Management and outcomes of primary anorectal melanoma in the United States.

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.

Local management of preinvasive and clinical T1-3 penile cancer: utilization of diverse treatment modalities.

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.

The Effects of Time to Treatment Initiation for Patients With Non-small-cell Lung Cancer in the United States.

BACKGROUND: The purpose of this study was to determine the effects of time from diagnosis to treatment (TTI) on survival in patients with nonmetastatic non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: The National Cancer Database was queried for patients with stages 1 to 3 NSCLC between 2004 and 2013. Patients with missing survival status/time, unknown TTI, or receipt of palliative therapy were excluded. Multivariable Cox proportional hazards modeling, logistic regression, and recursive partitioning analysis were performed to determine associated variables and survival outcomes. RESULTS: Altogether, 1,393,232 patients met inclusion criteria. The median follow-up was 36 months. The median TTI increased between 2004 and 2013 from 35 to 39 days (P < .001). On multivariable Cox proportional hazards modeling, TTI groups 31 to 60 days, 61 to 90 days, and > 90 days were independently related to poorer overall survival (OS) compared with TTI 1 to 30 days (hazard ratio, 1.04, 1.10, and 1.14; 95% confidence interval [CI], 1.02-1.06, 1.07-1.12, and 1.11-1.17, respectively; P < .001 for all). Recursive partitioning analysis revealed that TTI of ≤ 45 days was the most optimal threshold for survival (P < .001); patients with TTI ≤ 45 days had a median OS of 70.2 months (95% CI, 69.3-71.1 months) versus 61.5 months (95% CI, 60.5-62.4) (P < .001). There were significant disparities by age, race, ethnicity, and income for delayed (> 45 days) TTI (P < .001 for all). Subgroup analysis revealed that stage 1 and 2 patients with TTI > 45 days had a higher risk of mortality compared with TTI ≤ 45 days (hazard ratio, 1.15 and 1.05; 95% CI, 1.12-1.17 and 1.01-1.09, respectively) (P < .001). CONCLUSIONS: Increased TTI is independently associated with poorer survival in non-metastatic NSCLC. TTI ≤ 45 days is a clinically targetable time frame associated with improved outcomes and ought to be considered for patients with lung cancer undergoing definitive therapy.

Phase 1/2 Trial of Pembrolizumab and Concurrent Chemoradiation Therapy for Limited-Stage SCLC.

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.

Low-dose radiation treatment enhances systemic antitumor immune responses by overcoming the inhibitory stroma.

BACKGROUND: Despite some successes with checkpoint inhibitors for treating cancer, most patients remain refractory to treatment, possibly due to the inhibitory nature of the tumor stroma that impedes the function and entry of effector cells. We devised a new technique of combining immunotherapy with radiotherapy (XRT), more specifically low-dose XRT, to overcome the stroma and maximize systemic outcomes. METHODS: We bilaterally established 344SQ lung adenocarcinoma tumors in 129Sv/Ev mice. Primary and secondary tumors were irradiated with either high-dose or low-dose of XRT with systemic anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte associated protein 4 administration. Survival and tumor growth were monitored for the various groups, and secondary tumors were phenotyped by flow cytometry for immune populations. Tumor growth factor-beta (TGF-ß) cytokine levels were assessed locally after low-dose XRT, and specific immune-cell depletion experiments were conducted to identify the major contributors to the observed systemic antitumor effect. RESULTS: Through our preclinical and clinical studies, we observed that when tumor burden was high, there was a necessity of combining high-dose XRT to 'prime' T cells at the primary tumor site, with low-dose XRT directed to secondary (metastatic) tumors to 'modulate the stroma'. Low-dose XRT improved the antitumor outcomes of checkpoint inhibitors by favoring M1 macrophage polarization, enhancing natural killer (NK) cell infiltration, and reducing TGF-ß levels. Depletion of CD4+ T cells and NK cells abrogated the observed antitumor effect. CONCLUSION: Our data extend the benefits of low-dose XRT to reprogram the tumor environment and improve the infiltration and function of effector immune cells into secondary tumors.

Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer.

