spatial concordance relative to morphologic segmentation (DSC > 0.86 and MDA < 1.5 mm), and low intra-observer variability (DSC > 0.99, MDA < 0.2 mm, AD/BED metrics within 2%). For patients (58 lesions), spatial concordance between PS and MS was degraded compared to in-phantom (average DSC = 0.54, average MDA = 4.8 mm); the average mean tumor AD was 226 ± 153 and 197 ± 138 Gy, respectively for PS and MS. For patient AD metrics, the best Pearson correlation (r) and concordance correlation coefficient (ccc) between segmentation methods was found for mean AD (r = 0.94, ccc = 0.92), but worsened as the metric approached the minimum dose (for D90, r = 0.77, ccc = 0.69); BED metrics exhibited a similar trend. Patient PS showed low intra-observer variability (average DSC = 0.81, average MDA = 2.2 mm, average AD/BED metrics within 3.0%). CONCLUSIONS: 90Y PET gradient-based segmentation led to accurate/robust results in phantoms, and showed high concordance with MS for reporting mean tumor AD/BED in patients. However, tumor coverage metrics such as D90 exhibited worse concordance between segmentation methods, highlighting the need to standardize segmentation methods when reporting AD/BED metrics from post-therapy 90Y PET. Estimated differences in reported AD/BED metrics due to segmentation method will be useful for interpreting RE dosimetry results in the literature including tumor response data.

Patient-Reported Sexual Aid Utilization and Efficacy After Radiation Therapy for Localized Prostate Cancer.

PURPOSE: To report sexual health-related quality of life outcomes and utilization and efficacy of sexual aids in a contemporary cohort of patients treated for localized prostate cancer. PATIENTS AND METHODS: Between 2008 and 2013, 471 consecutive men with localized prostate cancer were treated on 2 institutional protocols (NCT01766492, NCT01618851) or on a prospective institutional registry with patient-reported health-related quality of life. All patients were treated with ultra-hypofractionated radiation therapy. Erectile function (EF) was defined as "firm enough for intercourse" with or without aids per Expanded Prostate Cancer Index Composite-26 (n = 222 at baseline); results apply to this cohort unless specifically noted. Sexual aid utilization and efficacy were patient reported. Multivariable analysis of EF was performed. RESULTS: Median follow-up was 60 months, median age was 67 years, and 70% had intermediate- or high-risk disease per National Comprehensive Cancer Network guidelines. At 24 and 60 months, questionnaire response rates were 86% and 67%, and EF was retained in 53% and 41%, respectively. Baseline sexual aid utilization was 37% (n = 82) and was associated with lower 24-month EF preservation on multivariable analysis (adjusted odds ratio 0.49, 95% confidence interval 0.26-0.92). By 60 months, 70% of men had tried aids. Of those who found aids helpful at baseline, 84% to 89% reported continued benefit at 24 to 60 months. Among aid-naïve patients, efficacy was 80% with first-time use within 12 months and 70% more than 12 months after radiation therapy (P = .02). Among men who developed erectile dysfunction but found sexual aids helpful, 25% were not current users at 60 months. CONCLUSIONS: One-third of men used sexual aids at baseline, which doubled by 5 years after radiation therapy. Self-reported efficacy was high and sustained. Despite significant declines in EF, a number of men reported helpfulness of aids but were not active users. Future study is required to understand drivers of aid utilization to optimize posttreatment sexual function.