Disease and toxicity outcomes for a modern cohort of patients with squamous cell carcinoma of cutaneous origin involving the parotid gland: Comparison of volumetric modulated arc therapy and pencil beam scanning proton therapy.

OBJECTIVES: We sought to describe outcomes for locally advanced cutaneous squamous cell carcinoma (SCC) involving the parotid treated with volumetric modulated arc therapy (VMAT) versus pencil beam scanning proton beam therapy (PBT). MATERIALS AND METHODS: Patients were gathered from 2016 to 2022 from 5 sites of a large academic RT department; included patients were treated with RT and had parotid involvement by: direct extension of a cutaneous primary, parotid regional spread from a previously or contemporaneously resected but geographically separate cutaneous primary, or else primary parotid SCC (with a cutaneous primary ostensibly occult). Acute toxicities were provider-reported (CTCAE v5.0) and graded at each on treatment visit. Statistical analyses were conducted. RESULTS: Median follow-up was 12.9 months (1.3 - 72.8); 67 patients were included. Positive margins/extranodal extension were present in 34 cases; gross disease in 17. RT types: 39 (58.2 %) VMAT and 28 (41.8 %) PBT. Concurrent systemic therapy was delivered in 10 (14.9 %) patients. There were 17 treatment failures (25.4 %), median time of 168 days. Pathologically positive neck nodes were associated with locoregional recurrence (p = 0.015). Oral cavity, pharyngeal constrictor, and contralateral parotid doses were all significantly lower for PBT. Median weight change was -3.8 kg (-14.1 - 5.1) for VMAT and -3 kg (-16.8 - 3) for PBT (p = 0.013). Lower rates of ≥ grade 1 xerostomia (p = 0.002) and ≥ grade 1 dysguesia (p < 0.001) were demonstrated with PBT. CONCLUSIONS: Cutaneous SCC involving the parotid can be an aggressive clinical entity despite modern multimodal therapy. PBT offers significantly lower dose to organs at risk compared to VMAT, which seemingly yields diminished acute toxicities.

Is noncoplanar plan more robust to inter-fractional variations than coplanar plan in treating bilateral HN tumors with pencil-beam scanning proton beams?

PURPOSE: Noncoplanar plans (NCPs) are commonly used for proton treatment of bilateral head and neck (HN) malignancies. NCP requires additional verification setup imaging between beams to correct residual errors of robotic couch motion, which increases imaging dose and total treatment time. This study compared the quality and robustness of NCPs with those of coplanar plans (CPs). METHODS AND MATERIALS: Under an IRB-approved study, CPs were created retrospectively for 10 bilateral HN patients previously treated with NCPs maintaining identical beam geometry of the original plan but excluding couch rotations. Plan robustness to the inter-fractional variation (IV) of both plans was evaluated through the Dose Volume Histograms (DVH) of weekly quality assurance CT (QACT) sets (39 total). In addition, delivery efficiency for both plans was compared using total treatment time (TTT) and beam-on time (BOT). RESULTS: No significant differences in plan quality were observed in terms of clinical target volume (CTV) coverage (D95) or organ-at-risk (OAR) doses (p > 0.4 for all CTVs and OARs). No significant advantage of NCPs in the robustness to IV was found over CP, either. Changes in D95 of QA plans showed a linear correlation (slope = 1.006, R2  > 0.99) between NCP and CP for three CTV data points (CTV1, CTV2, and CTV3) in each QA plan (117 data points for 39 QA plans). NCPs showed significantly higher beam delivery time than CPs for TTT (539 ± 50 vs. 897 ± 142 s; p < 0.001); however, no significant differences were observed for BOT. CONCLUSION: NCPs are not more robust to IV than CPs when treating bilateral HN tumors with pencil-beam scanning proton beams. CPs showed plan quality and robustness similar to NCPs while reduced treatment time (∼6 min). This suggests that CPs may be a more efficient planning technique for bilateral HN cancer proton therapy.

Post-treatment PET/CT for p16-positive oropharynx cancer treated with definitive proton therapy.

