Lost in the plot: missing visual elements in Kaplan-Meier plots of phase III oncology trials.

Missing visual elements (MVE) in Kaplan-Meier (KM) curves can misrepresent data, preclude curve reconstruction, and hamper transparency. This study evaluated KM plots of phase III oncology trials. MVE were defined as an incomplete y-axis range or missing number at risk table in a KM curve. Surrogate endpoint KM curves were additionally evaluated for complete interpretability, defined by (1) reporting the number of censored patients and (2) correspondence of the disease assessment interval with the number at risk interval. Among 641 trials enrolling 518 235 patients, 116 trials (18%) had MVE in KM curves. Industry sponsorship, larger trials, and more recently published trials were correlated with lower odds of MVE. Only 3% of trials (15 of 574) published surrogate endpoint KM plots with complete interpretability. Improvements in the quality of KM curves of phase III oncology trials, particularly for surrogate endpoints, are needed for greater interpretability, reproducibility, and transparency in oncology research.

Prevalence, trends, and characteristics of trials investigating local therapy in contemporary phase 3 clinical cancer research.

BACKGROUND: Although most patients with cancer are treated with local therapy (LT), the proportion of late-phase clinical trials investigating local therapeutic interventions is unknown. The purpose of this study was to determine the proportion, characteristics, and trends of phase 3 cancer clinical trials assessing the therapeutic value of LT over time. METHODS: This was a cross-sectional analysis of interventional randomized controlled trials in oncology published from 2002 through 2020 and registered on ClinicalTrials.gov. Trends and characteristics of LT trials were compared to all other trials. RESULTS: Of 1877 trials screened, 794 trials enrolling 584,347 patients met inclusion criteria. A total of 27 trials (3%) included a primary randomization assessing LT compared with 767 trials (97%) investigating systemic therapy or supportive care. Annual increase in the number of LT trials (slope [m] = 0.28; 95% confidence interval [CI], 0.15-0.39; p < .001) was outpaced by the increase of trials testing systemic therapy or supportive care (m = 7.57; 95% CI, 6.03-9.11; p < .001). LT trials were more often sponsored by cooperative groups (22 of 27 [81%] vs. 211 of 767 [28%]; p < .001) and less often sponsored by industry (5 of 27 [19%] vs. 609 of 767 [79%]; p < .001). LT trials were more likely to use overall survival as primary end point compared to other trials (13 of 27 [48%] vs. 199 of 767 [26%]; p = .01). CONCLUSIONS: In contemporary late-phase oncology research, LT trials are increasingly under-represented, under-funded, and evaluate more challenging end points compared to other modalities. These findings strongly argue for greater resource allocation and funding mechanisms for LT clinical trials. PLAIN LANGUAGE SUMMARY: Most people who have cancer receive treatments directed at the site of their cancer, such as surgery or radiation. We do not know, however, how many trials test surgery or radiation compared to drug treatments (that go all over the body). We reviewed trials testing the most researched strategies (phase 3) completed between 2002 and 2020. Only 27 trials tested local treatments like surgery or radiation compared to 767 trials testing other treatments. Our study has important implications for funding research and understanding cancer research priorities.

Management of chordoma and chondrosarcoma with definitive dose-escalated single-fraction spine stereotactic radiosurgery.

PURPOSE: The management of chordoma or chondrosarcoma involving the spine is often challenging due to adjacent critical structures and tumor radioresistance. Spine stereotactic radiosurgery (SSRS) has radiobiologic advantages compared with conventional radiotherapy, though there is limited evidence on SSRS in this population. We sought to characterize the long-term local control (LC) of patients treated with SSRS. METHODS: We retrospectively reviewed patients with chordoma or chondrosarcoma treated with dose-escalated SSRS, defined as 24 Gy in 1 fraction to the gross tumor volume. Overall survival (OS) was calculated by Kaplan-Meier functions. Competing risk analysis using the cause-specific hazard function estimated LC time. RESULTS: Fifteen patients, including 12 with chordoma and 3 with chondrosarcoma, with 22 lesions were included. SSRS intent was definitive, single-modality in 95% of cases (N = 21) and post-operative in 1 case (5%). After a median censored follow-up time of 5 years (IQR 4 to 8 years), median LC time was not reached (IQR 8 years to not reached), with LC rates of 100%, 100%, and 90% at 1 year, 2 years, and 5 years. The median OS was 8 years (IQR 3 years to not reached). Late grade 3 toxicity occurred after 23% of treatments (N = 5, fracture), all of which were managed successfully with stabilization. CONCLUSION: Definitive dose-escalated SSRS to 24 Gy in 1 fraction appears to be a safe and effective treatment for achieving durable local control in chordoma or chondrosarcoma involving the spine, and may hold particular importance as a low-morbidity alternative to surgery in selected cases.

