From cells to tissue: How cell scale heterogeneity impacts glioblastoma growth and treatment response.

Glioblastomas are aggressive primary brain tumors known for their inter- and intratumor heterogeneity. This disease is uniformly fatal, with intratumor heterogeneity the major reason for treatment failure and recurrence. Just like the nature vs nurture debate, heterogeneity can arise from intrinsic or environmental influences. Whilst it is impossible to clinically separate observed behavior of cells from their environmental context, using a mathematical framework combined with multiscale data gives us insight into the relative roles of variation from different sources. To better understand the implications of intratumor heterogeneity on therapeutic outcomes, we created a hybrid agent-based mathematical model that captures both the overall tumor kinetics and the individual cellular behavior. We track single cells as agents, cell density on a coarser scale, and growth factor diffusion and dynamics on a finer scale over time and space. Our model parameters were fit utilizing serial MRI imaging and cell tracking data from ex vivo tissue slices acquired from a growth-factor driven glioblastoma murine model. When fitting our model to serial imaging only, there was a spectrum of equally-good parameter fits corresponding to a wide range of phenotypic behaviors. When fitting our model using imaging and cell scale data, we determined that environmental heterogeneity alone is insufficient to match the single cell data, and intrinsic heterogeneity is required to fully capture the migration behavior. The wide spectrum of in silico tumors also had a wide variety of responses to an application of an anti-proliferative treatment. Recurrent tumors were generally less proliferative than pre-treatment tumors as measured via the model simulations and validated from human GBM patient histology. Further, we found that all tumors continued to grow with an anti-migratory treatment alone, but the anti-proliferative/anti-migratory combination generally showed improvement over an anti-proliferative treatment alone. Together our results emphasize the need to better understand the underlying phenotypes and tumor heterogeneity present in a tumor when designing therapeutic regimens.

Non-English language validation of patient-reported outcome measures in cancer clinical trials.

Patient-reported outcome measures (PROMs) are increasingly incorporated as endpoints in oncology clinical trials but are often only validated in English. ClinicalTrials.gov was queried for cancer-specific randomized control trials (RCTs) addressing a therapeutic intervention and enrolling primarily in the USA. Peer-reviewed validation of Spanish and Chinese versions of each PROM was assessed. Of 103 eligible trials, a PROM was used as a primary endpoint in 25 RCTs (24.3%) and as a secondary endpoint in 78 RCTs (75.7%). A total of 61 of the 103 eligible trials (59.2%) and 17 of the 25 trials with a PROM primary endpoint (68.0%) used a PROM with either no Spanish or Chinese validation. The absence of validated PROM translations may diminish the voices of non-English language speaking trial participants. With an increasingly diverse US population, validation of non-English PROM translations may decrease disparities in trial participation and improve generalizability of study results.

'Optimism bias' in contemporary national clinical trial network phase III trials: are we improving?

Background: Previous studies have found that overestimating treatment effects (i.e. 'optimism bias') leads to underpowered clinical trials. The prevalence of 'optimism bias' in contemporary National Clinical Trials Network (NCTN) cancer clinical trials is unknown. Methods: We conducted a systematic review of NCTN phase III randomized trials published from January 2007 to January 2017. We compared the hypothesized versus observed treatment effects in each trial, and examined whether trial-related factors were correlated with the study results. We also reviewed the methods of each protocol to assess whether a rationale for the hypothesized effect size was provided. Results: We identified 161 clinical trials, of which 130 were eligible for analysis. Original protocols could not be located for 8 trials (5.0%). Twenty-eight trials (21.5%) observed a statistically significant difference in the primary end point favoring the experimental treatment. The median ratio of observed-to-expected hazard ratios among trials that observed a statistically significant effect on the primary end point was 1.07 (range: 0.33-1.28) versus 1.32 (range: 0.86-2.02) for trials that did not, compared with 1.34 and 1.86, respectively, for National Cancer Institute (NCI) trials published between 1955 and 2006. An effect size at least as large as the one projected in the protocol trials was observed in 9.8% of trials, compared with 17% of NCI trials published from 1955 to 2006. Most trials (64.6%) provided no rationale to support the magnitude of the proposed treatment effect in the protocol. Conclusions: Despite a reduction in 'optimism bias' compared with previous eras, most contemporary NCTN phase III trials failed to establish statistically significant benefits of new cancer therapies. Better rationalization of proposed effect sizes in research protocols is needed.