Objectives: Given emerging data suggesting that uncertainty in the relative biologic effectiveness at the distal end of the Bragg peak results in increased mucosal injury in patients with oropharynx cancer receiving adjuvant proton therapy, we evaluated the results of post-treatment positron emission tomography-computed tomography (PET/CT) in patients with p16-positive oropharynx cancer (p16+OPC) treated with definitive intensity-modulated proton therapy (IMPT). Material and Methods: A retrospective cohort study of patients with p16+OPC treated with definitive IMPT between 2016 and 2022 was performed at a single institution. Patients with PET/CT scans within 6 months following completion of IMPT were included in the study. Positive post-treatment scans were defined by a maximum standard uptake values (SUVmax) >4.0 or a <65% reduction in SUVmax in either the primary tumor or lymph node. The Fisher's exact test was used to evaluate factors associated with positive post-treatment PET/ CT values. Results: Sixty-two patients were included for analysis. Median follow-up was 21 months (range: 3-71 months) with a median time to post-treatment PET/CT of 3 months (range: 2-6 months). Median post-treatment SUVmax of the primary disease and nodal disease was 0 (mean: 0.8, range: 0-7.7) and 0 (mean: 0.7, range: 0-9.5), respectively. Median post-treatment percent reduction in SUVmax for the primary site and lymph node was 100% (mean: 94%, range: 31.3-100%) and 100% (mean: 89%, range: 23-100%), respectively. Eleven patients had a positive post-treatment PET/CT with one biopsy-proven recurrence. Negative and positive predictive values (NPV and PPV) were 98% and 9.1%, respectively. There were no factors associated with positive post-treatment PET/CT. Conclusion: Similar to patients treated with photon-based radiation therapy, post-treatment PET/CT has a high NPV for patients with p16+OPC treated with definitive proton therapy and should be used to guide patient management. Additional patients and more events are needed to confirm the PPV of a post-treatment PET/CT in this favorable patient cohort.

Risk stratification of postoperative cardiopulmonary toxicity after trimodality therapy for esophageal cancer.

Purpose/objective: Postoperative toxicity for esophageal cancer impacts patient quality of life and potentially overall survival (OS). We studied whether patient and toxicity parameters post-chemoradiation therapy predict for post-surgical cardiopulmonary total toxicity burden (CPTTB) and whether CPTTB was associated with short and long-term outcomes. Materials/methods: Patients had biopsy-proven esophageal cancer treated with neoadjuvant chemoradiation and esophagectomy. CPTTB was derived from total perioperative toxicity burden (Lin et al. JCO 2020). To develop a CPTTB risk score predictive for major CPTTB, recursive partitioning analysis was used. Results: From 3 institutions, 571 patients were included. Patients were treated with 3D (37%), IMRT (44%), and proton therapy (19%). 61 patients had major CPTTB (score ≥ 70). Increasing CPTTB was predictive of decreased OS (p<0.001), lengthier post-esophagectomy length of stay (LOS, p<0.001), and death or readmission within 60 days of surgery (DR60, p<0.001). Major CPTTB was also predictive of decreased OS (hazard ratio = 1.70, 95% confidence interval: 1.17-2.47, p=0.005). The RPA-based risk score included: age ≥ 65, grade ≥ 2 nausea or esophagitis attributed to chemoradiation, and grade ≥ 3 hematologic toxicity attributed to chemoradiation. Patients treated with 3D radiotherapy had inferior OS (p=0.010) and increased major CPTTB (18.5% vs. 6.1%, p<0.001). Conclusion: CPTTB predicts for OS, LOS, and DR60. Patients with 3D radiotherapy or age ≥ 65 years and chemoradiation toxicity are at highest risk for major CPTTB, predicting for higher short and long-term morbidity and mortality. Strategies to optimize medical management and reduce toxicity from chemoradiation should be strongly considered.

Genomic biomarkers to guide precision radiotherapy in prostate cancer.

Our ability to prognosticate the clinical course of patients with cancer has historically been limited to clinical, histopathological, and radiographic features. It has long been clear however, that these data alone do not adequately capture the heterogeneity and breadth of disease trajectories experienced by patients. The advent of efficient genomic sequencing has led to a revolution in cancer care as we try to understand and personalize treatment specific to patient clinico-genomic phenotypes. Within prostate cancer, emerging evidence suggests that tumor genomics (e.g., DNA, RNA, and epigenetics) can be utilized to inform clinical decision making. In addition to providing discriminatory information about prognosis, it is likely tumor genomics also hold a key in predicting response to oncologic therapies which could be used to further tailor treatment recommendations. Herein we review select literature surrounding the use of tumor genomics within the management of prostate cancer, specifically leaning toward analytically validated and clinically tested genomic biomarkers utilized in radiotherapy and/or adjunctive therapies given with radiotherapy.

Factors Related to Small- and Mid-Capitalization Pharmaceutical Company Success Using Stock Performance as a Surrogate.

