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Purpose Quality assurance (QA) practices improve the quality level of oncology trials by ensuring that the protocol is followed and the results are valid and reproducible. This study investigated the utilization of QA among randomized controlled trials that involve radiotherapy (RT). Methods and Materials We searched ClinicalTrials.gov in February 2020 for all phase III oncology randomized clinical trials (RCTs). These trials were screened for RT-specific RCTs that had published primary trial results. Information regarding QA in each trial was collected from the study publications and trial protocol if available. Two individuals independently performed trial screening and data collection. Pearson’s Chi-square tests analyses were used to assess factors that were associated with QA inclusion in RT trials. Results Forty-two RCTs with RT as the primary intervention or as a mandatory component of the protocol were analyzed; the earliest was started in 1994 and one trial was still active though not recruiting. Twenty-nine (69%) trials mandated RT quality assurance (RTQA) practices as part of the trial protocol, with 19 (45%) trials requiring institutional credentialing. Twenty-one (50%) trials published protocol deviation outcomes. Clinical trials involving advanced radiation techniques (IMRT, VMAT, SRS, SBRT) did not include more RTQA than trials without these advanced techniques (73% vs. 65%, p=0.55). Trials that reported protocol deviation outcomes were associated with mandating RTQA in their protocols as compared to trials that did not report these outcomes (100% vs. 38%, p Conclusions There is a lack of RTQA utilization and transparency in RT clinical trials. It is imperative for RT trials to include increased QA for safe, consistent, and high-quality RT planning and delivery.

Pediatric central nervous system (CNS) tumors are the leading cause of pediatric cancer mortality. Research addressing genomic biomarkers and clinical outcomes is needed to inform therapeutic decision-making.We conducted a retrospective analysis of pediatric patients (age21) diagnosed with a primary CNS tumor at four upstate New York hospitals from 2008 to 2021. Clinical and histopathologic data were identified from each patient, including genomic analysis of somatic mutations and tumor mutational burden (TMB) where available. These variables were each compared with overall survival using Cox regression analyses. Multivariable analysis was conducted to identify patient characteristics that may independently predict survival.We identified 119 patients. Common tumor types included low-grade glioma (N = 51), high-grade glioma (N = 29), and medulloblastoma (N = 11). Common driver mutations included TP53 inactivation (N = 16), BRAF-KIAA1549 fusion (N = 16), FGFR1 amplification (N = 12), BRAF V600E mutation (N = 12), NF1 loss (N = 12), and H3F3A K28M mutation (N = 6). Median TMB was one mutation/megabase (mut/Mb, range = 0-132). Overall survival was 79.9%. Variables associated with poorer survival on univariable analysis were higher TMB (p = .002, HR 4.97), high-grade tumors (p = .009, HR 84.3), and high-grade glioma histology (p = .021, HR 3.14). Multivariable analyses further identified TMB (p = .011, HR 4.46) and high-grade histology (p = .015, HR 5.28) as independently predictive of worse survival. Tumor progression was more common in high-TMB (N = 15, 44%) than in low-TMB tumors (N = 19, 35%).High TMB is correlated with higher rates of progression and death as compared to low-TMB tumors. These findings may help identify patients who may benefit from alternative treatments, such as immunotherapies.

To report early findings from a phase II trial of high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer.Eligible patients had metastatic disease that progressed on immunotherapy within 6 months. Patients were given either HD-RT (20-70 Gy total; 3-12.5 Gy/f), or HD-RT + LD-RT (0.5-2 Gy/f up to 1-10 Gy total) to separate lesions, with continued immunotherapy. Radiographic response was assessed per RECIST 1.1 and Immune-Related Response Criteria (irRC). Primary endpoints: (1) 4-month disease control (DCR, complete/partial response [CR/PR] or stable disease [SD]) or an overall response (ORR, CR/PR) at any point in ≥10% of patients, per RECIST 1.1; (2) dose-limiting toxicity within 3 months not exceeding 30%. Secondary endpoint was lesion-specific response.Seventy-four patients (NSCLC, n = 38; melanoma n = 21) were analyzed (39 HD-RT and 35 HD-RT + LD-RT). The median follow-up time was 13.6 months. The primary endpoint was met for 72 evaluable patients, with a 4-month DCR of 42% (47% [16/34] vs. 37% [14/38] in HD-RT + LD-RT vs. HD-RT, P = 0.38), and 19% ORR at any time (26% [9/34] vs. 13% [5/38] in HD-RT + LD-RT vs. HD-RT, P = 0.27). Three patients had toxicity ≥grade 3. LD-RT lesion response (53%) was improved compared to nonirradiated lesions in HD-RT + LD-RT (23%, P = 0.002) and HD-RT (11%, P 0.001). T- and NK cell infiltration was enhanced in lesions treated with LD-RT.HD-RT plus LD-RT safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.

