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Despite the promise of combining immunotherapy and radiotherapy (RT) for metastatic cancers, existing randomized data have not been consistent on whether RT to a single irradiated site improves clinical outcomes. Mechanistically, this could result from a low quantity/diversity of tumor antigens released for immune detection, immunosuppressive molecules released by tumor masses, and the lack of immune infiltration into tumor bulk. Herein, multi-site RT is discussed as a potential solution, given that it can directly improve upon each of the mechanistic issues. Just as it is illogical to use systemic therapy alone in place of a dedicated local therapeutic option (e.g., RT) for most stage II-III malignancies, so too is illogical to irradiate one site only in case of metastatic neoplasms instead of implementing systemic therapy and/or multi-site RT. Although it may theoretically be possible to address all systemic disease with systemic therapy, that notion assumes that all areas of systemic disease will be responsive to systemic therapy in the first place. However, in reality, certain sites may develop innate or acquired resistance to systemic therapy, hence opening the door to multi-site localized treatment strategies. Further investigation is required to address whether multi-site RT would be effective in the setting of suboptimal immune function and/or resistance/refractoriness to multiple prior systemic therapies. Methods to improve the effectiveness of multi-site RT are also discussed, such as ablatively-/definitively-dosed RT, along with staggered timing of RT administration (pulsed RT). [ABSTRACT FROM AUTHOR]

Research has focused on buprenorphine prescribing with limited attention to the role of pharmacy access to buprenorphine for opioid use disorder. This study examines demographic and socioeconomic correlates to buprenorphine access in Georgia pharmacies. A 5-question (12 potential subqueries) telephone administered survey was used to investigate access and stocking patterns of specific dosages and formulations of buprenorphine in Georgia pharmacies (n = 119). Descriptive statistics characterized physician and pharmacy demographics and buprenorphine stocking practices. Correlations between various factors including buprenorphine stocking practices, geographic, and sociodemographic characteristics were identified using nonlinear regression models. The majority of pharmacies stocked the most commonly prescribed 8/2 mg dosage strength of buprenorphine/naloxone films and tablets (69.0% and 63.0%, respectively). Other strengths were less likely to be readily available. Pharmacies in Suburban Census tracts were 77.0% more likely to stock any type of buprenorphine monotherapy [odds ratio (OR) = 1.77, t = 2.37, P < 0.05] and 58.1% more likely to stock the 8 mg buprenorphine monotherapy formulation [OR = 1.58, t = 2.15, P < 0.05] than Urban tracts. Pharmacies in areas with above-average non-White populations were 29.6% more likely to stock a monotherapy product [OR = 1.30, t = 2.16, P < 0.05], and those in areas with above-average poverty rates were more likely to stock the 8 mg/2 mg buprenorphine/naloxone tablets [OR = 1.04, t = 2.02, P < 0.05]. There were no additional differences across the sample in formulation or dosage strengths. Pharmacists who endorsed challenges dispensing buprenorphine (23.3%) cited issues around insurance coverage, payment difficulty, prior authorization issues, and low stock of specific formulations. Results suggest that low availability of certain dosages or formulations of buprenorphine in local pharmacies could obstruct access for patients. Future research should address barriers to supplying buprenorphine and collaborative measures between pharmacists and prescribers to improve access. [ABSTRACT FROM AUTHOR]

Opioid Use Disorder (OUD) is a serious public health problem, and the behavioral and physiological effects of opioid withdrawal can be a major impediment to recovery. Medication for OUD is currently the mainstay of treatment; however, it has limitations and alternative approaches are needed. The purpose of this study was to assess the effects of transcutaneous cervical vagus nerve stimulation (tcVNS) on behavioral and physiological manifestations of acute opioid withdrawal. Patients with OUD undergoing acute opioid withdrawal were randomly assigned to receive double blind active tcVNS (N = 10) or sham stimulation (N = 11) while watching neutral and opioid cue videos. Subjective opioid withdrawal, opioid craving, and anxiety were measured using a Visual Analogue Scale (VAS). Distress was measured using the Subjective Units of Distress Scale (SUDS), and pain was measured using the Numerical Rating Scale (NRS) for pain. Electrocardiogram signals were measured to compute heart rate. The primary outcomes of this initial phase of the clinical trial (ClinicalTrials.gov NCT04556552) were heart rate and craving. tcVNS compared to sham resulted in statistically significant reductions in subjective opioid withdrawal (p =.047), pain (p =.045), and distress (p =.004). In addition, tcVNS was associated with lower heart rate compared to sham (p =.026). Craving did not significantly differ between groups (p =.11). tcVNS reduces behavioral and physiological manifestations of opioid withdrawal, and should be evaluated in future studies as a possible non-pharmacologic, easily implemented approach for adjunctive OUD treatment. • Transcutaneous cervical vagus nerve stimulation (tcVNS), compared to sham, reduced risk factors of opioid relapse. • tcVNS significantly reduced subjective withdrawal symptoms, pain, and distress. • tcVNS significantly reduced heart rate during stimulation. • Reductions in heart rate, distress, and withdrawal symptoms suggest autonomically mediated effects. • tcVNS should be further evaluated as a possible approach for adjunctive OUD treatment. [ABSTRACT FROM AUTHOR]