Current State of Neoadjuvant Therapy for Locally Advanced Rectal Cancer.

ABSTRACT: In locally advanced rectal cancer, neoadjuvant treatment has evolved from no preoperative treatment to the addition of radiation and systemic therapy and ultimately total neoadjuvant therapy. Total neoadjuvant therapy is the completion of preoperative radiation or chemoradiation and chemotherapy before surgery in order to maximize tumor response and improve survival outcomes. This review summarizes the literature of the neoadjuvant approaches related to locally advanced rectal cancer and highlights the nuances of selecting the appropriate treatment.

Long-Term Patient-Reported Dyspareunia After Definitive Chemoradiation for Anal Cancer: Using the Anterior Vaginal Wall as an Organ-at-Risk to Define an Actionable Dosimetric Goal.

Purpose: Chemoradiation therapy (CRT) is the standard treatment for squamous cell carcinoma of the anus (SCCA). This study aimed to investigate the relationship between vaginal dosimetry and long-term patient-reported dyspareunia after treatment. We further aimed to use the anterior vaginal wall (AVW) as an organ at risk to define an actionable dosimetric clinical goal to decrease the risk of patient-reported dyspareunia. Methods and Materials: Women with SCCA treated with intensity modulated radiation therapy-based CRT were surveyed at least 2 years after successfully completing therapy. A Female Sexual Function Index (FSFI) pain subscore ≤4 was used to define dyspareunia. Dosimetric parameters were calculated for both the full vaginal canal and AVW. Multivariable linear regression models were created to identify predictors of FSFI pain subscore using backward selection to identify final variables include in the models. An actionable dosimetric predictor for dyspareunia was established using the Youden index method for cutoff optimization. Results: Of 184 women who were contacted, 90 (49%) returned completed surveys. Of those who completed surveys, 51 (56.7%) reported being sexually active, and 47 had dosimetric data available for review. Of sexually active respondents, 32 (68%) had an FSFI pain subscore ≤4. Multiple regression models were generated using the full vaginal canal and AVW as organs at risk, and both models showed similar predictive relationships with volumetric dose parameters emerging as the best dosimetric predictors for dysparenuia. Age over 65 years was also associated with higher FSFI pain subscores (eg, less pain with intercourse) in both models. AVW V35 Gy < 60% was identified as the optimal cutoff to reduce the risk of patient-reported dyspareunia. Conclusions: Increased dose to the vaginal canal is significantly associated with worse patient-reported dyspareunia following CRT for SCCA. Minimizing dose to the AVW to V35 Gy < 60% may reduce the risk of this quality of life-limiting toxicity. Further prospective evaluation is needed to validate these findings.

Evaluating pre-consult patient education videos for patients with newly-diagnosed anal squamous cell carcinoma: Impact on patient comprehension, satisfaction and distress.

We hypothesized that pre-consult patient education videos can improve patient understanding about their diagnosis, lead to high satisfaction and low distress. In this pilot study, we developed a patient education video curriculum for patients with newly-diagnosed anal cancer. Comprehension of key content was evaluated by comparing pre- and post-test scores. Patient satisfaction scores were collected. Patient distress scores (0-10) were collected at the beginning of their consult visit prior to seeing the physician. We found that patient education videos prior to consult improved patient understanding, resulted in high patient satisfaction, and low patient distress at the time of consult.

Proportional Hazards Violations in Phase III Cancer Clinical Trials: A Potential Source of Trial Misinterpretation.

PURPOSE: Survival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHV) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase III oncology trials and assess the utility of restricted mean survival time and maximum combination test as additional analyses. EXPERIMENTAL DESIGN: Clinicaltrials.gov and PubMed were searched to identify two-arm, randomized, phase III superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals. RESULTS: Three hundred fifty-seven Kaplan-Meier comparisons across 341 trials were analyzed, encompassing 292,831 enrolled patients. PHVs were identified in 85/357 [23.8%; 95% confidence interval (CI), 19.7%, 28.5%] comparisons. In multivariable analysis, non-overall survival endpoints [OR, 2.16 (95% CI, 1.21, 3.87); P = 0.009] were associated with higher odds of PHVs, and immunotherapy comparisons [OR 1.94 (95% CI, 0.98, 3.86); P = 0.058] were weakly suggestive of higher odds of PHVs. Few trials with PHVs (25/85, 29.4%) prespecified a statistical plan to account for PHVs. Fourteen trials with PHVs exhibited discordant statistical signals with restricted mean survival time or maximum combination test, of which 10 (71%) reported negative results. CONCLUSIONS: PHVs are common across therapy types, and attempts to account for PHVs in statistical design are lacking despite the potential for results exhibiting nonproportional hazards to be misinterpreted.