Background Developing novel pharmaceuticals demands substantial investment despite high uncertainty of success and ultimate market value. While many established drug companies are highly profitable and have large portfolios of diversified assets, much of new drug innovation, a very high-risk, high-reward gambit, stems from smaller companies striving to bring their first products to market. While drug costs, and thus pharmaceutical company profits, can be controversial, it is unquestionable that the products from these companies provide great benefit to humanity. Hence, the ongoing success of the industry as a whole is quite relevant from a public health perspective. Methodology We sought to investigate factors influencing pharmaceutical company success using company stock performance on major US indices as a surrogate. As the profitability of large-capitalization (cap) pharmaceutical companies is well established, we focused on small- and mid-cap companies in this analysis. Small- and mid-cap pharmaceutical companies (both currently active and now defunct) and historical share prices were captured, including company details and the nature of drug pipelines. Funding by US academia was acquired via CMS.gov Open Payments and categorized into contributions < or ≥$100,000. Stock performance was considered good (+ ≥25%), mediocre (±25%), or poor (- ≥25%). Univariate and multivariate associations were assessed. Results Of the 420 companies included in the analysis, 101 (24%) had good, 76 (18%) mediocre, and 243 (58%) poor performance. The following were associated with performance in univariate analysis: initial public offering (IPO) price (P < 0.001), time from IPO (P < 0.001), number of drug programs (P = 0.019), and academic funding (P = 0.00013), with trend for diverse pipelines (both oncology and nononcology programs under development) (P = 0.069). On multivariate analysis, IPO price was inversely associated (P < 0.0001), while academic funding (P < 0.0001) and more drug programs (P = 0.0025) were positively associated with performance. Analysis of pharmaceutical IPOs since 2000 suggests a 20% rate of outright company failure. Conclusions The majority of included companies had lackluster stock performance, suggestive of low potential for drug development success and high probability of financial disaster. Robust drug pipelines and academic collaboration seem to be strongly related to company success.

Survival outcomes in patients with gastric and gastroesophageal junction adenocarcinomas treated with perioperative chemotherapy with or without preoperative radiotherapy.

BACKGROUND: Perioperative chemotherapy (POC) is one standard approach for the treatment of resectable cancers of the stomach and gastroesophageal junction (GEJ), whereas there has been growing interest in preoperative therapies. The objective of the current study was to compare survival between patients treated with preoperative chemoradiotherapy and adjuvant chemotherapy (PCRT) with those receiving POC using a large database. METHODS: The National Cancer Data Base was queried for patients diagnosed between 2004 and 2013 with American Joint Committee on Cancer clinical group stage IB to stage IIIC (excluding T2N0 disease) adenocarcinoma of the stomach or GEJ. Patients treated with definitive surgery and POC with or without preoperative radiotherapy of 41 to 54 Gy were included. Overall survival (OS) was defined from the date of definitive surgery and estimated using the Kaplan-Meier method. A total of 14 patient and treatment variables were used for propensity score matching (PSM). RESULTS: A total of 1048 patients were analyzed: 53.2% received POC and 46.8% received PCRT. The primary tumor site was the GEJ in 69.1% of patients and stomach in 30.9% of patients. The median age of the patients was 60 years, and the median follow-up was 25.8 months. The use of PCRT was associated with a greater pathologic complete response rate of 13.1% versus 8.2% (P = .01). POC was associated with a decreased risk of death in unmatched groups (hazard ratio [HR], 0.83; P = .043). Using PSM cohorts, POC decreased the risk of death with a median OS of 45.1 months versus 31.4 months (HR, 0.70; P = .016). The 2-year OS rate was 72.9% versus 62.5% and the 5-year OS rate was 40.7% versus 33.1% for POC versus PCRT, respectively. Survival favored POC in PSM gastric (HR, 0.41; P = .07) and GEJ (HR, 0.77; P = .08) patient subgroups. CONCLUSIONS: The addition of preoperative radiotherapy to POC appears to be associated with an increased risk of death in patients with resectable gastric and GEJ cancers.

Prognostic value of radiographically defined extranodal extension in human papillomavirus-associated locally advanced oropharyngeal carcinoma.

BACKGROUND: Pathologic extranodal extension (ENE) has traditionally guided the management of head and neck cancers. The prognostic value of radiographic ENE (rENE) in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (HPV + OPX) is uncertain. METHODS: Patients with HPV + OPX with adequate pretreatment radiographic nodal evaluation from a single institution were analyzed. rENE status was determined by neuroradiologists' at time of diagnosis. Distant metastasis-free survival (DMFS), overall survival (OS), and locoregional recurrence-free survival (LRFS) were estimated using Kaplan-Meier methods. Cox proportional hazards models were fit to assess the impact of rENE on survival endpoints. RESULTS: Hundred sixty-eight patients with OPX + squamous cell carcinomas diagnosed between April 2008 and December 2014 were included for analysis with median follow-up of 3.3 years. Eighty-eight percent of patients received concurrent chemoradiotherapy. rENE was not prognostic; its presence in patients with HPV + OPX did not significantly impact OS, LRFS, or DMFS. CONCLUSIONS: In patients with HPV + OPX, rENE was not significantly associated with OS, LRFS, or DMFS.