Metastatic cancer is inherently heterogeneous, and patients with metastatic disease can experience vastly different oncologic outcomes depending on several patient- and disease-specific characteristics. Designing trials for such a diverse population is challenging yet necessary to improve treatment outcomes for metastatic—previously thought to be incurable—disease. Here we review core considerations for designing and conducting clinical trials involving radiation therapy and immunotherapy for patients with metastatic cancer. [ABSTRACT FROM AUTHOR]

This study aimed to compare and contrast the American Society for Radiation Oncology (ASTRO) model policies (MPs) for intensity modulated radiation therapy (IMRT), stereotactic radiosurgery (SRS), stereotactic ablative radiation therapy (SABR), and proton beam therapy (PBT) with the coverage policies constructed by 5 of the largest publicly available commercial insurers throughout the United States (ie, Aetna, Anthem, Cigna, Humana, and United Healthcare). Appropriate indications for IMRT, SRS, SABR, and PBT by disease site (and particular clinical setting thereof) were extracted from the most recently published ASTRO MPs and published coverage policies (2019 editions) of the 5 carriers. After tabulation, concordance between ASTRO MPs and insurance policies were calculated for each modality. All 5 insurer policies supported IMRT for neoplasms of the central nervous system, head/neck, hepatopancreaticobiliary, anal, and prostate cancers. The least covered diseases were retroperitoneal tumors (n = 0 carriers) and bladder cancer (n = 1). For SRS, all carriers covered benign brain tumors, brain metastases, arteriovenous malformations, and trigeminal neuralgia. None of the insurance carriers covered SRS for medically refractory epilepsy. For SABR, primary liver, lung, and low- or intermediate-risk prostate cancer were covered by all insurers, and none allowed SABR for primary biliary neoplasms. Only one insurance carrier each covered SABR for primary/metastatic adrenal disease and primary renal cancer. All carriers approved PBT for ocular melanoma, skull base tumors, and pediatric malignancies. The ASTRO MPs listed 4 PBT scenarios (ie, spinal disease, retroperitoneal sarcoma, head/neck neoplasms, and patients with genetic radiosensitivity syndromes) not covered by any insurer. Concordance between insurance carriers and ASTRO MPs was 67.8% for IMRT, 72.0% for SRS, 58.4% for SABR, and 41.8% for PBT (P =.005). Coverage guidelines for IMRT, SRS, SABR, and PBT vary across 5 major insurance providers and may be substantially discordant compared with ASTRO coverage guidelines. There remain several specific areas where ongoing and future dialogues between ASTRO members, payers, and policymakers remain essential. [ABSTRACT FROM AUTHOR]

Background: Placental perfusion can be evaluated by 3D power Doppler ultrasound (3D PD-US), particularly using the validated tool 3D Fractional Moving Blood Volume (3D-FMBV); however regional variability and size limitations beyond the first trimester mean that multiple 3D PD-US volumes are required to evaluate the whole organ.Purpose: We assessed the feasibility of manual offline stitching of second trimester 3D PD-US volumes of the placenta to assess whole organ perfusion using 3D-FMBV.Materials and Methods: This was a single-centre, prospective, observational cohort study of 36 normal second trimester singleton pregnancies with anterior placentas. 3D PD-US placental volumes were manually segmented offline and stitched together by rigid registration using manually selected, pair-wise coordinates. Data acquisition and offline volume segmentation and stitching were triplicated by a single observer with Dice similarity coefficient (DSC) and Hausdorff distance used to assess consistency. Intraclass correlation coefficient (ICC) was used to assess intra-observer repeatability of 3D-FMBV and placental volume.Results: Acquisition and stitching success were 94% and 88%, respectively. Median time for acquisition, segmentation and stitching were 13 min, 40 min and 95 min, respectively. Median intra-observer DSCs were 0.94 and 0.88, and Hausdorff distances were 11.85 mm and 36.6 mm, for segmentations and stitching, respectively.Conclusion: 3D-ultrasound volume stitching of the placenta is technically feasible. Intra-observer repeatability was good to excellent for all measured parameters. This work demonstrates technical feasibility; further studies may provide the basis of an in-vivo assessment tool to measure the placenta in mid-to late pregnancy. [ABSTRACT FROM AUTHOR]