Chronic Electroconvulsive Therapy May Induce Calvarial Hyperemia and Marrow Replacement.

ABSTRACT: Electroconvulsive therapy (ECT) is a treatment option for a number of psychiatric disorders, including refractory major depression and obsessive compulsive disorder. There are no known structural sequelae of ECT. Here we present a patient with severe refractory obsessive compulsive disorder and major depression treated over 2 years with ECT every 2 weeks. Planning magnetic resonance imaging intended for a potential procedural intervention for her psychiatric disease incidentally demonstrated a new area of increased enhancement and loss of marrow signal within the right frontal bone. Imaging findings were suggestive of underlying bone marrow or bone changes, although there was no evidence of bone destruction on bone-windowed computed tomography (CT) and there was no uptake on nuclear bone scan. The CT chest/abdomen/pelvis were also reassuring that this did not represent metastatic disease, and findings were unchanged on repeat magnetic resonance imaging 4 months later. Thus, this area corresponded to the site directly underlying the unilateral ECT electrode placement, suggestive of never-before described ECT-induced hyperemia. We report for the first time that frequent, chronic ECT may induce asymptomatic skull bone marrow hyperemia with radiologic findings. This appears to be a direct consequence of electrical current leading to chronic inflammatory and edematous marrow replacement. Electroconvulsive therapy should be added to the neuroradiological differential diagnosis of calvarial enhancement and loss of marrow signal. Psychiatrists should counsel patients on the possibility of this rare radiological finding, which may be confused for other processes.

An autoimmune-based, paraneoplastic neurologic syndrome following checkpoint inhibition and concurrent radiotherapy for merkel cell carcinoma: case report.

PURPOSE: Merkel cell carcinoma is highly sensitive to both radiation and immunotherapy. Moreover, concurrent radioimmunotherapy may capitalize on anti-tumor immune activity and improve Merkel cell treatment response, although an enhanced immune system may cross-react with native tissues and lead to significant sequelae. METHODS: Here we present a case study of a patient with metastatic Merkel cell carcinoma treated with radiotherapy concurrent with pembrolizumab. RESULTS: After radioimmunotherapy, the patient developed sensory neuropathy, visual hallucinations, and mixed motor neuron findings. Neurologic dysfunction progressed to profound gastrointestinal dysmotility necessitating parenteral nutrition and intubation with eventual expiration. CONCLUSION: This case represents a unique autoimmune paraneoplastic neurologic syndrome, likely specific to neuroendocrine tumors and motivated by concurrent radioimmunotherapy. Recognition of the potential role of radioimmunotherapy may provide an advantage in anticipating these severe sequelae.

Systemic inflammatory dynamics during chemoradiotherapy predict response, relapse, metastasis, and survival in esophageal carcinoma.

BACKGROUND AND OBJECTIVES: Lymphopenia associated with chemoradiotherapy predicts prognosis in esophageal carcinoma. The purpose of our study was to evaluate alterations in hematologic measures of inflammation during chemoradiation. METHODS: We performed an observational study evaluating adults treated with chemoradiation in the neoadjuvant or definitive setting for stage II-III esophageal carcinoma. Multivariable logistic regression evaluated predictors of pathologic response. Survival was analyzed by time-varying multivariable Cox proportional hazards regressions. RESULTS: A total of 94 patients were included with median follow-up of 1.6 years. Elevated neutrophil:lymphocyte ratio (NLR) was predictive of incomplete pathologic response to neoadjuvant chemoradiation (OR, 1.07; P = .0030) as well as shorter distant metastasis-free survival (HR, 1.01; P = .0369) and reduced overall survival (HR, 1.01; P = .0448). An NLR > 5.55 in week two of chemoradiation predicted shorter overall survival (P = .0070). Upon adjusted analysis, NLR was independently associated with reduced probability of complete pathologic response (OR, 0.80; P = .0291), as well as poor histologic response to neoadjuvant chemoradiation (OR, 1.05; P = .0303), shorter disease-free survival (HR, 1.02; P = .0077), and reduced overall survival (HR, 1.02; P = .0070). CONCLUSIONS: Dynamic time-dependent changes in NLR during chemoradiation predict response, relapse, metastasis, and survival in esophageal carcinoma. Prospective validation is warranted.