Sparing Cardiac Substructures With Optimized Volumetric Modulated Arc Therapy and Intensity Modulated Proton Therapy in Thoracic Radiation for Locally Advanced Non-small Cell Lung Cancer.

PURPOSE: Increasing radiation dose to the heart is associated with worse survival in stage III non-small cell lung cancer. We sought to evaluate the ability of optimized volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) to spare cardiac substructures. We also wanted to determine how a cardiac optimization treatment planning algorithm influences dose distribution to other thoracic organs at risk (OARs). METHODS AND MATERIALS: Cardiac substructures were retrospectively contoured for all patients with stage III non-small cell lung cancer who were treated at our institution with VMAT to 60 Gy in 2-Gy fractions. The structures included valves, atrioventricular node, coronary arteries, chambers, and great vessels. New cardiac-optimized VMAT plans were created to spare these structures while preserving planning target volume coverage and maintaining standard dose constraints to OARs. Dosimetry variables for the new cardiac-optimized VMAT plans were compared via paired t test with the original VMAT plans. IMPT plans were also created, and the cardiac-optimized VMAT plans were then similarly compared with the IMPT plans. RESULTS: Twenty-six patients who were treated from July 2013 to September 2017 were included. Compared with the original VMAT plans, statistically significant improvements were demonstrated for all cardiac structures for the new cardiac-optimized VMAT plans while maintaining or improving appropriate lung, esophagus, and spinal cord constraints and planning target volume coverage goals. Compared with cardiac-optimized VMAT, IMPT demonstrated additional statistically significant improvements for some cardiac dosimetry metrics while maintaining or improving other thoracic OAR constraints. CONCLUSIONS: VMAT is now widely available, and high-quality VMAT plans that incorporate cardiac substructures into the optimization process can provide overall improvements in dose to OARs and, in particular, substantial sparing of critical cardiac structures. IMPT provides some incremental dosimetric improvements beyond cardiac-optimized VMAT, the clinical significance of which remains uncertain.

Survival outcomes by high-risk human papillomavirus status in nonoropharyngeal head and neck squamous cell carcinomas: A propensity-scored analysis of the National Cancer Data Base.

BACKGROUND: The prognostic relevance of human papillomavirus (HPV) status in patients with nonoropharyngeal (OPX) squamous cell cancer (SCC) of the head and neck is controversial. In the current study, the authors evaluated the impact of high-risk HPV status on overall survival (OS) in patients with non-OPX SCC using a large database approach. METHODS: The National Cancer Data Base was queried to identify patients diagnosed from 2004 through 2014 with SCC of the OPX, hypopharynx (HPX), larynx, and oral cavity (OC) with known HPV status. Survival was estimated using Kaplan-Meier methods; distributions were compared using log-rank tests. Propensity score-matching and inverse probability of treatment weighing (IPTW) methods were used; cohorts were matched based on age, sex, Charlson-Deyo score, clinical American Joint Committee on Cancer (AJCC) group stage, treatments received, and anatomic subsite. Propensity analyses were stratified by group stage of disease. RESULTS: A total of 24,740 patients diagnosed from 2010 through 2013 were analyzed: 1085 patients with HPX, 4804 with laryngeal, 4,018 with OC, and 14,833 with OPX SCC. The percentages of HPV-positive cases by disease site were 17.7% for HPX, 11% for larynx, 10.6% for OC, and 62.9% for OPX. HPV status was found to be prognostic in multiple unadjusted and propensity-adjusted non-OPX populations. HPV positivity was associated with superior OS in patients with HPX SCC with a hazard ratio (HR) of 0.61 (P < .001 by IPTW), in patients with AJCC stage III to IVB laryngeal SCC (HR, 0.79; P = .019 by IPTW), and in patients with AJCC stage III to IVB OC SCC (HR, 0.78; P = .03 by IPTW). CONCLUSIONS: Positive high-risk HPV status appears to be associated with longer OS in multiple populations of patients with non-OPX head and neck disease (HPX, locally advanced larynx, and OC). If prospectively validated, these findings have implications for risk stratification.

Hemorrhagic and Cystic Brain Metastases Are Associated With an Increased Risk of Leptomeningeal Dissemination After Surgical Resection and Adjuvant Stereotactic Radiosurgery.