The goal of our research was to quantify the placental vascularity in 3-D at 11-13 + 6 wk of pregnancy at precise distances from the utero-placental interface (UPI) using 3-D power Doppler ultrasound. With this automated image analysis technique, differences in vascularity between normal and pathologic pregnancies may be observed. The algorithm was validated using a computer-generated image phantom and applied retrospectively in 143 patients. The following features from the PD data were recorded: The number of spiral artery jets into the inter-villous space, total geometric and PD area. These were automatically measured at discrete millimeter distances from the UPI. Differences in features were compared with pregnancy outcomes: Pre-eclamptic versus normal, all small-for-gestational age (SGA) to appropriate-for-gestational age (AGA) patients and AGA versus SGA in normotensives (Mann-Whitney). The Benjamini-Hochberg procedure was used (false discovery rate 10%) for multiple comparison testing. Features decreased with increasing distance from the UPI (Kruskal-Wallis test; p <0.001). At 2- 3 mm from the UPI, all features were smaller in pre-eclamptic compared with normal patients and for some in SGA compared with AGA patients (p <0.05). For AGA versus SGA in normotensive patients, no significant differences were found. Number of jets measured at 2-5 mm from the UPI did not vary because of the position of the placenta in the uterus (ANOVA; p > 0.05). This method provides a new in-vivo imaging tool for examining spiral artery development through pregnancy. Size and number of entrances of blood flow into the UPI could potentially be used to identify high-risk pregnancies and may provide a new imaging biomarker for placental insufficiency. [ABSTRACT FROM AUTHOR]

Abstract: We propose new volumetric indices derived from three-dimensional (3-D) power Doppler (PD) using spatiotemporal imaging correlation (STIC) to overcome the influence of machine settings and attenuation. In this study, we describe these indices and evaluate their interobserver reliability: two static-3-D and two STIC PD datasets were acquired from 60 women and two observers (blinded analysis) evaluated vascularization index (VI), the flow index (FI) and the vascularization flow index (VFI) of standardized spherical samples of endometrium. Three new indices were determined based on maximum, minimum and mean values (vPI, vRImax-min, vS/Dmax-min) and two indices from frames subjectively defined as systole and diastole (vRIsys-dia, vS/Dsys-dia). Highest intraclass coefficient correlations (ICCs) were obtained from vPI derived from VI or VFI (0.77–0.76), followed by vRImax-min (0.72–0.72) and vS/Dmax-min (0.52–0.49). ICCs from indices based on subjectively systole and diastole or FI were consistently lower (<0.40). We conclude that the subjective choice of systolic and diastolic frames only lacks reliability but indices based on complete evaluation may reliably be used. [Copyright &y& Elsevier]

Purpose: Treatment of glioblastoma multiforme (GBM) continues to pose a significant therapeutic challenge, with most tumors recurring within the previously irradiated tumor bed. To improve outcomes, we must be able to identify and treat resistant cell populations. Rad51, an enzyme involved in homologous recombinational repair, leads to increased resistance of tumor cells to cytotoxic treatments such as radiotherapy. We hypothesized that Rad51 might contribute to GBM''s apparent radioresistance and consequently influence survival. Methods and Materials: A total of 68 patients with an initial diagnosis of GBM were retrospectively evaluated; for 10 of these patients, recurrent tumor specimens were used to construct a tissue microarray. Rad51 protein expression was then correlated with the actual and predicted survival using recursive partitioning analysis. Results: Rad51 protein was elevated in 53% of the GBM specimens at surgery. The Rad51 levels correlated directly with survival, with a median survival of 15 months for patients with elevated Rad51 compared with 9 months for patients with low or absent levels of Rad51 (p = .05). At disease recurrence, 70% of patients had additional increases in Rad51 protein. Increased Rad51 levels at disease recurrence similarly predicted for improved overall survival, with a mean survival of 16 months from the second craniotomy compared with only 4 months for patients with low Rad51 levels (p = .13). Conclusion: Elevated levels of the double-stranded DNA repair protein Rad51 predicted for an increase survival duration in patients with GBM, at both initial tumor presentation and disease recurrence. [Copyright &y& Elsevier]