Outcomes of stereotactic radiosurgery and hypofractionated stereotactic radiotherapy for refractory Cushing's disease.

PURPOSE: Hypofractionated stereotactic radiotherapy (HSRT) for refractory Cushing's disease may offer a condensed treatment schedule for patients with large tumors abutting the optic chiasm unsuitable for stereotactic radiosurgery (SRS). To-date only four patients have been treated by HSRT in the published literature. We investigated the feasibility, toxicity, and efficacy of HSRT compared to SRS. METHODS: After approval, we retrospectively evaluated patients treated at our institution for refractory Cushing's disease with SRS or HSRT. Study outcomes included biochemical control, time to biochemical control, local control, and late complications. Binary logistic regression and Cox proportional hazards regression evaluated predictors of outcomes. RESULTS: Patients treated with SRS (n = 9) and HSRT (n = 9) were enrolled with median follow-up of 3.4 years. Clinicopathologic details were balanced between the cohorts. Local control was 100% in both cohorts. Time to biochemical control was 6.6. and 9.5 months in the SRS and HSRT cohorts, respectively (p = 0.6258). Two patients in each cohort required salvage bilateral adrenalectomy. Late complications including secondary malignancy, radionecrosis, cranial nerve neuropathy, and optic pathway injury were minimal for either cohort. CONCLUSIONS: HSRT is an appropriate treatment approach for refractory Cushing's disease, particularly for patients with large tumors abutting the optic apparatus. Prospective studies are needed to validate these findings and identify factors suggesting optimal fractionation approaches.

Feasibility and Tolerability of Adjuvant Capecitabine-Based Chemoradiation in Patients With Breast Cancer and Residual Disease After Neoadjuvant Chemotherapy: A Prospective Clinical Trial.

PURPOSE: Addition of adjuvant capecitabine improves overall survival for patients with breast cancer lacking pathologic complete response to standard-of-care neoadjuvant chemotherapy. Combining radiosensitizing capecitabine concurrent with radiation may further improve disease control, although the feasibility and tolerability of chemoradiation in this setting is unknown. This study aimed to determine the feasibility of this combination. Secondary objectives included the effect of chemoradiation on physician-reported toxicity, patient-reported skin dermatitis, and patient-reported quality of life compared with patients with breast cancer treated with adjuvant radiation. METHODS AND MATERIALS: Twenty patients with residual disease following standard neoadjuvant chemotherapy were enrolled in a prospective single-arm trial and treated with adjuvant capecitabine-based chemoradiation. Feasibility was defined as ≥75% of patients completing chemoradiation as planned. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 5.0 and the patient-reported radiation-induced skin reaction scale. Quality of life was measured using the RAND Short-Form 36-Item Health Survey. RESULTS: Eighteen patients (90%) completed chemoradiation without interruption or dose reduction. The incidence of grade ≥3 radiation dermatitis was 5% (1 of 20 patients). Patient-reported radiation dermatitis did not show a clinically meaningful difference following chemoradiation (mean increase, 55 points) compared with published reports of patients with breast cancer treated with adjuvant radiation alone (mean increase, 47 points). On the other hand, patient-reported quality of life demonstrated a clinically meaningful decline at the end of chemoradiation (mean, 46; SD, 7) compared with the reference population of patients treated with adjuvant radiation alone (mean, 50; SD, 6). CONCLUSIONS: Adjuvant chemoradiation with capecitabine is feasible and tolerable in patients with breast cancer. Although current studies using adjuvant capecitabine for residual disease following neoadjuvant chemotherapy have specified sequential treatment of capecitabine and radiation, these results support the conduct of randomized trials in this setting to investigate the efficacy of concurrent radiation with capecitabine and provide patient-reported toxicity estimates for trial design.

Differential Treatment Effects of Subgroup Analyses in Phase 3 Oncology Trials From 2004 to 2020.