BACKGROUND: Brain metastases (BM) treated with surgical resection and focal postoperative radiotherapy have been associated with an increased risk of subsequent leptomeningeal dissemination (LMD). BMs with hemorrhagic and/or cystic features contain less solid components and may therefore be at higher risk for tumor spillage during resection. OBJECTIVE: To investigate the association between hemorrhagic and cystic BMs treated with surgical resection and stereotactic radiosurgery and the risk of LMD. METHODS: One hundred thirty-four consecutive patients with a single resected BM treated with adjuvant stereotactic radiosurgery from 2008 to 2016 were identified. Intracranial outcomes including LMD were calculated using the cumulative incidence model with death as a competing risk. Univariable analysis and multivariable analysis were assessed using the Fine & Gray model. Overall survival was analyzed using the Kaplan-Meier method. RESULTS: Median imaging follow-up was 14.2 mo (range 2.5-132 mo). Hemorrhagic and cystic features were present in 46 (34%) and 32 (24%) patients, respectively. The overall 12- and 24-mo cumulative incidence of LMD with death as a competing risk was 11.0 and 22.4%, respectively. On multivariable analysis, hemorrhagic features (hazard ratio [HR] 2.34, P = .015), cystic features (HR 2.34, P = .013), breast histology (HR 3.23, P = .016), and number of brain metastases >1 (HR 2.09, P = .032) were independently associated with increased risk of LMD. CONCLUSION: Hemorrhagic and cystic features were independently associated with increased risk for postoperative LMD. Patients with BMs containing these intralesion features may benefit from alternative treatment strategies to mitigate this risk.

The addition of chemotherapy in the definitive management of high risk prostate cancer.

In attempt to improve long-term disease control outcomes for high-risk prostate cancer, numerous clinical trials have tested the addition of chemotherapy (CTX)-either adjuvant or neoadjuvant-to definitive local therapy, either radical prostatectomy (RP) or radiation therapy (RT). Neoadjuvant trials generally confirm safety, feasibility, and pre-RP PSA reduction, but rates of pathologic complete response are rare, and no indications for neoadjuvant CTX have been firmly established. Adjuvant regimens have included CTX alone or in combination with androgen deprivation therapy (ADT). Here we provide a review of the relevant literature, and also quantify utilization of CTX in the definitive management of localized high-risk prostate cancer by querying the National Cancer Data Base. Between 2004 and 2013, 177 patients (of 29,659 total) treated with definitive RT, and 995 (of 367,570 total) treated with RP had CTX incorporated into their treatment regimens. Low numbers of RT + CTX patients precluded further analysis of this population, but we investigated the impact of CTX on overall survival (OS) for patients treated with RP +/- CTX. Disease-free survival or biochemical-recurrence-free survival are not available through the National Cancer Data Base. Propensity-score matching was conducted as patients treated with CTX were a higher-risk group. For nonmatched groups, OS at 5-years was 89.6% for the CTX group vs. 95.6%, for the no-CTX group (P < 0.01). The difference in OS between CTX and no-CTX groups did not persist after propensity-score matching, with 5-year OS 89.6% vs. 90.9%, respectively (Hazard ratio 0.99; P = 0.88). In summary, CTX was not shown to improve OS in this retrospective study. Multimodal regimens-such as RP followed by ADT, RT, and CTX; or RT in conjunction with ADT followed by CTX-have shown promise, but long-term follow-up of randomized data is required.

Radiation Therapy Is Associated With an Increased Incidence of Cardiac Events in Patients with Small Cell Lung Cancer.

PURPOSE: Cardiac radiation dose was a predictor of inferior overall survival in the Radiation Therapy Oncology Group 0617 non-small cell lung cancer trial. We examined the association between radiation therapy (RT) and cardiac events (CE) for patients with small cell lung cancer (SCLC). METHODS AND MATERIALS: The US population-based Surveillance, Epidemiology, and End Results Program and Medicare claims databases were queried for rates of CE among patients with SCLC treated with chemotherapy (CTX) ± RT. Propensity score matching (PSM) and multivariate analysis were conducted. Patients were matched for actual/theoretical RT start date (to prevent immortal time bias) and then full PSM balanced clinical characteristics. Cumulative incidence function curves were generated. RESULTS: From 2000 to 2011, 7060 patients were included: 2892 limited-stage SCLC (LS-SCLC) and 4168 extensive-stage SCLC. Grouping LS-SCLC and extensive-stage SCLC together, the incidence of CE for the CTX + RT and CTX-only groups was 44.1% versus 39% at 60 months (P = .008). After PSM (5286 patients), the incidence of CE for the CTX + RT and CTX-only groups was 43% versus 38.6% at 60 months (P = .033). Analysis of only LS-SCLC (2016 patients) demonstrated that the incidence of CE for CTX + RT versus CTX-only groups was 50.3% versus 42% at 60 months (P = .0231). Multivariate analysis again demonstrated an association between CE and RT (hazard ratio 1.20; 95% confidence interval 1.06-1.37; P = .005). After PSM (1614 patients), the incidence of CE for CTX + RT versus CTX-only groups was 51.7% versus 41.6% at 60 months (P = .0042). CONCLUSIONS: Patients with SCLC are at significant risk of developing CE posttreatment; RT is associated with an absolute increase in the rate of CE at 5 years of approximately 5% for all patients with SCLC and up to 10% for patients with LS-SCLC. Cardiac risk management and cardiac-sparing RT techniques should be further evaluated for patients with SCLC.