Purpose: Journal impact factor (IF) is often used to measure research quality and importance. We assessed trial factors associated with the publication of cancer trials in journals with higher IF and publications receiving higher citations. Materials and Methods: Cancer-specific phase III RCTs were screened through https://clinicaltrials.gov. We identified trials with published primary endpoints, along with their corresponding journal IF and relative citation ratio (RCR). Results: Seven-hundred ninety manuscripts were included in our study. Trials that met their primary endpoint were more commonly published in journals with higher IF (Median IF: positive trials 35.4 vs. negative trials 26.3, P < 0.001). Furthermore, trials that led to subsequent FDA drug approvals were also published in journals with higher IF (Median IF: 59.1 vs. 26.3 in trials not leading to FDA approvals, P < 0.001). When analyzing RCR, trial positivity (meeting primary endpoint) was not associated with increased citations on multivariable analysis (P = 0.56). Lastly, publications of trials leading to FDA approvals (P < 0.001), and publications of trials in journals with higher IF (P < 0.001) were associated with increased RCR. Conclusions: Positive trials are commonly published in journals with high IF, but do not necessarily lead to increased citations. Moreover, trials published in journals with higher IF are more likely to receive increased citations.

ImportancePrimary end point (PEP) changes to an active clinical trial raise questions regarding trial quality and the risk of outcome reporting bias. It is unknown how the frequency and transparency of the reported changes depend on reporting method and whether the PEP changes are associated with trial positivity (ie, the trial met the prespecified statistical threshold for PEP positivity).ObjectivesTo assess the frequency of reported PEP changes in oncology randomized clinical trials (RCTs) and whether these changes are associated with trial positivity.Design, Setting, and ParticipantsThis cross-sectional study used publicly available data for complete oncology phase 3 RCTs registered in ClinicalTrials.gov from inception through February 2020.Main Outcomes and MeasuresThe main outcome was change between the initial PEP and the final reported PEP, assessed using 3 methods: (1) history of tracked changes on ClinicalTrials.gov, (2) self-reported changes noted in the article, and (3) changes reported within the protocol, including all available protocol documents. Logistic regression analyses were performed to evaluate whether PEP changes were associated with US Food and Drug Administration approval or trial positivity.ResultsOf 755 included trials, 145 (19.2%) had PEP changes found by at least 1 of the 3 detection methods. Of the 145 trials with PEP changes, 102 (70.3%) did not have PEP changes disclosed within the manuscript. There was significant variability in rates of PEP detection by each method (χ2 = 72.1; P χ2 = 18.7; P P = .003).Conclusions and RelevanceThis cross-sectional study revealed substantial rates of PEP changes among active RCTs; PEP changes were markedly underreported in published articles and mostly occurred after reported study completion dates. Significant discrepancies in the rate of detected PEP changes call into question the role of increased protocol transparency and completeness in identifying key changes occurring in active trials.

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

Phase 3 clinical trials are widely recognized as the highest level of evidence to support a particular intervention/therapy in the medical literature. The ability to draw clinically meaningful conc...

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

Findings Overall, 148 patients were included in the pooled analysis, 76 of whom had been assigned pembrolizumab and 72 who had been assigned pembrolizumab plus radiotherapy. Median follow-up for all patients was 33 months (IQR 32?4?33?6). 124 (84%) of 148 patients had non-squamous histological features and 111 (75%) had previously received chemotherapy. Baseline variables did not differ between treatment groups, including PD-L1 status and metastatic disease volume. The most frequently irradiated sites were lung metastases (28 of 72 [39%]), intrathoracic lymph nodes (15 of 72 [21%]), and lung primary disease (12 of 72 [17%]). Best ARR was 19?7% (15 of 76) with pembrolizumab versus 41?7% (30 of 72) with pembrolizumab plus radiotherapy (odds ratio [OR] 2?96, 95% CI 1?42?6?20; p=0?0039), and best ACR was 43?4% (33 of 76) with pembrolizumab versus 65?3% (47 of 72) with pembrolizumab plus radiotherapy (2?51, 1?28?4?91; p=0?0071). Median progression-free survival was 4?4 months (IQR 2?9?5?9) with pembrolizumab alone versus 9?0 months (6?8?11?2) with pembrolizumab plus radiotherapy (hazard ratio [HR] 0?67, 95% CI 0?45?0?99; p=0?045), and median overall survival was 8?7 months (6?4?11?0) with pembrolizumab versus 19?2 months (14?6?23?8) with pembrolizumab plus radiotherapy (0?67, 0?54?0?84; p=0?0004).Methods Inclusion criteria for the PEMBRO-RT and MDACC trials were patients (aged ?18 years) with metastatic nonsmall-cell lung cancer and at least one unirradiated lesion to monitor for out-of-field response. In the PEMBRO-RT trial, patients had previously received chemotherapy, whereas in the MDACC trial, patients could be either previously treated or newly diagnosed. Patients in both trials were immunotherapy-naive. In the PEMBRO-RT trial, patients were randomly assigned (1:1) and stratified by smoking status (