Importance: Subgroup analyses are often performed in oncology to investigate differential treatment effects and may even constitute the basis for regulatory approvals. Current understanding of the features, results, and quality of subgroup analyses is limited. Objective: To evaluate forest plot interpretability and credibility of differential treatment effect claims among oncology trials. Design, Setting, and Participants: This cross-sectional study included randomized phase 3 clinical oncology trials published prior to 2021. Trials were screened from ClinicalTrials.gov. Main Outcomes and Measures: Missing visual elements in forest plots were defined as a missing point estimate or use of a linear x-axis scale for hazard and odds ratios. Multiplicity of testing control was recorded. Differential treatment effect claims were rated using the Instrument for Assessing the Credibility of Effect Modification Analyses. Linear and logistic regressions evaluated associations with outcomes. Results: Among 785 trials, 379 studies (48%) enrolling 331 653 patients reported a subgroup analysis. The forest plots of 43% of trials (156 of 363) were missing visual elements impeding interpretability. While 4148 subgroup effects were evaluated, only 1 trial (0.3%) controlled for multiple testing. On average, trials that did not meet the primary end point conducted 2 more subgroup effect tests compared with trials meeting the primary end point (95% CI, 0.59-3.43 tests; P = .006). A total of 101 differential treatment effects were claimed across 15% of trials (55 of 379). Interaction testing was missing in 53% of trials (29 of 55) claiming differential treatment effects. Trials not meeting the primary end point were associated with greater odds of no interaction testing (odds ratio, 4.47; 95% CI, 1.42-15.55, P = .01). The credibility of differential treatment effect claims was rated as low or very low in 93% of cases (94 of 101). Conclusions and Relevance: In this cross-sectional study of phase 3 oncology trials, nearly half of trials presented a subgroup analysis in their primary publication. However, forest plots of these subgroup analyses largely lacked essential features for interpretation, and most differential treatment effect claims were not supported. Oncology subgroup analyses should be interpreted with caution, and improvements to the quality of subgroup analyses are needed.

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.

Challenges, Complexities, and Considerations in the Design and Interpretation of Late-Phase Oncology Trials.

Optimal management of cancer patients relies heavily on late-phase oncology randomized controlled trials. A comprehensive understanding of the key considerations in designing and interpreting late-phase trials is crucial for improving subsequent trial design, execution, and clinical decision-making. In this review, we explore important aspects of late-phase oncology trial design. We begin by examining the selection of primary endpoints, including the advantages and disadvantages of using surrogate endpoints. We address the challenges involved in assessing tumor progression and discuss strategies to mitigate bias. We define informative censoring bias and its impact on trial results, including illustrative examples of scenarios that may lead to informative censoring. We highlight the traditional roles of the log-rank test and hazard ratio in survival analyses, along with their limitations in the presence of nonproportional hazards as well as an introduction to alternative survival estimands, such as restricted mean survival time or MaxCombo. We emphasize the distinctions between the design and interpretation of superiority and noninferiority trials, and compare Bayesian and frequentist statistical approaches. Finally, we discuss appropriate utilization of phase II and phase III trial results in shaping clinical management recommendations and evaluate the inherent risks and benefits associated with relying on phase II data for treatment decisions.

Prevalence and implications of significance testing for baseline covariate imbalance in randomised cancer clinical trials: The Table 1 Fallacy.

BACKGROUND: The 'Table 1 Fallacy' refers to the unsound use of significance testing for comparing the distributions of baseline variables between randomised groups to draw erroneous conclusions about balance or imbalance. We performed a cross-sectional study of the Table 1 Fallacy in phase III oncology trials. METHODS: From ClinicalTrials.gov, 1877 randomised trials were screened. Multivariable logistic regressions evaluated predictors of the Table 1 Fallacy. RESULTS: A total of 765 randomised controlled trials involving 553,405 patients were analysed. The Table 1 Fallacy was observed in 25% of trials (188 of 765), with 3% of comparisons deemed significant (59 of 2353), approximating the typical 5% type I error assertion probability. Application of trial-level multiplicity corrections reduced the rate of significant findings to 0.3% (six of 2345 tests). Factors associated with lower odds of the Table 1 Fallacy included industry sponsorship (adjusted odds ratio [aOR] 0.29, 95% confidence interval [CI] 0.18-0.47; multiplicity-corrected P < 0.0001), larger trial size (≥795 versus <280 patients; aOR 0.32, 95% CI 0.19-0.53; multiplicity-corrected P = 0.0008), and publication in a European versus American journal (aOR 0.06, 95% CI 0.03-0.13; multiplicity-corrected P < 0.0001). CONCLUSIONS: This study highlights the persistence of the Table 1 Fallacy in contemporary oncology randomised controlled trials, with one of every four trials testing for baseline differences after randomisation. Significance testing is a suboptimal method for identifying unsound randomisation procedures and may encourage misleading inferences. Journal-level enforcement is a possible strategy to help mitigate this fallacy.

Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer: The EXTEND Phase 2 Randomized Clinical Trial.

Importance: Despite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial. Objective: To determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone. Design, Setting, Participants: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022. Interventions: Patients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression. Main Outcomes and Measures: The primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing. Results: The study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P < .001). Eugonadal PFS was also improved with MDT (median not reached) compared with the hormone therapy only (6.1 months; 95% CI, 3.7 months to not estimable) (hazard ratio, 0.32; 95% CI, 0.11-0.91; P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm. Conclusions and Relevance: In this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals. Trial Registration: ClinicalTrials.gov Identifier: NCT03599765.

Comparative Analysis of Recidivism After Endoscopic and Microscopic-Based Cholesteatoma Resection.

OBJECTIVES: 1) To analyze outcomes of cholesteatoma resection utilizing postauricular microscopic and endoscopic ear surgery (EES) approaches.2) To analyze predictors of residual and recurrent cholesteatoma. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: Three hundred seventy-five adult and pediatric patients with cholesteatoma (2012-2017). INTERVENTIONS: Patients underwent surgical resection of cholesteatoma with EES (n = 122) and microscopic (n = 253) approach. MAIN OUTCOME MEASURES: Residual cholesteatoma, recurrent cholesteatoma, second-look procedures. RESULTS: The endoscopic cohort included significantly more pediatric cases (p = 0.0008). There was no difference in laterality, gender distribution, congenital or acquired cholesteatoma, and revision cases between the cohorts. Out of 122 EES cases, 16 (13%) developed residual disease and 9 (7%) developed recurrent disease. Of 253 microscopic cases 16 (6%) developed residual disease while 11 (4%) developed recurrent disease. Second look procedures were more commonly used in EES cohort (50 vs 18%). Single predictor analysis revealed 12 predictors for residual disease and 5 for recurrent disease. Multivariable model identified pediatric case distribution and higher disease stage to be significant predictors for both residual (p = 0.04, 0.007) and recurrent disease (p = 0.02, 0.01). EES approach was associated with a weak significance for residual disease (p = 0.049) but not recurrent disease (p = 0.34). CONCLUSIONS: EES approach for cholesteatoma resection seems to perform similarly to microscopic approach with no difference in rates of recurrent disease. However, it is associated with a higher rate of residual disease; this may be a reflection of a greater rate of second look procedures done in this group.

Noninvasive Capsulotomy for Refractory Depression by Frameless Stereotactic Radiosurgery.

PURPOSE: Effective treatment options for refractory depression are needed. Recent advancements permit both precise ablative radiation and functional neurologic connectome analysis using standard magnetic resonance imaging. We combined these innovations to perform stereotactic radiosurgical capsulotomy for the treatment of medically refractory major depressive disorder and study connectome response using a novel tractography-based approach. METHODS AND MATERIALS: Patients with medically refractory depression were enrolled on a prospective pilot single-arm observational trial from 2020 to 2021 at a single academic tertiary referral center. Bilateral ablation of the anterior limb of the internal capsule was accomplished by mask-based linear accelerator stereotactic radiosurgery. Beck's Depression Inventory measured efficacy. Montreal Cognitive Assessment evaluated cognition. RESULTS: Three patients were enrolled. Depression burden was improved by 88% at 12-month follow-up and by 55% at 18-month follow-up for patient 1 and 2, respectively. Patient 1 discontinued ketamine therapy, and patient 2 discontinued electroconvulsive therapy. Patient 3 reported global improvement in symptoms and function at 3 months. All 3 patients had reduction or resolution of suicidal ideation. No patient experienced cognitive decline or neurologic toxicity, and Montreal Cognitive Assessment score, as well as subjective patient-reported evaluations of concentration and attention, were superior after treatment. Tractography confirmed intended disruption of the cortico-striatal-thalamo-cortical loop with structural reorganization in the connectome. Connectome change was consistent between patients. Observed increases in caudate and putamen connectivity and decreases in thalamic connectivity may explain improved concentration, attention, and depression. The diversity and magnitude of connectome change may correlate with degree of clinical response. CONCLUSIONS: In 3 patients with refractory depression, radiosurgical capsulotomy significantly reduced the burden of depression. Functional connectome reorganization offers neurobiological evidence to support further investigations of the role of radiosurgery in depression.