Background: Treatment of opioid use disorder (OUD) in adolescents and young adults is imperative to reduce the risk of overdose and other opioid-related harms. Limited information has been published about national trends in health disparities including utilization, access to medication for opioid use disorder (MOUD), and treatment retention of adolescents and young adults with OUD.Methods: This secondary data analysis tested for trends and age-related disparities in national OUD treatment admissions, as well as length of stay (defined as continuous enrollment in some form of treatment at a program) and planned use of MOUD for adolescents (age 12-17) and young adults (age 18-24) using the Treatment Episode Data Set from 2008 to 2017. The study also used data from the National Survey on Drug Use and Health to identify population prevalence of OUD and presentation to OUD treatment in adolescents and young adults compared to older adults (age 25+).Results: OUD treatment admissions significantly decreased over the decade by 63% (z = 2.61, p < .01) for adolescents and 13% (z = 2.25, p < .01) for young adults. The rate of planned MOUD at intake increased from 1.1% to 3.0% for adolescents but did not achieve significance. MOUD was more commonly recommended in young adults across the time period (13.5 to 21.8%, z = 2.24, p < .01). Treatment length of stay did not change significantly for adolescents, but did increase for young adults from 2008 to 2017 in the 91+ (19.9-23.9%, z = 2.22, p < .01) and 181+ days (9.7-12.5%, z = 2.26, p < .01) categories. Relative to older adults, the percent of people with OUD presenting for OUD treatment is significantly lower for adolescents (44.6% vs. 3.6%, OR = 0.05, p < .05) and young adults (44.6% vs. 22.2%, OR = 0.36, p < .05). Among those who initiated treatment, lower rates occurred of planned MOUD for adolescents (93% vs. 2%, OR = 0.002, p < .05) and young adults (93% vs. 56%, OR = 0.10, p < .05).Conclusions: A significant unmet need exists for OUD treatment and recommendation of MOUD in adolescents and young adults with OUD. These trends are concerning given increasing rates of opioid-related emergency room admissions and deaths during the same time period. Federal and state funders should examine adolescent and young adult's services separately from older adults (25+) to reduce age-related access disparities and ensure adequate MOUD treatment capacity. [ABSTRACT FROM AUTHOR]

Adolescent substance use is a significant public health concern within the United States that remains largely undertreated. The COVID-19 pandemic has exacerbated many preexisting risk factors for adolescent substance use, such as early life stress, social isolation, school connection, and boredom. Other effects include the potential for arrest in adolescent development, which can occur when there is disruption in expected developmental milestones. New cohorts of adolescents who may not otherwise initiate substances may now be at risk. The pandemic is also straining family systems, with potential for increased conflict and relapse that can occur in a bidirectional fashion. In parallel, the way in which we treat substance use disorders in youth has also shifted, with a dominance in digitally based platforms for delivery of most outpatient treatment. Challenges to utilizing virtual technology include fewer means of monitoring substance use remotely; privacy concerns; and ease of nonadherence with treatment by signing off the computer. Practitioners can utilize considerable opportunities for virtual care to reach adolescents at risk of developing a substance use disorder and/or those who may already have relapsed. Primary care providers and other general practitioners who frequently interface with youth should increase their baseline screening of youth. [ABSTRACT FROM AUTHOR]

• Retrospective analysis of a clinical trial to identify predictors for RIL in NSCLC. • Age, lung V5 and XRCC1 rs25487 were independent risk factors for sereve RIL. • Number of these risk factors stratified patients at different risk for severe RIL. We investigated clinical and genetic factors associated with severe radiation-induced lymphopenia (RIL) in a randomized clinical trial of photon vs. proton radiation, with chemotherapy, for non-small cell lung cancer. XRCC1 rs25487 was genotyped in lymphocytes from serial peripheral blood samples. Severe RIL was defined as absolute lymphocyte count (ALC) < 0.3 × 109 cells/L. Univariate and multivariate analyses were used to identify independent risk factors, which were then used to group patients for risk of severe RIL. Univariate analysis of the 178 patients in this analysis showed that older age, larger tumors, higher lung V5 and mean lung dose, and higher heart V5 and mean heart dose were associated with severe RIL during treatment (P < 0.05). The XRCC1 rs25487 AA genotype was also associated with increased risk of severe RIL during treatment (AA vs. others: hazard ratio [HR] = 1.665, 95% confidence interval [CI] 1.089–2.500, P = 0.018). Multivariate analyses showed that older age (HR = 1.031, 95% CI 1.009–1.054, P = 0.005), lung V5 (HR = 1.039, 95% CI 1.023–1.055, P < 0.0001), and AA genotype (AA vs. others, HR = 1.768, 95% CI 1.165–2.684, P = 0.007) were independently associated with higher incidence of severe RIL. These three risk factors (age ≥ 56 years, lung V5 ≥ 51% and XRCC1 rs25487 AA) distinguished patients at different risk of developing severe RIL (P < 0.0001). Age, lung V5 and XRCC1 rs25487 AA were all linked with risk of severe RIL. Our predictive risk model may be helpful for identifying patients at high risk of severe RIL so that treatment can be modified. [ABSTRACT FROM AUTHOR]