A 73-year-old woman with metastatic vaginal mucosal melanoma that had progressed on ipilimumab and nivolumab experienced clinical and radiographic complete response to dual checkpoint inhibitor immunotherapy given in combination with high-dose plus low-dose radiation. General characteristics and treatment options in this disease are highlighted.

Radiation therapy (RT) is emerging as an interventional modality in the cancer-immunity cycle, augmenting the activation of an adaptive immune response against tumors. RT, particularly in combination with immunotherapy, can enhance immune memory effects and shape the tumor-directed T-cell populations. However, a single cycle of RT delivered to a limited number of polymetastatic lesions is rarely sufficient to achieve systemic control. We hypothesize that several rounds of RT, akin to several rounds of immunotherapeutic drugs, is likely to provide greater clinical benefit to patients with metastatic disease. We propose that the repeated exposure to tumor antigens released by ""pulsed-RT"" (i.e., treating 2-4 tumor lesions with 3 irradiation cycles given one month apart) may amplify the adaptive immune response by expanding the tumor-specific T-cell receptor repertoire, the production of high-affinity tumor antibodies, and the generation of memory lymphocytes and thereby improve immune control of systemic disease., National Cancer Institute; National Institutes of Health; Cancer Center Support (Core) Grant

Highlights • High-dose RT upregulated pDCs within the tumor microenvironment. • The administration of intratumoral TLR9 agonist (CMP-001) after stereotactic RT significantly enhanced the anti-tumor immune response both locally and at secondary tumor site. • CMP-001 Post-RT delayed the abscopal tumor growth and extended the survival rate via increasing the percentages of activated CD4+ and CD8+ T-cells within the tumor microenvironment. • The treatment proved efficacious in both lung adenocarcinoma and colon carcinoma syngeneic models used., Radiotherapy (RT) has been used to control tumors by physically damaging DNA and inducing apoptosis; it also promotes antitumor immune responses via neoantigens release and augmenting immune-oncology agents to elicit systemic response. Tumor regression after RT can recruit inflammatory cells, such as tumor-associated macrophages and CD11b+ myeloid cell populations, a major subset of which may actually be immunosuppressive. However, these inflammatory cells also express Toll-like receptors (TLRs) that can be stimulated to reverse suppressive characteristics and promote systemic antitumor outcomes. Here, we investigated the effects of adding CMP-001, a CpG-A oligodeoxynucleotide TLR9 agonist delivered in a virus-like particle (VLP), to RT in two murine models (344SQ metastatic lung adenocarcinoma and CT26 colon carcinoma). High-dose RT (12Gy x 3 fractions) significantly increased the percentages of plasmacytoid dendritic cells within the tumor islets 3- and 5-days post-RT; adding CMP-001 after RT also enhanced adaptive immunity by increasing the proportion of CD4+ and CD8+ T cells. RT plus CMP-001-mediated activation of the immune system led to significant inhibition of tumor growth at both primary and abscopal tumor sites, thereby suggesting a new combinatorial treatment strategy for systemic disease., Graphical Abstract Image, graphical abstract