Association of differential censoring with survival and suboptimal control arms among oncology clinical trials.

Differential censoring, which refers to censoring imbalance between treatment arms, may bias the interpretation of survival outcomes in clinical trials. In 146 phase III oncology trials with statistically significant time-to-event surrogate primary endpoints, we evaluated the association between differential censoring in the surrogate primary endpoints, control arm adequacy, and the subsequent statistical significance of overall survival results. Twenty-four (16%) trials exhibited differential censoring that favored the control arm, whereas 15 (10%) exhibited differential censoring that favored the experimental arm. Positive overall survival was more common in control arm differential censoring trials (63%) than in trials without differential censoring (37%) or with experimental arm differential censoring (47%; odds ratio = 2.64, 95% confidence interval = 1.10 to 7.20; P = .04). Control arm differential censoring trials more frequently used suboptimal control arms at 46% compared with 20% without differential censoring and 13% with experimental arm differential censoring (odds ratio = 3.60, 95% confidence interval = 1.29 to 10.0; P = .007). The presence of control arm differential censoring in trials with surrogate primary endpoints, especially in those with overall survival conversion, may indicate an inadequate control arm and should be examined and explained.

Escalated-dose radiotherapy for unresected locally advanced pancreatic cancer: Patterns of care and survival in the United States.

INTRODUCTION: With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated-dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. METHODS: We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas-directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional-dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. RESULTS: Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas-directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80-0.91; p < 0.001) with longer OS versus CDR. DISCUSSION AND CONCLUSIONS: Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real-world results additionally provide an estimate of effect size of EDR for future prospective trials.

Measurable imaging-based changes in enhancement of intrahepatic cholangiocarcinoma after radiotherapy reflect physical mechanisms of response.

Background: Although escalated doses of radiation therapy (RT) for intrahepatic cholangiocarcinoma (iCCA) are associated with durable local control (LC) and prolonged survival, uncertainties persist regarding personalized RT based on biological factors. Compounding this knowledge gap, the assessment of RT response using traditional size-based criteria via computed tomography (CT) imaging correlates poorly with outcomes. We hypothesized that quantitative measures of enhancement would more accurately predict clinical outcomes than size-based assessment alone and developed a model to optimize RT. Methods: Pre-RT and post-RT CT scans of 154 patients with iCCA were analyzed retrospectively for measurements of tumor dimensions (for RECIST) and viable tumor volume using quantitative European Association for Study of Liver (qEASL) measurements. Binary classification and survival analyses were performed to evaluate the ability of qEASL to predict treatment outcomes, and mathematical modeling was performed to identify the mechanistic determinants of treatment outcomes and to predict optimal RT protocols. Results: Multivariable analysis accounting for traditional prognostic covariates revealed that percentage change in viable volume following RT was significantly associated with OS, outperforming stratification by RECIST. Binary classification identified ≥33% decrease in viable volume to optimally correspond to response to RT. The model-derived, patient-specific tumor enhancement growth rate emerged as the dominant mechanistic determinant of treatment outcome and yielded high accuracy of patient stratification (80.5%), strongly correlating with the qEASL-based classifier. Conclusion: Following RT for iCCA, changes in viable volume outperformed radiographic size-based assessment using RECIST for OS prediction. CT-derived tumor-specific mathematical parameters may help optimize RT for resistant tumors.

Phase I trial of single-photon emission computed tomography-guided liver-directed radiotherapy for patients with low functional liver volume.