Noninvasive Thalamotomy for Refractory Tremor by Frameless Radiosurgery.

PURPOSE: We sought to determine whether a more widely accessible, noninvasive, frameless approach to radiosurgical thalamotomy would improve objective measures of refractory essential or parkinsonian tremor without added toxicity compared with reports of frame-based radiosurgery. METHODS AND MATERIALS: We conducted a single-arm pilot observational prospective trial of adult patients with essential or parkinsonian tremor from 2013 to 2019 and report results at 1-year follow-up. Patients were treated with frameless unilateral radiosurgical ablation of the thalamic ventral intermediate nucleus to a maximum dose of 160 Gy. Treatment response was measured by the Fahn-Tolosa-Marin (FTM) tremor rating scale and the Quality of Life in Essential Tremor or Parkinson's Disease Questionnaire obtained before treatment and at 3, 6, 9, and 12 months. RESULTS: Thirty-three patients, including 23 with essential tremor and 10 with Parkinson's disease, were enrolled. Overall treatment response rate per FTM was 83% (15 of 18) at 6 months. There was a marked improvement in tremor, with an average total FTM reduction of 21% at 3 months (from 46 to 30 points; P = .003) and 41% at 6 months (from 46 to 24 points; P = .001). At 6 months, functional decline had regressed by 54% (from 15 to 7 points; P = .001). Quality of life improved by 57% (P = .001) at 6 months in patients with essential tremor, and patients with Parkinson's disease had unchanged quality of life. At 1-year follow-up, grade 2 neurologic adverse events were observed in 6% (2 of 33) of patients without any grade ≥ 3 events. CONCLUSION: Noninvasive, frameless radiosurgical thalamotomy may be a feasible treatment for patients with refractory tremor and demonstrates short-term safety at 1-year follow-up. This pilot study provides promising preliminary descriptions of efficacy, and definitive estimates of long-term safety and benefit require further study with longer follow-up.

Definitive Local Consolidative Therapy for Oligometastatic Solid Tumors: Results From the Lead-in Phase of the Randomized Basket Trial EXTEND.

PURPOSE: The benefit of local consolidative therapy (LCT) for oligometastasis across histologies remains uncertain. EXTernal beam radiation to Eliminate Nominal metastatic Disease (EXTEND; NCT03599765) is a randomized phase 2 basket trial evaluating the effectiveness of LCT for oligometastatic solid tumors. We report here the prospective results of the single-arm "lead-in" phase intended to identify histologies most likely to accrue to histology-specific endpoints in the randomized phase. METHODS AND MATERIALS: Eligible histologies included colorectal, sarcoma, lung, head and neck, ovarian, renal, melanoma, pancreatic, prostate, cervix/uterine, breast, and hepatobiliary. Patients received LCT to all sites of active metastatic disease and primary/regional disease (as applicable) plus standard-of-care systemic therapy or observation. The primary endpoint in EXTEND was progression-free survival (PFS), and the primary endpoint of the lead-phase was histology-specific accrual feasibility. Adverse events were graded by Common Terminology Criteria for Adverse Events version 4.0. RESULTS: From August 2018 through January 2019, 50 patients were enrolled and 49 received definitive LCT. Prostate, breast, and kidney were the highest enrolling histologies and identified for independent accrual in the randomization phase. Most patients (73%) had 1 or 2 metastases, most often in lung or bone (79%), and received ablative radiation (62%). Median follow-up for censored patients was 38 months (range, 16-42 months). Median PFS was 13 months (95% confidence interval, 9-24), 3-year overall survival rate was 73% (95% confidence interval, 57%-83%), and local control rate was 98% (93 of 95 tumors). Two patients (4%) had Common Terminology Criteria for Adverse Events grade 3 toxic effects related to LCT; no patient had grade 4 or 5 toxic effects. CONCLUSIONS: The prospective lead-in phase of the EXTEND basket trial demonstrated feasible accrual, encouraging PFS, and low rates of severe toxic effects at mature follow-up. The randomized phase is ongoing with histology-based baskets that will provide histology-specific evidence for LCT in oligometastatic disease.

Predictors of Recurrence After Sub-total or Near-total Resection of Vestibular Schwannoma: Importance of Tumor Volume and Ventral Extension.