INTRUDUCTION: Radiation and immunotherapy have separately been shown to confer survival advantages to patients with extensive-stage small cell lung cancer (ESCLC), but failure rates remain high and combination therapy has been understudied. In this single-arm phase I trial (NCT02402920), we assessed the safety of combining pembrolizumab with thoracic radiotherapy (TRT) after induction chemotherapy for SCLC. METHODS: Patients with ESCLC who had completed chemotherapy received TRT with pembrolizumab. The maximum tolerated dose of pembrolizumab was assessed by 3+3 dose-escalation; doses began at 100 mg and increased in 50 mg increments to 200 mg. Pembrolizumab was given every 3 weeks for up to 16 cycles; TRT was prescribed as 45 Gy in 15 daily fractions. Toxicity was evaluated with the Common Terminology Criteria for Adverse Events v4.0. The primary endpoint was safety of the combined therapy based on the incidence of dose-limiting toxicity in the 35 days following initiation of treatment. RESULTS: Thirty-eight patients with ESCLC (median age 65 years, range: 37-79 years) were enrolled from September 2015 through September 2017; 33 received per-protocol treatment, and all tolerated pembrolizumab at 100 to 200 mg with no dose-limiting toxicity in the 35-day window. There were no grade 4-5 toxicities; 2 (6%) patients experienced grade 3 events (n = 1 rash, n = 1 asthenia/paresthesia/autoimmune disorder) that were unlikely/doubtfully related to protocol therapy. The median follow-up time was 7.3 months (range: 1-13 months); median progression-free and overall survival times were 6.1 months (95% confidence interval: 4.1-8.1) and 8.4 months (95% confidence interval: 6.7-10.1). CONCLUSIONS: Concurrent pembrolizumab-TRT was tolerated well with few high-grade adverse events in the short-term; progression-free and overall survival rates are difficult to interpret due to heterogeneity in eligibility criteria (e.g., enrolling progressors on induction chemotherapy). Although randomized studies have shown benefits to TRT alone and immunotherapy alone, the safety of the combined regimen supports further investigation as a foundational approach for future prospective studies.

Glycosylation and Antitumor Immunity.

Glycosylation and its by-product, the glycan, play a crucial role in many cellular processes. Aberrant glycan structures and mutations of the glycosylation pathway have been intricately linked with the development of cancer and more recently with cancer's ability to escape the innate immune system. This chapter aims to elucidate how glycosylation interacts with the immune system to promote tumor deviation through endogenous lectins, mutated glycosphingolipids, sialic acid domains, and more. This chapter also explores the mechanisms of glycosylation that may lead to powerful translational therapeutic tools, such as glycotransferase inhibitors, glycan/glycopeptide-based vaccines, and antibody-based immunotherapies, all of which have shown great promise clinically in the field of immuno-oncology.

Management of Unresectable T4b Esophageal Cancer: Practice Patterns and Outcomes From the National Cancer Data Base.

PURPOSE: Patients with unresectable cT4b esophageal cancer (EC) are rare and largely excluded from prospective trials. As a result, current treatment recommendations are based on limited evidence. This study sought to evaluate national practice patterns and outcomes for this population and evaluated 3 primary cohorts: patients receiving chemotherapy (CT) with or without subtherapeutic radiotherapy (RT), definitive chemoradiotherapy (CRT), or CT with or without RT followed by definitive surgery. MATERIALS AND METHODS: The National Cancer Data Base was queried for cT4b Nany M0 EC. Exclusion criteria were patients with unspecified staging, palliative treatment, improper, or no histologic confirmation, or lack of CT. Multivariable logistic regression determined factors predictive of receiving surgical therapy. Kaplan-Meier analysis evaluated overall survival (OS), and Cox proportional hazards modeling determined variables associated with OS. RESULTS: Altogether, 519 patients met inclusion criteria; 195 (38%) underwent CT, 291 (56%) underwent definitive CRT, and 33 (6%) underwent surgical-based therapy. Surgery was more likely performed in patients residing in rural areas, living farther from the treating facility, and N1 status (P<0.05 for all). Median OS in the respective cohorts were 6.0, 12.7, and 43.9 months (P<0.001). On multivariate Cox proportional hazards modeling, among others, nonsurgical treatment was associated with poorer OS (P<0.05 for both). CONCLUSIONS: In the largest study to date evaluating patterns of care for cT4b EC, as compared with CT alone, addition of definitive RT was associated with higher OS. Although causation is clearly not implied, well-selected responders to CT and/or RT may be able to undergo resection and numerically prolonged survival, but patient selection remains paramount.

Stereotactic body radiation therapy for prostate cancer: systematic review and meta-analysis of prospective trials.