Introduction Few advancements in treating limited-stage SCLC (LS-SCLC) have been made in decades. We report here a phase 1/2 trial of concurrent chemoradiotherapy (CRT) and pembrolizumab. Methods This single-center, open-label phase 1/2 study recruited adults with LS-SCLC or other neuroendocrine tumors and good performance status (Eastern Cooperative Oncology Group ≤ 2). The primary end point was safety, as assessed by dose-limiting toxicities. Concurrent CRT consisted of etoposide and a platin with 45 Gy radiotherapy (30 twice daily). Prophylactic cranial irradiation (25 Gy, 10 fractions) was given at the physician’s discretion. Pembrolizumab was started concurrently with CRT and continued for up to 16 cycles. The phase 1 portion consisted of a 3 + 3 design. Toxicity was assessed with Common Terminology Criteria for Adverse Events version 4.0. Secondary outcomes were progression-free survival, overall survival, and tumor response as measured by the immune-related response criteria. Results A total of 45 patients were screened, and 40 were enrolled. All completed radiation therapy and received greater than or equal to one cycle of pembrolizumab. A total of 27 (61%) received percutaneous coronary intervention. One dose-limiting toxicity was observed in the phase 1 portion. There were no grade 5 toxicities, but there were three grade 4 events (two neutropenia, one respiratory failure). Pneumonitis rate was 15% (three grade 2 and three grade 3). All 17 esophagitis events (42.5%) were grades 1 to 2. At median follow-up time of 23.1 months, the median progression-free survival time was 19.7 months (95% confidence interval: 8.8‒30.5) and the median overall survival time was 39.5 months (95% confidence interval: 8.0‒71.0). Conclusion Concurrent CRT and pembrolizumab for LS-SCLC was well tolerated and yielded favorable outcomes, providing a basis for randomized studies.

Aim: To explore management trends in preinvasive and cT1–T3 penile cancer. Materials & methods: The National Cancer Database was queried (2004–2013) for cT1–T3 M0 penile cancer with specified nonpalliative surgical techniques and histologies (n = 5,728). Results: Local excision (39%) and partial penectomy (38%) were most commonly utilized. Patients with cTis/Ta or cT1 disease more often received nonpenectomy approaches (p < 0.05); cT2–T3 cases more likely underwent penectomy (p < 0.001). No survival differences were observed between penectomy (49.3 months) and nonpenectomy approaches (50.3 months) in the overall cohort (p = 0.107) and when stratifying by T-stage (p > 0.20 for all). Conclusion: This study provides contemporary insight into the landscape for management of this rare disease and can serve as a benchmark for future evaluation of treatment trends.

Aims: To analyze outcomes in primary anorectal melanoma, a rare disease with limited data and treatment guidelines. Materials & methods: We analyzed 305 subjects in the National Cancer Database from 2004 to 2015. The primary end point was overall survival (OS). Results: Surgery was predictive of OS (median 2.24 vs 1.18 years; p = 0.009) with no survival difference between local and transabdominal approaches (p = 0.77). No OS benefit was seen with chemotherapy (p = 0.16), radiotherapy (p = 0.31) or adjuvant therapy post surgery (p > 0.05 for all groups). Targeted therapy trended toward higher survival in metastatic patients (1.33 vs 0.55 years; p = 0.06). Conclusion: In nonmetastatic patients, surgery of any method is associated with a survival benefit. The trend for improved survival following targeted therapy in metastatic patients merits further exploration.

BACKGROUND Tumor mutational burden (TMB) and driver mutations are potential biomarkers to guide targeted therapy selection. Malignant gliomas with high TMB in children may preferentially benefit from treatment with immune checkpoint inhibitors (ICPIs). Higher TMB may relate to lower incidence of driver mutations, but this relationship has not been studied in pediatric brain tumors. PROCEDURE Comprehensive genomic profiling was performed on 723 pediatric (≤21 years) brain tumor samples using DNA extracted from formalin-fixed paraffin-embedded tissue. TMB was calculated as mutations per megabase and categorized as low (0-6), intermediate (6-20), or high (>20). Analysis included 80 clinically relevant driver mutations; genomic alterations known to confer a selective growth advantage. RESULTS Of 723 brain tumors, TMB was low in 91.8%, intermediate in 6.1%, and high in 2.1%. In the high TMB cohort, 93% of tumors harbored a driver mutation; 70% and 63% in the intermediate and low TMB cohorts, respectively (P

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

Purpose This review explores the use of intensity modulated radiation therapy (IMRT) after lung-sparing surgery in malignant pleural mesothelioma (MPM). Because severe toxicities have been documented after radiation therapy for MPM, its use remains controversial, especially as modern surgical management has shifted toward lung-sparing pleurectomy/decortication. IMRT is an advanced technique that may allow for safer radiation therapy delivery, but there remains limited data (including no summative data) to support this notion. Methods and Materials We performed a systematic review evaluating the safety and efficacy of post-pleurectomy IMRT (P-IMRT). A systematic review of PubMed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted for publications of all dates that specifically reported clinical outcomes and/or toxicities of P-IMRT in patients with MPM. Ten original studies were included in this review. Results The incidence of grade 3 pneumonitis ranged from 0% to 16%, with all but 2 studies reporting rates below 9%. Grade 4 and 5 pneumonitis were observed in less than 1.5% of cases, except in one publication that used hypofractionated radiation therapy to doses >60 Gy. Crude local failure rates ranged from 19% to 60%, median progression free survival ranged from 12 to 16 months, and median overall survival ranged from 19 to 28 months. Conclusions P-IMRT produces relatively few higher-grade toxicities and has reasonable disease-related outcomes, especially when delivered using conventionally fractionated regimens to doses of 45 to 54 Gy and exercising careful attention to dose constraints during treatment planning. IMRT can thus be considered in well-selected patients in whom adequate survival after pleurectomy is expected. These data also support the initiation of the phase III NRG-LU006 trial of extended pleurectomy/decortication and chemotherapy with or without IMRT.