Purpose We report our single-institution experience with stereotactic ablative radiotherapy (SABR) for adrenal metastasis and identify factors influencing outcomes, patterns of failure, and dosimetric thresholds for toxicity. Methods and materials We identified patients with adrenal metastases treated with SABR from 2009 to 2015. Toxicity was evaluated with Common Terminology Criteria for Adverse Events v4.0. Local failures were categorized as in-field, marginal, or out-of-field. New or progressive disease outside the treated adrenal gland was considered distant failure. Survival and time to local and distant failure were estimated by the Kaplan-Meier method. Prognostic factors were evaluated with a Cox proportional hazards model. Fisher’s exact tests were used to compare toxicity between dosimetric thresholds. Results Forty-three patients with 49 adrenal metastases (84% from lung) were treated with SABR to a median prescribed dose of 60 Gy in 10 fractions. Median overall survival time was 19 months, and 1- and 2-year rates were 65% and 42%, respectively. Bilateral adrenal metastases were associated with worse overall survival ( P = .01). Median progression-free survival (PFS) time was 6 months, with most progressions being distant failure (most often to brain or bone). PFS was better in patients with a solitary adrenal metastasis ( P = .03). Median time to local failure was not reached; the 1-year freedom from local failure rate was 74%. Nine failures were in field and 1 was marginal; no local failures occurred in lesions treated with biologically equivalent doses of >100 Gy. No patient experienced grade 3-5 toxicity. Low-grade gastrointestinal toxicity was common, but grade 2 toxicity was avoided in patients with a maximum stomach-bowel point dose of ≤50 Gy ( P = .03). Low-grade adrenal insufficiency was common with bilateral treatment. Conclusion SABR was well tolerated and resulted in good 1-year local control; PFS was promising for patients with solitary metastases. Low-grade toxicity was common, but can be minimized with strict dosimetric constraints. [ABSTRACT FROM AUTHOR]

It is crucial to economically justify the use of promising therapies such as stereotactic ablative radiotherapy (SABR) for oligometastatic disease (OMD). The goal of this systematic review was to provide a summative evaluation of publications that analyzed the cost-effectiveness (CE) of SABR for OMD. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided methodology, PubMed and Embase were searched for modeling-based CE studies for various forms of limited metastatic disease. Only full publications that specifically compared SABR with a systemic therapy-based approach were included. In total, 9 studies met inclusion criteria; 4 pertained to OMD with mixed histologies, 2 to oligometastatic non-small cell lung cancer, 1 to pulmonary OMD, 1 to liver OMD, and 1 to low-volume oligorecurrent castration-sensitive prostate cancer. All but 1 investigation illustrated that SABR was cost-effective for the studied population (or a subpopulation); of these studies, the incremental CE ratios for SABR (when reported) ranged from $28,000/quality-adjusted life-year (QALY) to $55,000/QALY. Of studies that reported the probability of SABR being cost-effective at common willingness-to-pay values, the median (range) probability of achieving CE was roughly 61% (30%-88%) at a $50,000/QALY threshold and 78% (31%-100%) at a $100,000/QALY threshold. Taken together, the available evidence suggests that SABR appears to be a cost-effective approach for OMD, which has implications for value-based oncologic practice and construction of future health policies. However, reassessment is required in the context of modern systemic therapies (eg, immunotherapy) as well as long-term follow-up of existing and newly reported randomized trials. Prudent patient selection remains the single most important factor influencing the CE of SABR for OMD. [ABSTRACT FROM AUTHOR]

Purpose: The successes of local therapy for oligometastatic cancers cannot be extrapolated to oligoprogressive disease (OPD) because they are distinct clinical entities. Given the limited prospective data on OPD to date, summative analyses are urgently needed.Methods and Materials: Inclusion criteria for this Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review were as follows. First, only prospective data were included. Second, progression had to have occurred on active/ongoing systemic therapy. Third, the number of progressing areas of disease had to be explicitly listed and ≤5 in number. Fourth, all progressing sites had to undergo local therapy (radiation therapy [RT] /surgery/nonradiation ablative procedures).Results: Eight trials met criteria (summing 290 patients), the vast majority of which used stereotactic RT as the local modality (most commonly, 19-20 Gy in 1 fraction, 27-33 Gy in 3 fractions, or 35-50 Gy in 5 fractions). A study on non-small cell lung cancer (NSCLC) demonstrated that stereotactic RT improved progression-free survival (PFS) and overall survival compared with historical values with systemic therapy alone. Two additional studies on epidermal growth factor receptor mutated (EGFRm) NSCLC also showed acceptable PFS with local therapy, particularly in patients who oligoprogressed on osimertinib. The only randomized trial analyzed herein showed that local therapy improved PFS for NSCLC but not breast cancer. Two trials in castration-resistant prostate cancer illustrated that a substantial proportion of patients did not require any changes in hormonal therapy or delayed the need to change systemic therapies. Lastly, 2 trials of renal cell carcinoma showed high (90%-100%) local control and median PFS of 9 months, and potentially a prolonged time to change systemic therapy. Lastly, from all patients in all trials, local therapy was tolerated well, with only 7 instances of grade 3+ toxicities.Conclusions: Based on the limited data, local therapy for oligoprogression is safe and yields encouraging short-term preliminary outcomes, but trials with larger sample sizes and longer follow-up are required for more robust conclusions. [ABSTRACT FROM AUTHOR]