Targeted sequencing and intracranial outcomes of patients with lung adenocarcinoma brain metastases treated with radiotherapy.

BACKGROUND: Treatment for advanced lung adenocarcinoma (AC) has become increasingly personalized based on molecular results. However, for patients with AC brain metastases (BMs), intracranial outcomes based on molecular subtype and the frequency of molecular aberrations are less well defined. This study sought to report targeted next-generation sequencing results and investigate molecularly based outcomes for patients with AC-BMs treated with radiotherapy. METHODS: The records of 132 patients with AC-BMs treated at Emory University from September 2008 to August 2016 with successful next-generation sequencing were reviewed. Rates of local disease recurrence, distant brain failure (DBF), and salvage whole-brain radiotherapy (WBRT) were estimated using cumulative incidence with competing risk analysis. Univariate and multivariate analyses were performed. RESULTS: The most common aberrations included tumor protein 53 (TP53) (60%), KRAS (29%), epidermal growth factor receptor (EGFR) (20.5%), phosphatase and tensin homolog (PTEN) loss (15.5%), and MET amplification (13%). The majority of patients (62%) were treated with stereotactic radiosurgery alone. In these patients, KRAS mutation, anaplastic lymphoma kinase (ALK) rearrangement, and having ≥ 6 BMs were associated with an increased risk of salvage WBRT (P < .05). KRAS mutation remained significant for an increased risk of salvage WBRT when compared with EGFR/ALK/KRAS-negative patients (hazard ratio, 5.17; P < .05), despite a similar risk of DBF. PTEN loss was associated with increased risk of DBF (P < .05), whereas EGFR and ALK aberrations were associated with a decreased risk of local disease recurrence (P < .05). CONCLUSIONS: The results of the current study quantified the frequency of genetic aberrations in patients with AC-BMs and demonstrated their association with intracranial outcomes. In particular, a cohort of patients with KRAS mutations and ≥6 BMs were identified to be at high risk of requiring salvage WBRT after undergoing upfront stereotactic radiosurgery.

Increase in PD-L1 expression after pre-operative radiotherapy for soft tissue sarcoma.

Soft tissue sarcomas (STS) have minimal expression of PD-L1, a biomarker for PD-1 therapy efficacy. Radiotherapy (RT) has been shown to increase PD-L1 expression pre-clinically. We examined the expression of PD-L1, pre- and post-RT, in 46 Stage II-III STS patients treated with pre-operative RT (50-50.4 Gy in 25-28 fractions) followed by resection. Five additional patients who did not receive RT were utilized as controls. PD-L1 expression on biopsy and resection samples was evaluated by immunochemistry using the anti PD-L1 monoclonal antibody (E1L3 N clone; Cell Signaling). Greater than 1% membranous staining was considered positive PD-L1 expression. Changes in PD-L1 expression were analyzed via the Fisher exact test. Kaplan-Meier statistics were used to correlate PD-L1 expression to distant metastases (DM) rate. The majority of STS were T2b (87.0%), high-grade (80.4%), undifferentiated pleomorphic histology (71.7%), and originated from the extremities (84.6%). Zero patients demonstrated PD-L1 tumor expression pre-RT. Post-RT, 5 patients (10.9%) demonstrated PD-L1 tumor expression (p = 0.056). Tumor associated macrophages (TAM) expression of PD-L1 increased after RT: 15.2% to 45.7% (p = 0.003). Samples from controls demonstrated no baseline (0%) or change in tumor PD-L1 expression. Freedom from DM was lower for patients with PD-L1 TAM expression post-RT (3 years: 49.7% vs. 87.8%, log-rank p = 0.006); TAM PD-L1 positivity remained an independent predictor for DM on multivariate analyses (Hazard ratio - 0.16, 95% confidence interval: 0.034-0.721, p = 0.042). PD-L1 expression on human STS tumor and TAM appears to elevate after pre-operative RT. Expression of PD-L1 on TAM after RT was associated with a higher rate of DM.

Does size matter? Investigating the optimal planning target volume margin for postoperative stereotactic radiosurgery to resected brain metastases.