PURPOSE/OBJECTIVE(S) To report updated findings from a prospective phase II trial of salvage high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer (NCT02710253). MATERIALS/METHODS Eligible patients had metastatic disease that progressed on immunotherapy within the prior 6 months. Patients were given either HD-RT (20-70Gy total; 3-12.5Gy/fraction), or HD-RT and LD-RT to separate lesions (LD-RT comprised of < 2Gy/fraction up to 10Gy total), with continued immunotherapy. Radiographic response was assessed per RECIST1.1 and Immune-Related Response Criteria (irRC). Primary endpoints were 1) 4-month disease control (complete/partial response [CR/PR] or stable disease [SD]) or an overall response (CR/PR) at any point in ≥10% of patients, and 2) dose-limiting toxicity within 3 months not exceeding 30%. Also, where applicable, biopsies pre- and post- low-dose RT were collected, FFPE slides were prepared and analyzed by Multiplex Immunofluorescence (Multi-IF) microscopy for immune-cell infiltration. RESULTS Seventy-four patients were analyzed (39 in HD-RT group and 35 in HD-RT+LD-RT group), mostly with non-small cell lung cancer (n = 38) or melanoma (n = 21). Patients received immunotherapy for a median of 7.1 months (3.7-10.6 months) before RT, and 95% maintained the same therapy after RT. The median follow-up time was 13.8 months. The site most commonly treated with HD- or LD-RT was lung/mediastinum. The primary endpoint was met for the 72 evaluable patients, with a 4-month overall disease control rate of 42% (RECIST1.1, 47% [16/34] for the HD-RT+LD-RT group and 37% [14/38] for the HD-RT only group). Three (4.2%) patients experienced grade ≥3 toxicity. LD-RT treated lesion response rates (irRC, 53%) was improved compared to nonirradiated lesions in the HD-RT+LD-RT (23%, P = 0.002) and HD-RT only (11%, P < 0.001) group. The median PFS was 7.0 months vs. 5.8 months, while median OS was 15.9 months vs. 10.5 months for the HD-RT+LD-RT group vs. HD-RT only group respectively; however, statistical significance was not reached. Furthermore, the addition of LD-RT did not significantly affect the absolute lymphocyte counts (ALC), with ALC reduction after treatment recorded as 420/μL vs. 340/μL in the HD-RT only vs. HD-RT+LD-RT groups (P = 0.44). The Multi-IF data for 3 analyzed biopsies of LD-RT lesions showed strong correlation between T cell and NK cell infiltration and clinical response rate. Lesion 1 for example (24% SD), had CD56+ NK cell numbers increase from 67 to 1837 n/mm2 post LD-RT. Lesion 2 (-80% PR) had its CD3+CD4+ T cells increase from 287 to 1233 n/mm2 and NK cells increase from 0 to 187 n/mm2; while lesion 3 (-8% SD) showed an increase from 79 to 131 n/mm2 and 3.6 to 7.3 n/mm2 in the T cell and NK cell compartments respectively. CONCLUSION Low-dose RT is an effective and safe way to enhance individual lesion-specific response rates among progressing patients with solid tumors, with the ability to improve the infiltration of effector immune cells into the tumor microenvironment.