Background: A previous pooled analysis of the STARS and ROSEL trials showed higher survival after stereotactic ablative radiotherapy (SABR) than with surgery for operable early-stage non-small-cell lung cancer (NSCLC), but that analysis had notable limitations. This study reports long-term results of the revised STARS trial, in which the SABR group was re-accrued with a larger sample size, along with a protocol-specified propensity-matched comparison with a prospectively registered, contemporary institutional cohort of patients who underwent video-assisted thoracoscopic surgical lobectomy with mediastinal lymph node dissection (VATS L-MLND).Methods: This single-arm prospective trial was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and enrolled patients aged 18 years or older with a Zubrod performance status of 0-2, newly diagnosed and histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma, large cell, or NSCLC not otherwise specified), and a tumour diameter of 3 cm or less. This trial did not include patients from the previous pooled analysis. SABR dosing was 54 Gy in three fractions (for peripheral lesions) or 50 Gy in four fractions (for central tumours; simultaneous integrated boost to gross tumour totalling 60 Gy). The primary endpoint was the 3-year overall survival. For the propensity-matching analysis, we used a surgical cohort from the MD Anderson Department of Thoracic and Cardiovascular Surgery's prospectively registered, institutional review board-approved database of all patients with clinical stage I NSCLC who underwent VATS L-MLND during the period of enrolment in this trial. Non-inferiority could be claimed if the 3-year overall survival rate after SABR was lower than that after VATS L-MLND by 12% or less and the upper bound of the 95% CI of the hazard ratio (HR) was less than 1·965. Propensity matching consisted of determining a propensity score using a multivariable logistic regression model including several covariates (age, tumour size, histology, performance status, and the interaction of age and sex); based on the propensity scores, one patient in the SABR group was randomly matched with one patient in the VATS L-MLND group using a 5:1 digit greedy match algorithm. This study is registered with ClinicalTrials.gov, NCT02357992.Findings: Between Sept 1, 2015, and Jan 31, 2017, 80 patients were enrolled and included in efficacy and safety analyses. Median follow-up time was 5·1 years (IQR 3·9-5·8). Overall survival was 91% (95% CI 85-98) at 3 years and 87% (79-95) at 5 years. SABR was tolerated well, with no grade 4-5 toxicity and one (1%) case each of grade 3 dyspnoea, grade 2 pneumonitis, and grade 2 lung fibrosis. No serious adverse events were recorded. Overall survival in the propensity-matched VATS L-MLND cohort was 91% (95% CI 85-98) at 3 years and 84% (76-93) at 5 years. Non-inferiority was claimed since the 3-year overall survival after SABR was not lower than that observed in the VATS L-MLND group. There was no significant difference in overall survival between the two patient cohorts (hazard ratio 0·86 [95% CI 0·45-1·65], p=0·65) from a multivariable analysis.Interpretation: Long-term survival after SABR is non-inferior to VATS L-MLND for operable stage IA NSCLC. SABR remains promising for such cases but multidisciplinary management is strongly recommended.Funding: Varian Medical Systems and US National Cancer Institute (National Institutes of Health). [ABSTRACT FROM AUTHOR]

Metastatic cancer is a heterogeneous entity, some of which could benefit from local consolidative radiation therapy (RT). Although randomized evidence is growing in support of using RT for oligometastatic disease, a highly active area of investigation relates to whether RT could benefit patients with polymetastatic disease. This article highlights the preclinical and clinical rationale for using RT for polymetastatic disease, proposes an exploratory framework for selecting patients best suited for these types of treatments, and briefly reviews potential challenges. The goal of this hypothesis-generating review is to address personalized multimodality systemic treatment for patients with metastatic cancer. The rationale for using high-dose RT is primarily for local control and immune activation in either oligometastatic or polymetastatic disease. However, the primary application of low-dose RT is to activate distinct antitumor immune pathways and modulate the tumor stroma in efforts to better facilitate T cell infiltration. We explore clinical cases involving high- and low-dose RT to demonstrate the potential efficacy of such treatment. We then group patients by extent of disease burden to implement high- and/or low-dose RT. Patients with low-volume disease may receive high-dose RT to all sites as part of an oligometastatic paradigm. Subjects with high-volume disease (for whom standard of care remains palliative RT only) could be treated with a combination of high-dose RT to a few sites for immune activation, while receiving low-dose RT to several remaining lesions to enhance systemic responses from high-dose RT and immunotherapy. We further discuss how emerging but speculative concepts such as immune function may be integrated into this approach and examine therapies currently under investigation that may help address immune deficiencies. The review concludes by addressing challenges in using RT for polymetastatic disease, such as concerns about treatment planning workflows, treatment times, dose constraints for multiple-isocenter treatments, and economic considerations. [ABSTRACT FROM AUTHOR]