BACKGROUND: Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single-photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection. METHODS: This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose-limiting toxicities were assessed 6-8 weeks and 6 months after completing radiotherapy. RESULTS: All 12 patients had colorectal liver metastases and received prior hepatotoxic chemotherapy; 8 patients underwent prior liver resection. Median computed tomography anatomical nontumor liver volume was 1584 cc (range = 764-2699 cc). Median SPECT functional liver volume was 1117 cc (range = 570-1928 cc). Median nontarget computed tomography and SPECT liver volumes below the volumetric dose constraint were 997 cc (range = 544-1576 cc) and 684 cc (range = 429-1244 cc), respectively. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. No dose-limiting toxicities were observed during follow-up. One-year in-field control was 57%. One-year overall survival was 73%. CONCLUSION: Liver-directed radiotherapy can be safely delivered to high doses when incorporating functional SPECT into the radiation treatment planning process, which may enable sparing of lower volumes of liver than traditionally accepted in patients with preserved liver function. TRIAL REGISTRATION: NCT02626312.

Addition of Metastasis-Directed Therapy to Systemic Therapy for Oligometastatic Pancreatic Ductal Adenocarcinoma (EXTEND): A Multicenter, Randomized Phase II Trial.

PURPOSE: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC). METHODS: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response measures. RESULTS: Between March 19, 2019, and February 13, 2023, 41 patients were randomly assigned and 40 were eligible for the primary analysis of PFS (19 patients in the MDT arm; 21 patients in the control arm). At a median follow-up time of 17 months, the median PFS time was 10.3 months (95% CI, 4.6 to 14.0) in the MDT arm versus 2.5 months (95% CI, 1.7 to 5.1) in the control arm. PFS was significantly improved by the addition of MDT to systemic therapy (P = .030 for stratified log-rank test) with a hazard ratio of 0.43 (95% CI, 0.20 to 0.94). No grade ≥3 or greater adverse events related to MDT were observed. Systemic immune activation events were associated with MDT and correlated with improved PFS. CONCLUSION: This study supports the addition of MDT to systemic therapy for patients with oligometastatic PDAC. Induction of systemic immunity is a possible mechanism of benefit. These results warrant confirmatory trials to refine treatment strategy and provide external validation.

Patient-Reported Sexual Function, Bladder Function and Quality of Life for Patients with Low Rectal Cancers with or without a Permanent Ostomy.

BACKGROUND: Despite the increasing utilization of sphincter and/or organ-preservation treatment strategies, many patients with low-lying rectal cancers require abdominoperineal resection (APR), leading to permanent ostomy. Here, we aimed to characterize overall, sexual-, and bladder-related patient-reported quality of life (QOL) for individuals with low rectal cancers. We additionally aimed to explore potential differences in patient-reported outcomes between patients with and without a permanent ostomy. METHODS: We distributed a comprehensive survey consisting of various patient-reported outcome measures, including the FACT-G7 survey, ICIQ MLUTS/FLUTS, IIEF-5/FSFI, and a specific questionnaire for ostomy patients. Descriptive statistics and univariate comparisons were used to compared demographics, treatments, and QOL scores between patients with and without a permanent ostomy. RESULTS: Of the 204 patients contacted, 124 (60.8%) returned completed surveys; 22 (18%) of these had a permanent ostomy at the time of survey completion. There were 25 patients with low rectal tumors (≤5 cm from the anal verge) who did not have an ostomy at the time of survey completion, of whom 13 (52%) were managed with a non-operative approach. FACTG7 scores were numerically lower (median 20.5 vs. 22, p = 0.12) for individuals with an ostomy. Sexual function measures IIEF and FSFI were also lower (worse) for individuals with ostomies, but the results were not significantly different. MLUTS and FLUTS scores were both higher in individuals with ostomies (median 11 vs. 5, p = 0.06 and median 17 vs. 5.5, p = 0.01, respectively), suggesting worse urinary function. Patient-reported ostomy-specific challenges included gastrointestinal concerns (e.g., gas, odor, diarrhea) that may affect social activities and personal relationships. CONCLUSIONS: Despite a limited sample size, this study provides patient-centered, patient-derived data regarding long-term QOL in validated measures following treatment of low rectal cancers. Ostomies may have multidimensional negative impacts on QOL, and these findings warrant continued investigation in a prospective setting. These results may be used to inform shared decision making for individuals with low rectal cancers in both the settings of organ preservation and permanent ostomy.

Microbiome Dynamics During Chemoradiation Therapy for Anal Cancer.