Tumor mutational burden (TMB) has been studied across numerous cancer types as a means of risk stratification. To examine the prognostic relevance of TMB to pediatric central nervous system (CNS) tumors, we conducted a retrospective analysis of patients at Albany Medical Center diagnosed from 2012 to present. Patients were

e18826 Background: New cancer treatments have the potential to cause economic stress at the personal and societal level. Little is known on the evaluation of financial outcomes in clinical trials. We hypothesized that randomized controlled trials (RCTs) are unlikely to have pre-planned analyses to look at economic outcomes that address financial toxicity to patients and cost-effectiveness to society. Methods: Interventional therapeutic-intent phase 3 cancer-specific RCTs were identified through ClinicalTrials.gov. Pre-planned economic outcomes addressing financial toxicity or cost-effectiveness were identified. Results: We identified 1,069 interventional phase 3 oncology RCTs. Overall, 101 (9.4%) had pre-planned to evaluate quality of life using the European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire (EORTC QLQ-C30) instrument, of which a single question (Q28) relates to financial toxicity. However, only ten (0.94%) trials included pre-planned financial/economic endpoints; all were secondary endpoints. Among those planning to evaluate economic outcomes, 6/10 planned to collect data and report on financial distress using Q28 on EORTC QLQ-C30 and 3/10 pre-planned performing cost-effectiveness analyses. One study planned to perform an economic evaluation, including health utilities, as measured by the EuroQol-Five Dimension (EQ-5D) Questionnaire. All ten trials were industry–sponsored, and two were co-sponsored by a National Cancer Institute (NCI) cooperative group. The majority (8/10) were superiority-designed trials, and 6/10 included progression-free survival as the primary endpoint. The majority (6/10) assessed targeted therapy as the primary intervention. Multinational enrollment was predominant (8/10). Of the 10 trials, nine had a published manuscript. One was closed because of accrual issues. Among the six trials that had pre-specified reporting on financial distress, two published on financial toxicity. Of the two trials that had a priori planned to do a cost-effective analysis, one was published. However, overall 3/9 had published a cost-effective analysis. Conclusions: Less than one percent of oncology RCTs have pre-specified plans to evaluate economic outcomes associated with personal financial distress or cost-effectiveness. For the trials that had pre-planned reporting on financial toxicity, the instrument used to evaluate financial toxicity is a single question which has not been validated as a standalone assessment. Cost-effectiveness analyses were more likely to be published than on financial toxicity and were often completed as a post-hoc analysis. Given that many newly investigated therapies increase the financial burden on patients and add cost to the healthcare system more broadly, pre-planned evaluation of economic outcomes in RCTs is imperative in order to create a value-based framework in assessing new therapies.

Context Advanced gynecologic malignancies can cause significant vaginal bleeding. Radiotherapy (RT) is often used to palliate symptoms, but limited data exist concerning the optimal dose and expected time to bleeding hemostasis in this population. Objectives 1) To investigate the overall hemostasis response and kinetics of hemostasis in women with gynecologic malignancies receiving palliative RT. 2) To compare the efficacy of short-course RT (SCRT, less than or equal to five fractions, >3.5 Gy per fraction) vs. conventionally fractionated long-course regimens (greater than five fractions). Methods We identified women receiving palliative RT for bleeding gynecologic malignancies. Initial and maximal hemostasis responses (IHR and MHR) were recorded and categorized as progressive bleeding (PD), stable disease (SD), partial response (PR), or complete response (CR). Clinical variables were correlated with response or toxicity using binary logistic regression statistical methods. Results Thirty-three women (median age 63) were identified between 2010 and 2019. Median follow-up and survival after RT were 131 days. About 54.5% (18 of 33) received SCRT. Median time to IHR was five days (two-and-a-half days with SCRT) and 78.8% (26 of 33) responded during treatment. Median time to MHR was 13 days. About 100% achieved PR or CR at MHR. Rates of CR were similar between SCRT (83%) and conventionally fractionated schedules (87%). Average durability of hemostatic control was 5.4 months. Overall rate of rebleeding and Grade 3+ toxicity was 9.1% (3 of 33 each). Conclusion Women receiving SCRT for bleeding gynecologic malignancies achieved rapid symptom control (often during treatment) with minimal rebleeding. In a population whose median survival is four months, SCRT effectively addresses symptomatic disease while minimizing patient burden and toxicity.