Purpose: Research to elucidate predictive factors of the abscopal effect is an essential first step toward potentially modifying these factors to increase the incidence of systemic antitumor effects. This study, using data from 3 institutional phase 1/2 trials, examined the predictive capacity of recorded parameters in patients undergoing combined radiation therapy (RT) and immunotherapy and explored outcomes based on those predictive factors.Methods and Materials: All patients underwent combined immunotherapy and RT and had at least 1 nonirradiated noncontiguous lesion to evaluate out-of-field (abscopal) responses, defined as the best Response Evaluation Criteria in Solid Tumors response.Results: Altogether, 153 patients met study criteria, and the median follow-up was 21.1 months. The most common cancer types were non-small cell lung carcinoma (n = 62), small cell lung carcinoma (n = 25), head and neck cancers (n = 16), and renal cell carcinoma (n = 13). Immunotherapies included ipilimumab (n = 98) and pembrolizumab (n = 55). Multivariable linear regression indicated that post-RT absolute lymphocyte count (ALC), when analyzed as a continuous variable, correlated with abscopal responses (P < .001). For post-RT ALC, the abscopal response rate was 34.2% in the cohort with ALC higher than the median value, compared with 3.9% in patients with ALC lower than the median (P < .0001). Corresponding figures for pre-RT ALC were 30.3% versus 7.8%, respectively (P = .0004). Cox multivariate analysis confirmed that lower post-RT ALC also associated with poorer progression-free survival (P = .009) and overall survival (P = .026).Conclusions: Lymphopenia, measured as the continuous variable of post-RT ALC, may affect the occurrence of abscopal responses and thus influence prognosis in patients treated with RT and immunotherapy. Although this hypothesis-generating finding requires corroboration by additional data, it suggests the importance of ALC monitoring and the potential of therapeutic manipulation of this parameter to induce abscopal effects. [ABSTRACT FROM AUTHOR]

• Lymphopenia may negatively affect outcomes in cancer patients. • Immune function predicts response in patients receiving immunoradiotherapy. • Radiotherapy technique (SBRT versus traditional RT) affects ALC and outcomes. • Dosimetry independently affects ALC, but not outcomes. Immune function (e.g. absolute lymphocyte count (ALC)) and modifiable predictors thereof (e.g. volume of the heart/lungs receiving low-dose radiation) impact outcomes of cancer patients, but this has not been well-studied in the immunotherapy era. This investigation of metastatic lung cancer assessed the interaction of dosimetric parameters (e.g. lung/heart V5), radiotherapy technique (e.g. stereotactic (SBRT) or traditional radiotherapy), lymphopenia, and survival outcomes. Patients were collected from three institutional phase I/II trials of combined immunotherapy and lung irradiation. SBRT referred to 50 Gy/4 fractions or 60 Gy/10 fractions, and traditional RT as 45 Gy/15 fractions. Blood collections were standardized on the first and last day of radiotherapy and each cycle of immunotherapy. Statistics included multivariable linear regression to identify variables associated with ALC decline, Kaplan-Meier analysis of overall and progression-free survival (PFS), and Cox multivariate analysis. The median follow-up of the 165 patients was 21 months. The only factor independently predictive of ALC decline was traditional RT (p < 0.001). Therefore, the analysis was repeated for traditional RT and SBRT separately; lung V5 was associated with lymphopenia for traditional RT (p < 0.001) but not SBRT (p = 0.12). Pre-radiotherapy ALC was independently associated with PFS in both cohorts (p < 0.05 for both); post-RT ALC predicted for PFS in the traditional RT (p = 0.048) but not the SBRT (p = 0.90) group. Neither heart nor lung V5 was independently associated with PFS. When combined with immunotherapy, SBRT may better preserve lymphocytes (and hence improve outcomes) than traditional RT. When administering traditional RT, constraining the lung V5 may indirectly impact outcomes by means of ALC preservation. [ABSTRACT FROM AUTHOR]

Purpose: Management of synchronous early-stage non-small cell lung cancer (NSCLC) remains controversial because resection is not always feasible. This study evaluates efficacy and patterns of failure after SABR for synchronous early-stage NSCLC.Methods and Materials: From 2005 to 2015, patients presenting with ≥2 synchronous NSCLC tumors (T1a-T2b) and receiving SABR to ≥1 lesion were reviewed. The most common prescriptions were 50 Gy in 4 or 70 Gy in 10 fractions. Patients underwent multidisciplinary management with workup including chest computed tomography and positron emission tomography/computed tomography, plus brain imaging and endoscopic bronchial ultrasound for most patients to rule out mediastinal and distant disease. Synchronous lesions were defined as multiple ipsilateral or contralateral intrapulmonary lesions diagnosed within 6 months.Results: Of 912 patients treated with SABR for early-stage NSCLC at our institution, 82 (9%) presented with synchronous disease, with a total of 169 lesions. SABR was delivered to 142 lesions (84%), with 57 patients (69.5%) receiving SABR for all sites. Median overall survival (OS) and progression-free survival (PFS) were 5.1 and 2.7 years, respectively. At a median follow-up of 58 months, OS was 67% and 52% at 3 and 5 years, and corresponding PFS was 47% and 29%. Thirty-nine patients (48%) had progression, with 21 (26%) experiencing distant failure, and intralobar recurrence was among the first failure for 15 patients (18%). Of the 142 SABR-treated sites, these included 6 in-field (4%) and 4 marginal (3%) recurrences. There were no grade ≥3 adverse events. Among patients receiving SABR for all sites, there were no differences in OS (P = .946), PFS (P = .980), local control (P = .683), regional and distant control (P = .656), or toxicity (P = .791). On multivariable analysis, ipsilateral synchronous disease was associated with greater regional and distant failure (hazard ratio, 2.691; P = .025).Conclusions: Synchronous NSCLC can be managed with definitive local therapy. With high control rates and favorable outcomes, SABR is an effective and feasible treatment for synchronous early-stage NSCLC. [ABSTRACT FROM AUTHOR]