OBJECTIVE: To evaluate the predictors of remnant tumor regrowth and need for salvage therapy after less than gross total resection (GTR) of vestibular schwannoma (VS). STUDY DESIGN: Retrospective chart review. SETTING: Tertiary neurotologic referral center. PATIENTS: Patients who underwent VS resection between 2008 and 2019 either with GTR, near total resection (NTR), and subtotal resection (STR). INTERVENTIONS: Microsurgical resection, salvage radiosurgery. MAIN OUTCOME MEASURES: Regrowth free interval, salvage free interval, tumor doubling rate. RESULTS: Three hundred eighty five cases (GTR = 236, NTR = 77, and STR = 71) from 2008 to 2019 were included. STR cohort had much larger and complex tumors with significant differences in tumor volume, ventral extension and brainstem compression (p  < 0.001). On single predictor analysis, tumor volume, ventral extension, brainstem compression as well as STR strategy was associated with significant increased risk of regrowth and need for salvage therapy. Multivariate analysis revealed STR strategy as significant predictor of regrowth (hazard ratio 3.79, p  < 0.0005). Absolute remnant volume and extent of resection (EOR) did not predict regrowth. A small proportion of cases (NTR = 4%, STR = 15%) eventually needed salvage radiosurgery with excellent ultimate local tumor control with no known recurrence to date. CONCLUSIONS: Conservative surgical strategy employing NTR or STR can be employed safely in large and complex VS. While there is increased risk of regrowth in the STR cohort, excellent local control can be achieved with appropriate use of salvage radiosurgery. No disceret radiologic or operative predictors of regrowth were identified.

The birth, decline, and contemporary re-emergence of endovascular brachytherapy for prevention of in-stent restenosis.

Despite the advent of drug-eluting stents and dual antiplatelet therapy in the interventional management of cardiovascular disease, restenosis rates remain high with significant sequelae. Endovascular brachytherapy-popular in the 1990s and early 2000s-has recently resurfaced as a cost-effective treatment option. In this work, we outline the history of endovascular brachytherapy starting with its earliest promise in the 1990s. We discuss the development of drug-eluting stents and dual antiplatelet strategies and their impact on the perceived benefit of endovascular brachytherapy. For the contemporary era, we propose novel roles for endovascular brachytherapy in complex coronary artery disease and in high-risk patients managed with drug-eluting stents. We discuss the impetus for reducing the requirement and duration of dual antiplatelet therapy using endovascular brachytherapy. We also review innovative opportunities for endovascular brachytherapy after bare-metal stent placement in both coronary and noncoronary territories and offer economic arguments in favor of endovascular brachytherapy. Trials of endovascular brachytherapy in these regimes are merited.

Transient Subacute Facial Nerve Dysfunction After Dual Modality Treatment of Large Vestibular Schwannomas.

OBJECTIVES: 1: Describe subacute facial nerve paralysis after salvage stereotactic radiosurgery (SRS). 2: To analyze predictors of facial nerve weakness after dual modality treatment. PATIENTS: Adult patients with Vestibular Schwannoma who underwent sub-total resection (STR) followed by salvage radiation. INTERVENTIONS: Microsurgical resection of VS, stereotactic radiosurgery, intensity-modulated radiotherapy, proton radiotherapy. MAIN OUTCOME MEASURES: Serial facial nerve function (House-Brackmann scale). RESULTS: Thirteen patients who underwent dual modality treatment for large VS were included (mean age = 43.6 years, 77% females). The mean pre-operative tumor volume was 11.7 cm3 (SD = 6.5) and the immediate mean post-operative remnant volume was 1.5 cm3 (SD = 1.4) with a mean extent of resection of 86.7% (SD = 9.5). The mean salvage-free interval was 20.8 months (SD = 13.3). All patients had excellent one-year FN outcome (HB grade 1, 2) after resection. Three patients developed subacute facial nerve weakness after salvage SRS (4.2-9.4 months after SRS). This paralysis responded to high dose systemic steroids and no surgical interventions for facial rehabilitation were required. At last follow up (mean 61.6 months, SD = 28.5), facial nerve function was favorable (HB grade 1-2 in 12 patients and HB grade 3 in 1 patient). There were no significant associations between various predictors and subacute deterioration of facial nerve function after SRS. CONCLUSIONS: Sub-acute transient facial nerve dysfunction can develop infrequently over a variable time frame after post-operative salvage SRS and usually responds to steroids. Patients should be adequately counseled about potential of transient deterioration of facial nerve function after salvage SRS.