INTRODUCTION We evaluated outcomes of patients with newly diagnosed MBM treated with concurrent immune checkpoint inhibition (ICI) and stereotactic radiosurgery (SRS) (concurrentTx), defined as treatment delivery within 30 days of each other. METHODS Screening of 2,617 melanoma patients who received ICI (anti-CTLA4/anti-PD1/both) between 2011-2019 identified 151 pts who received concurrentTx for MBM. Among these, 51 had newly-diagnosed MBM and received no prior ICI or SRS, and were included in the current study. Overall survival (OS) and distant brain failure (DBF) were estimated using the Kaplan-Meier method. Incidence of radiation necrosis (RN) was captured. RESULTS Median follow up from treatment initiation (either ICI or SRS, whichever occurred first) was 37 months. Median OS was 30 months. Median interval between ICI/SRS was 12 days (range: 1-29). Twenty-two patients received ICI first and 29 received SRS first, without differences in OS (p=0.22), DBF (p=0.91), or development of RN (p=0.86). However, the interval between ICI and SRS was significant. Patients who received concurrentTx 1-11 days apart (n=25, “early”) experienced a significant improvement in OS and DBF compared to 12-29 days apart (n=26, “delayed”) (p=0.01, HR 2.8; 95%CI 1.3-6.2 for OS and p=0.02, HR 2.5; 95%CI 1.2-5.6 for DBF). OS and DBF at 36 months were 67% vs. 26% and 60% vs. 27%, respectively, for the early vs. delayed groups. Time to concurrentTx as a continuous variable was significantly associated with DBF (p=0.02), but not OS (p=0.06). Although not significant, more patients developed RN in the early (26.0%) versus delayed (3.8%) group (p=0.07). No additional patient or treatment differences were identified. CONCLUSIONS Early concurrentTx was associated with prolonged OS and improved DBF in newly diagnosed MBM patients who did not receive prior CNS-directed therapy. This finding suggests therapeutic synergism related to combined early treatment and should be validated in a prospective clinical trial.

2020 Background: Randomized controlled trials (RCTs) in oncology power their studies to detect expected effect sizes. Prior studies have shown that there is optimism bias, the a priori overestimation of treatment effect size among cooperative-group-supported RCTs. However, it is unknown whether such bias is present among industry-supported trials. Methods: All published phase 3 clinical oncology RCTs were identified through ClinicalTrials.gov. Only superiority-design RCTs assessing a therapeutic intervention to improve disease-related outcomes were included. We compared the ratio of observed to expected hazard ratio (OEHRR) between trial subgroups using the Mann-Whitney U-test; comparisons of median OEHRR to a hypothetical median of 1 was performed using the Wilcoxon Signed Rank test. Results: We identified 140 phase 3 trials with available hazard ratio (HR) data. Of these, 123 trials (88%) were industry-sponsored, and 38 trials (27%) were cooperative-group-supported. For all trials, the median OEHRR was 1.099 (IQR = 0.855-1.291), demonstrating evidence of optimism bias when compared to a hypothetical median OEHRR of 1 (p = 0.018). In the subgroup analysis, compared to non-industry-sponsored trials (median OEHRR 1.253, IQR 1.061-1.334), industry-supported trials (median OEHRR 1.061, IQR 0.829-1.274) had a significantly lower OEHRR (p = 0.022) and did not demonstrate optimism bias (p = 0.15). Similarly non-cooperative group trials (median OEHRR 1.208, IQR 1.019-1.317) had a significantly lower OEHRR (p = 0.005) and did not demonstrate optimism bias (p = 0.562) compared to cooperative group trials (median OEHRR 1.208, IQR 1.019-1.317), which did demonstrate optimism bias (p < 0.001). Conclusions: Cooperative group trials, which represent a minority of trials, suffer from optimism bias. In contrast, industry-funded trials, which account for the majority of trials, do not demonstrate evidence of optimism bias, and have very close concordance between observed and expected effect size. These findings suggest that the powering and design of industry-funded trials better models the outcomes eventually observed. The reasons for this are likely complex and multifactorial, but may include financial constraint considerations, as industry-supported trials may not be as financially-limited as cooperative group studies. Therefore, industry-supported studies may be able to power trials with sufficient participants to reflect the estimated effect size.

Numerous trials have been launched over the prior decade examining the safety and efficacy of therapy de-escalation in human papillomavirus (HPV)-associated oropharyngeal cancer (OPC). Because no summative assessment of these prospective trials exists to date, we systematically reviewed the outcomes and toxicities associated with therapy de-intensification for this population. PRISMA-guided systematic PubMed searches (along with articles known to the authors and references thereof) were performed for prospective studies reporting clinical outcomes and/or toxicities of de-intensified RT and/or systemic therapy (with or without surgery), exclusively for HPV-associated OPC. Ten prospective studies were analyzed. Performing a meta-analysis was not entirely possible owing to the heterogeneity of treatment paradigms and the lack of >2 studies for most paradigms; however, because just one paradigm (induction chemotherapy followed by reduced-dose RT and/or systemic therapy) had 4 associated articles, an exploratory meta-analysis was conducted for that subset. Two trials of dose-reduced concurrent chemoradiotherapy (60 Gy/weekly cisplatin) demonstrated 3-year distant metastasis-free survival and overall survival (OS) ranging from 91 to 100% and 95%, respectively; acute grade 3+ mucositis and dysphagia occurred in 33–35% and 21–39%, respectively. In the four trials of induction chemotherapy (platinum/taxane-based) followed by dose-reduced RT, 2-year progression-free and OS ranged from 80 to 95% and 83 to 98%, respectively; acute grade 3+ dysphagia, dermatitis, and mucositis ranged from 9 to 15%, 7 to 20%, and 9 to 30% (excluding one outlier), respectively. For these four trials, the exploratory meta-analysis showed a pooled 2-year PFS and OS of 89% (95% confidence interval, 80–96%) and 96% (92–99%). The pooled rates of grade ≥3 dysphagia, dermatitis, and mucositis were 13% (7–19%), 9% (5–14%), and 28% (9–53%). However, there was significant heterogeneity in the 2-year PFS (I2 = 57%, p = 0.07) and grade ≥3 mucositis (I2 90%, p