OBJECTIVE: The optimal margin size in postoperative stereotactic radiosurgery (SRS) for brain metastases is unknown. Herein, the authors investigated the effect of SRS planning target volume (PTV) margin on local recurrence and symptomatic radiation necrosis postoperatively. METHODS: Records of patients who received postoperative LINAC-based SRS for brain metastases between 2006 and 2016 were reviewed and stratified based on PTV margin size (1.0 or > 1.0 mm). Patients were treated using frameless and framed SRS techniques, and both single-fraction and hypofractionated dosing were used based on lesion size. Kaplan-Meier and cumulative incidence models were used to estimate survival and intracranial outcomes, respectively. Multivariate analyses were also performed. RESULTS: A total of 133 patients with 139 cavities were identified; 36 patients (27.1%) and 35 lesions (25.2%) were in the 1.0-mm group, and 97 patients (72.9%) and 104 lesions (74.8%) were in the > 1.0-mm group. Patient characteristics were balanced, except the 1.0-mm cohort had a better Eastern Cooperative Group Performance Status (grade 0: 36.1% vs 19.6%), higher mean number of brain metastases (1.75 vs 1.31), lower prescription isodose line (80% vs 95%), and lower median single fraction-equivalent dose (15.0 vs 17.5 Gy) (all p < 0.05). The median survival and follow-up for all patients were 15.6 months and 17.7 months, respectively. No significant difference in local recurrence was noted between the cohorts. An increased 1-year rate of symptomatic radionecrosis was seen in the larger margin group (20.9% vs 6.0%, p = 0.028). On multivariate analyses, margin size > 1.0 mm was associated with an increased risk for symptomatic radionecrosis (HR 3.07, 95% CI 1.13-8.34; p = 0.028), while multifraction SRS emerged as a protective factor for symptomatic radionecrosis (HR 0.13, 95% CI 0.02-0.76; p = 0.023). CONCLUSIONS: Expanding the PTV margin beyond 1.0 mm is not associated with improved local recurrence but appears to increase the risk of symptomatic radionecrosis after postoperative SRS.

Comparative outcomes and toxicities for ruthenium-106 versus palladium-103 in the treatment of choroidal melanoma.

For the treatment of choroidal melanoma, palladium-103 (Pd) and ruthenium-106 (Ru) plaque brachytherapy shows reduced toxicity compared with the historical standard iodine-125. No report has directly compared the clinical outcomes between Pd and Ru, and the reasons for the selection of one over the other remain purely theoretical. Patients with choroidal melanoma with apical tumor height up to 5 mm were included. Patients from Emory University were treated with Pd between 1993 and 2012. Patients from Cleveland Clinic were treated with Ru between 2005 and 2010. Medical records were retrospectively reviewed. We compared post-treatment visual acuity (VA), toxicity, and oncologic outcomes. Pd patients (n=124) and Ru patients (n=42) had a median follow-up of 4.2 and 5.0 years, respectively. Radiation retinopathy-free survival was similar for both radioisotopes, but Ru had lower grades of retinopathy (P=0.006). Pd was associated with worse VA preservation (≥20/40) by year 3 (odds ratio: 3.8; 95% confidence interval: 1.01-14.31, P=0.048). Pd was associated with higher distant metastases-free survival (DMFS) in multivariate analysis (hazard ratio: 0.10; 95% confidence interval: 0.02-0.38; P<0.001). Ru had lower grades of radiation retinopathy and improved long-term VA preservation, but also inferior DMFS, compared with Pd. Because of the inherent limitations of a retrospective analysis, the significance of the inferior DMFS for Ru remains unclear, although the suggestion of a slight inferiority in terms of DMFS for Ru is consistent with the other limited literature. On the basis of this study, we believe that both radioisotopes remain appropriate for the treatment of small choroidal melanomas up to 5 mm in apical height.

Brainstem dose is associated with patient-reported acute fatigue in head and neck cancer radiation therapy.