PURPOSE: Patients with localized squamous cell carcinoma of the anus (SCCA) who experience treatment toxicity or recurrences have few therapeutic options. Investigation into the microbiome's influence on treatment toxicity and its potential use as a predictive biomarker could improve these patients' outcomes. Our study presents the first longitudinal characterization of the SCCA tumor microbiome and its associations with treatment-related toxicities. METHODS AND MATERIALS: This prospective cohort study included patients with nonmetastatic SCCA receiving standard-of-care chemoradiation therapy. Anorectal swabs of the tumor site were collected before, during, and after treatment. Patient-reported quality-of-life metrics were collected at similar time points. 16S rRNA gene sequencing was used to perform diversity and taxonomic characterization of the SCCA microbiome. Wilcoxon signed-rank tests were used to compare microbial diversity and abundance over time. Wilcoxon rank-sum tests were used to compare microbial profiles of high and low toxicity groups. RESULTS: Twenty-two patients with SCCA were included in this study with a median age of 58.5 years (range, 39-77 years), and 18 (82%) were women. Alpha diversity remained relatively stable throughout chemoradiation therapy except for decreases in the Observed Features (P = .03) index at week 5 relative to baseline. Tumor microbial compositions changed significantly by the end of treatment (P = .03). Differential enrichment of bacteria at specific time points occurred during treatment, including the enrichment of Clostridia at follow-up (vs week 5, q = 0.019) and Corynebacterium at week 5 (vs baseline, q = 0.015; vs follow-up, q = 0.022). Patients experiencing high toxicity at week 5 had higher relative counts of Clostridia, Actinobacteria, and Clostridiales at baseline (P = .03 for all). CONCLUSIONS: The tumor microbiome changes during and after chemoradiation therapy, and patient-reported toxicity levels are associated with patients' microbial profiles. Further studies into these microbial characterizations and toxicity associations will elucidate the tumor microbiome's role in predicting treatment-related outcomes for patients with SCCA.

Stereotactic Versus Conventional Radiation Therapy for Patients With Pancreatic Cancer in the Modern Era.

PURPOSE: Patients with pancreatic cancer often receive radiation therapy before undergoing surgical resection. We compared the clinical outcomes differences between stereotactic body radiation therapy (SBRT) and 3-dimensional (3D)/intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: We retrospectively collected data from the University of Texas MD Anderson Cancer Center. Patients with borderline resectable/potentially resectable or locally advanced pancreatic cancer receiving neoadjuvant SBRT (median, 36.0 Gy/5fx), 3D conformal radiation (median, 50.4 Gy/28 fx) or IMRT (median, 50.4 Gy/28 fx) were included. Overall survival (OS) and progression-free survival were analyzed using Cox regression. RESULTS: In total, 104 patients were included in our study. Fifty-seven patients (54.8%) were treated with SBRT, and 47 patients (45.2%) were treated with 3D/IMRT. Patients in the SBRT group were slightly older (median age: 70.3 vs 62.7 in the 3D/IMRT group). Both groups had similar proportions of patients with locally advanced pancreatic cancer (SBRT: 30, 52.6%; 3D/IMRT: 24, 51.1%). All patients were treated with chemotherapy. Patients in the SBRT group underwent more surgical resection compared with the 3D/IMRT group (38.6% vs 23.4%, respectively). At a median follow-up of 22 months, a total of 60 patients (57.7%) died: 25 (25/57, 43.9%) in the SBRT group, and 35 (35/47, 74.5%) in the 3D/IMRT group. Median OS was slightly higher in the SBRT group (29.6 months vs 24.1 months in the 3D/IMRT group). On multivariable Cox regression, the choice of radiation therapy technique was not associated with differences in OS (adjusted hazard ratios [aHR] = 0.5; 95% confidence interval [CI], 0.2%-1.3%, P = .18). Moreover, patients that underwent surgical resection had better OS (aHR = 0.3, 95% CI, 0.1%-0.8%, P = .01). Furthermore, progression-free survival was also similar between patients treated with SBRT and those treated with 3D/IMRT (aHR = 0.9, 95% CI, 0.5%-1.8%, P = .81). CONCLUSIONS: SBRT was associated with similar clinical outcomes compared with conventional radiation techniques, despite being delivered over a shorter period of time which would spare patients prolonged treatment burden. Future prospective data are still needed to better assess the role of SBRT in patients with pancreatic cancer.

Radiation therapy for patients with locally advanced pancreatic cancer: Evolving techniques and treatment strategies.