129 Background: Ovarian cancer is the 2nd most common gynecologic malignancy with surgery and platinum-based chemotherapy as the mainstay of initial treatment. However, ovarian cancer has generally high rates of recurrence and metastasis after primary therapy. For patients with progressive or symptomatic disease, radiation therapy (RT) can be utilized as an effective option for palliation. Methods: A retrospective review was conducted of patients treated with palliative RT for symptomatic or recurrent ovarian cancer between 2015-2019 at a single institution. 17 women were identified who received 20 courses of RT. Response was classified as complete response (CR), partial response (PR), and progressive disease (PD). Overall response rate (ORR) was the sum of CR and PR. Results: Median age at RT was 57 (range 36-76). Histologic subtypes were high grade serous (65%), low grade serous (12%), clear cell (12%), and other (12%). The most common indications were pain (65%), bleeding (30%), and asymptomatic progression (20%). 18 of 20 RT courses were delivered to soft tissue or nodal metastases. RT techniques included 2D/3D (60%), IMRT (30%), and SBRT (10%). Dose ranged from 20-60 Gy in 3-28 fractions. 20 Gy in 5 fractions (25%) and 30-31 Gy in 10 fractions (25%) were most common. Of the 16 RT courses for symptomatic disease, clinical ORR was 87.5% within 3 months of RT (50% PR and 37.5% CR). 3 treatments had sustained response beyond 3 months. 2 developed PD. Of 11 RT courses with follow-up imaging, radiographic ORR was 36.1% (27% PR and 9.1% CR) within 3 months of RT. 1 had sustained PR beyond 3 months. Of the 10 RT courses for symptomatic high grade serous histology, PR and CR was seen in 50% and 40% of patients within 3 months (90% ORR). Conclusions: Palliative RT offers high rates of clinical response for symptomatic patients with metastatic ovarian cancer within 3 months of treatment delivery. Rapid clinical response rates were particularly favorable for those with high grade serous histology. RT should be considered as a standard palliative option for patients with symptomatic ovarian cancer metastases. Further prospective studies are warranted to establish the optimal timing, dose, and relation to chemosensitivity in this setting.

Tumor mutational burden (TMB) and driver mutations are potential biomarkers to predict efficacy of immune checkpoint inhibitors (ICPI). Studies demonstrated malignant gliomas with high TMB in children and adults may preferentially benefit from treatment with ICPI. To characterize the association between TMB and known drivers in pediatric brain tumors, comprehensive genomic profiling (CGP) was performed on 723 pediatric (≤18 years) glioma samples using DNA extracted from 40 microns of formalin-fixed paraffin-embedded tissue. CGP utilized hybridization-captured, adaptor ligation based libraries sequenced to a mean coverage depth of >500X for up to 315 cancer-related genes. TMB was calculated as mutations per megabase and categorized as low (0-6), intermediate (6-20), or high (20+). Analysis included 80 clinically relevant driver mutations; genomic alterations known to confer a selective growth advantage. Of 723 brain tumors, TMB was low in 91.8%, intermediate in 6.1%, and high in 2.1%. When excluding tumor suppressor genes (TSGs), there was a trend toward decreased incidence of driver mutations in tumors with high TMB. Additionally, we determined that BRAF alterations were not identified in high TMB tumors, but were enriched in low TMB tumors. However, when including TSGs, 93% of tumors in the high TMB cohort harbored a driver mutation; 63% and 70% in the low and intermediate TMB cohorts, respectively. There is an association between high TMB and incidence of TSGs. In contrast, there is an association between low TMB and BRAF mutations. These represent populations in which ICPI may be more or less effective and further studies are needed.