BACKGROUND AND PURPOSE: Radiation (RT) dose to the central nervous system (CNS) has been implicated as a contributor to treatment-related fatigue in head and neck cancer (HNC) patients undergoing radiation therapy (RT). This study evaluates the association of RT dose to CNS structures with patient-reported (PRO) fatigue scores in a population of HNC patients. MATERIALS AND METHODS: At pre-RT (baseline), 6th week of RT, and 1-month post-RT time points, Multidimensional Fatigue Inventory (MFI-20) scores were prospectively obtained from 124 patients undergoing definitive treatment for HNC. Medulla, pons, midbrain, total brainstem, cerebellum, posterior fossa, and pituitary dosimetry were evaluated using summary statistics and dose-volume histograms, and associations with MFI-20 scores were analyzed. RESULTS: Maximum dose (Dmax) to the brainstem and medulla was significantly associated with MFI-20 scores at 6th week of RT and 1-month post-RT time points, after controlling for baseline scores (p<0.05). Each 1Gy increase in medulla Dmax resulted in an increase in total MFI-20 score over baseline of 0.30 (p=0.026), and 0.25 (p=0.037), at the 6th week of RT and 1-month post-RT, respectively. Each 1Gy increase in brainstem Dmax resulted in an increase in total MFI-20 score over baseline of 0.30 (p=0.027), and 0.25 (p=0.037) at the 6th week of RT, 1-month post-RT, respectively. Statistically significant associations were not found between dosimetry for the other CNS structures and MFI-20 scores. CONCLUSIONS: In this analysis of PRO fatigue scores from a population of patients undergoing definitive RT for HNC, maximum dose to the brainstem and medulla was associated with a significantly increased risk of acute patient fatigue.

Reproducibility in contouring the neurovascular bundle for prostate cancer radiation therapy.

PURPOSE: Efforts to define the neurovascular bundle (NVB) for prostate radiation have varied. In this series, we sought to determine the reproducibility and reliability of contouring the classical posterolateral NVB on dedicated pelvic magnetic resonance imaging (MRI) scans. METHODS AND MATERIALS: A total of 120 NVB structures were defined on 10 3-Tesla pelvic MRI scans in patients with prostate cancer but without extraprostatic extension. One pelvic radiologist served as the expert in contouring the right and left NVB for each case. Five radiation oncologists, with varying levels of experience, contoured the right and left NVBs on these same cases. The intraclass correlation coefficient across each rater and the expert, Pearson correlation coefficient between each rater and the expert, and the Dice similarity coefficient (DSC) between each rater and the expert were calculated to evaluate contour agreement and overlap. RESULTS: The overall intraclass correlation coefficient was 0.89 (95% confidence interval [CI], 0.81-0.95). The Pearson correlation coefficient was 0.95 (95% CI, 0.86-0.98) for rater 1, 0.98 (95% CI, 0.95-0.99) for rater 2, 0.94 (95% CI, 0.86-0.98) for rater 3, 0.98 (95% CI, 0.95-0.99) for rater 4, and 0.84 (95% CI, 0.63-0.93) for rater 5. The mean DSC was 0.72 (standard deviation [SD], 0.07) for rater 1, 0.72 (SD, 0.06) for rater 2, 0.73 (SD, 0.09) for rater 3, 0.74 (SD, 0.09) for rater 4, and 0.68 (SD, 0.13) for rater 5. Overall, across all raters, the average DSC was 0.72 (SD, 0.09). CONCLUSIONS: The classic posterolateral NVB can be accurately and reliably contoured on 3-Tesla pelvic MRI scans by radiation oncologists.

Musculoskeletal outcomes and the effect of radiation to the vertebral bodies on growth trajectories for long-term survivors of high-risk neuroblastoma.

OBJECTIVE: Here, we report musculoskeletal outcomes and the impact of radiotherapy dose on vertebral body growth for an institutional series of long-term survivors of high-risk neuroblastoma. METHODS: We conducted a retrospective study of 23 patients who were disease-free and at least 36 months from the end of treatment. The patients were initially treated from July 2003 to May 2012. Patient records were reviewed for growth percentiles (obtained at approximately 6-month intervals from onset of treatment to the last follow-up) and musculoskeletal comorbidities. RT plans and most recent surveillance CT scans were reviewed for locations of in-field vertebral bodies and corresponding vertebral growth patterns. RESULTS: The median follow-up was 7.93 years. The median prescribed radiation dose was 21.6 Gy. Musculoskeletal abnormalities included scoliosis (5 patients), muscular hypoplasia (3), and hypodontia (1). The median growth percentile at treatment onset was 35.5 (range, 4.7-100) versus 10 (0-94.1) at the last follow-up. The median numbers of vertebral bodies encompassed (by at least half of their volume) by the 5-, 10-, 15-, and 20-Gy isodose lines were 7 (mean, 6.78), 7 (6.56), 6 (6.17), and 6 (5.52), respectively. Sixteen patients (70.0%) had in-field abnormalities in vertebral body growth, manifesting as stretches of successive vertebral bodies at the same height, while normally there is a gradual vertebral body height increase progressing caudally down the spinal column. CONCLUSIONS: Musculoskeletal abnormalities, below average height, and stunted in-field vertebral body growth are routine in long-term survivors of high-risk neuroblastoma. Sparing vertebral bodies when feasible may lead to improvement in patient growth trajectories.