Despite ongoing efforts, patients with locally advanced pancreatic cancer (LAPC) continue to have a dismal prognosis. Such tumors are unresectable, and optimal treatment with chemotherapy and/or radiation therapy is still not established. While chemotherapy is conventionally aimed at preventing metastatic spread of disease, radiation therapy acts locally, improving local control which can potentially improve overall survival and most importantly quality of life. Here, we aim to review the primary literature assessing the role of diverse radiation therapy strategies for patients with LAPC. Many radiation regimens can be considered, and no standard treatment has demonstrated a clear improvement in clinical outcomes. We advise that the modality of choice be dependent on the availability of equipment, the dose and fractionation of treatment, as well as the dose received by normal tissue. Moreover, a candid discussion with the patient concerning treatment goals is equally as essential. Three notable strategies for LAPC are intensity-modulated radiation therapy, volumetric modulated arc therapy, and proton. These radiation modalities tend to have improved dose distribution to the target volumes, while minimizing the radiation dose to surrounding normal tissues. Stereotactic body radiation therapy can also be considered in LAPC patients in cases where the tumor does not invade the duodenum or other neighboring structures. Because of the high doses delivered by stereotactic body radiation therapy, proper respiratory and tumor motion management should be implemented to reduce collateral radiation dosing. Despite improved clinical outcomes with modern radiation modalities, evolving techniques, and more accurate planning, future studies remain essential to elucidate the optimal role for radiation therapy among patients with LAPC.

Multi-institutional retrospective review of stereotactic radiosurgery for brain metastasis in patients with small cell lung cancer without prior brain-directed radiotherapy.

Introduction: Patients with small cell lung cancer (SCLC) brain metastasis (BM) typically receive whole brain radiotherapy (WBRT) as data regarding upfront radiosurgery (SRS) in this setting are sparse. Methods: Patients receiving SRS for SCLC BM without prior brain radiation were identified at three U.S. institutions. Overall survival (OS), freedom from intracranial progression (FFIP), freedom from WBRT (FFWBRT), and freedom from neurologic death (FFND) were determined from time of SRS. Results: Thirty-three patients were included with a median of 2 BM (IQR 1-6). Median OS and FFIP were 6.7 and 5.8 months, respectively. Median FFIP for patients with ≤2 versus >2 BM was 7.1 versus 3.6 months, p=0.0303. Eight patients received salvage WBRT and the 6-month FFWBRT and FFND were 87.8%. and 90.1%, respectively. Conclusions: Most SCLC patients with BM who received upfront SRS avoided WBRT and neurologic death, suggesting that SRS may be an option in select patients.

Predictors of urinary toxicity with MRI-assisted radiosurgery for low-dose-rate prostate brachytherapy.

PURPOSE: MRI-assisted radiosurgery (MARS) is a modern technique for prostate brachytherapy that provides superior soft tissue contrast. The purpose of this analysis was to evaluate treatment planning factors associated with urinary toxicity, particularly damage to the membranous urethra (MUL) and external urethral sphincter (EUS), after MARS. MATERIAL AND METHODS: We retrospectively reviewed 227 patients treated with MARS. Comparisons were made between several factors including preimplantation length of the MUL and EUS dosimetric characteristics after implantation with longitudinal changes in American Urological Association (AUA) urinary symptom score. RESULTS: Rates of grade 3 urinary incontinence and obstructive urinary symptoms were 4% and 2%. A piecewise mixed univariate model revealed that MUL and V200, V150, V125, and D5 to the EUS were all associated with increased rates of urinary toxicity over time. On univariate logistic regression, MUL >14.2 mm (odds ratio [OR] 2.03 per cm3, 95% confidence interval [CI] 1.10-3.77, p = 0.025), V125 to the EUS (OR 3.21 cm3, 95% CI 1.18-8.71, p = 0.022), and use of the I-125 isotope (OR 3.45, 95% CI 1.55-7.70, p = 0.001) were associated with subacute urinary toxicity (i.e., that occurring at 4-8 months). Optimal dose-constraint limits to the EUS were determined to be V200 < 0.04 cm3 (p = 0.002), V150 < 0.12 cm3 (p = 0.041), V125 < 0.45 cm3 (p = 0.033), D30 < 160 Gy (p = 0.004), and D5 < 218 Gy (p = 0.016). CONCLUSIONS: MARS brachytherapy provides detailed anatomic information for treatment planning, implantation, and quality assurance. Overall rates of urinary toxicity are low; however, several dosimetric variables associated with the EUS were found to correlate with urinary toxicity.