• Retrospective analysis of stereotactic ablative radiation therapy (SABR) for lung metastases. • SABR improved local, intra-thoracic control, and overall survival at a median 24-month follow-up. • Metastases from adrenal, colorectal, sarcoma, or pancreatic tumors were less likely to respond. • Nomogram for local control probability at 24 months. • Irradiating all thoracic metastases improved overall survival and suppressed new lesions. Stereotactic ablative radiation therapy (SABR) is an emerging treatment option for patients with pulmonary metastases; identifying patients who would benefit from SABR can improve outcomes. We retrospectively analyzed local failure (LF), distant failure (DF), overall survival (OS), and toxicity in 317 patients with 406 pulmonary metastases treated with SABR in January 2006–September 2017 at a tertiary cancer center. Median follow-up time was 23 months. Primary adrenal, colorectal, sarcoma, or pancreatic ("less responsive") tumors led to high rates of LF. LF rates for patients with less responsive vs. responsive tumors were 4.6% vs. 1.6% at 12 months and 12.8% vs. 3.9% at 24 months (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.11–0.73; Log-Rank P = 0.0087). A nomogram for 24-month local control was created using Cox multivariate factors (surgical history, planning target volume, primary disease site, lung lobe location). Treating patients with ≤3 pulmonary metastases vs. >3 pulmonary metastases was associated with improved 24-month (74.2% vs. 59.3%) and 48-month (47.7% vs. 35.1%) OS (HR 0.66, 95% CI 0.47–0.95; Log-Rank P = 0.043), and reduced 12-month (22.5% vs. 50.8%) and 24-month (31.8% vs. 61.4%) intrathoracic DF (HR 0.53, 95% CI 0.38–0.74; Log-Rank P < 0.0001). The most common toxicity was asymptomatic pneumonitis (14.8%). Six patients had grade 3 events (5 pneumonitis, 1 brachial plexus). SABR for pulmonary metastases was effective and well tolerated. Irradiating limited intrathoracic sites of disease led to improved OS and intrathoracic DM. Higher SABR doses or surgery could be considered for less radio-responsive primary tumors. [ABSTRACT FROM AUTHOR]

Purpose: Our purpose was to develop predictive nomograms for overall survival (OS), progression-free survival (PFS), and time-to-progression (TTP) at 5 years in patients with early-stage non-small cell lung cancer (ES-NSCLC) treated with stereotactic ablative radiation therapy (SABR).Methods and Materials: The study cohort included 714 ES-NSCLC patients treated with SABR from 2004-2015 with median follow-up of 59 months, divided into training and testing sets (8:2), with the former used for nomogram development. The least absolute shrinkage and selection operator were initially employed to screen for predictors of OS, PFS, and TTP, and identified predictors were subsequently applied toward Cox proportional hazards regression modeling. Significant predictors (P < .05) on multivariable regression were then used to develop nomograms, which were validated via evaluation of concordance indexes (C-index) and calibration plots. Finally, Kaplan-Meier method and Gray's test were employed to compare and confirm differences in outcomes among various groups and explore prognostic factors associated with local versus distant disease progression.Results: Significant predictors of both OS and PFS at 5 years included age, sex, Charlson comorbidity index, diffusing capacity of carbon monoxide, systemic immune-inflammation index, and tumor size (P ≤ .01 for all). Eastern Cooperative Oncology Group performance status predicted for OS as well (P = .01), and both tumor size (P < .01) and minimum biological equivalent dose to 95% of planning target volume (PTV D95 BED10; P < .01) were predictive of TTP. The C-indexes for the OS, PFS, and TTP nomograms were 0.73, 0.68, and 0.60 in the training data set and 0.72, 0.66, and 0.59 in the testing data set, respectively. Tumor size > 2.45 cm and PTV D95 BED10 < 113 Gy were significantly associated with both local and distant progression.Conclusions: These prognostic nomograms can accurately predict for OS, PFS, and TTP at 5 years after SABR for ES-NSCLC and may thus help identify high-risk patients who could benefit from additional systemic therapy. [ABSTRACT FROM AUTHOR]