Background: Despite the increasing worldwide utilization of stereotactic body radiation therapy (SBRT) for prostate cancer, there are no known summative data regarding its safety and efficacy. To address this knowledge gap, we conducted a PRISMA-guided systematic review and meta-analysis of prospective prostate SBRT trials. Results: Fourteen trials with a total of 2,038 patients were included. Median follow-up was 37 months (range 6-55 months). Most patients had cT1-T2a, Gleason ≤7 disease with median pre-treatment PSAs of 5-10; 1,042 (51%) were low-risk, 744 (37%) were intermediate-risk, 158 (8%) were high-risk, and the remainder were unreported. Doses ranged from 33.5-50.0 Gy, most typically in 5 fractions, with nearly all studies delivering nondaily fractionation with some type of daily image guidance. Outcomes were converted into counts at the end of one year. The pooled rate of FFBF was 98% [95% confidence interval, 97-98%]. The pooled rate of late grade ≥3 gastrointestinal and genitourinary toxicities were 1% [0-5%] and 2% [1-3%], respectively. Methods: PubMed and Google Scholar were queried for prospective studies evaluating survival and/or toxicity outcomes in SBRT (≤5 fractions) for localized prostate cancer. Pooled rates of freedom from biochemical failure (FFBF) and late grades ≥3 gastrointestinal (GI) and genitourinary (GU) toxicities were assessed. Meta-analysis of proportions was logit transformed and pooled using generalized linear mixed models (both fixed and random effects) and subsequently back transformed to standard proportions. Conclusions: Despite the lack of long-term follow-up and heterogeneity of the available evidence, prostate SBRT affords appropriate biochemical control with few high-grade toxicities. These data have implications for ongoing worldwide utilization of prostate SBRT as well as ongoing prospective investigations.

Racial and Insurance-related Disparities in Delivery of Immunotherapy-type Compounds in the United States.

Racial and/or socioeconomic factors affect the type of therapies delivered for non-small cell lung cancer (NSCLC). Given the rapid expansion of immunotherapy for NSCLC, it is a crucial public health priority to evaluate disparities in administration thereof. The National Cancer Database (NCDB) was queried for newly diagnosed metastatic NSCLC. Patients were dichotomized based on receipt of immunotherapy-type compounds (ICs) based on NCDB coding. Multivariable logistic regression ascertained factors associated with IC delivery. Subgroup analysis, performed by univariate logistic regression modeling, evaluated the effect of race while stratifying for insurance type. Of 504,447 patients, 11,420 (2.3%) received ICs, and 493,027 (97.7%) did not. From 2004 to 2012, ≤1% of patients received ICs; however, 4.9% did so in 2013, 6.6% in 2014, and 8.7% in 2015. ICs were more likely administered to younger and healthier patients, those living farther from treating facilities, and in more educated areas (P<0.05 for all). ICs were more often delivered to adenocarcinomas, and patients who received chemotherapy but not radiotherapy (P<0.05 for all). In addition to geographic differences, uninsured and Medicaid populations received ICs less often, along with African Americans. On subgroup analysis, African Americans were less likely to receive ICs even when stratified for Medicare, Medicaid, or private insurances. Because IC utilization is expected to amplify even further going forward, these public health and economic issues are essential to identify and address appropriately, and have implications on pharmaceutical/insurance companies, value-based oncology, and public health policy. Methods to address these inequalities are also discussed.

Triple Therapy with MerTK and PD1 Inhibition Plus Radiotherapy Promotes Abscopal Antitumor Immune Responses.

PURPOSE: Radiotherapy (RT) traditionally has been used for local tumor control in the treatment of cancer. The recent discovery that radiotherapy can have anticancer effects on the immune system has led to recognition of its ability to sensitize the tumor microenvironment to immunotherapy. However, radiation can also prompt adverse immunosuppressive effects that block aspects of systemic response at other tumor sites. Our hypothesis was that inhibition of the MER proto-oncogene tyrosine kinase (MerTK) in combination with anti-programmed cell death-1 (α-PD1) checkpoint blockade will enhance immune-mediated responses to radiotherapy. EXPERIMENTAL DESIGN: We tested the efficacy of this triple therapy (Radiation + α-PD1 + α-MerTK mAbs) in 129Sv/Ev mice with bilateral lung adenocarcinoma xenografts. Primary tumors were treated with stereotactic radiotherapy (36 Gy in 3 12-Gy fractions), and tumors were monitored for response. RESULTS: The triple therapy significantly delayed abscopal tumor growth, improved survival rates, and reduced numbers of lung metastases. We further found that the triple therapy increased the activated CD8+ and NK cells populations measured by granzyme B expression with upregulation of CD8+CD103+ tissue-resident memory cells (TRM) within the abscopal tumor microenvironment relative to radiation only. CONCLUSIONS: The addition of α-PD1 + α-MerTK mAbs to radiotherapy could alter the cell death to be more immunogenic and generate adaptive immune response via increasing the retention of TRM cells in the tumor islets of the abscopal tumors which was proven to play a major role in survival of non-small cell lung cancer patients.

Influence of low-dose radiation on abscopal responses in patients receiving high-dose radiation and immunotherapy.

BACKGROUND: Preclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor's response to immunotherapy, when combined with high-dose radiation to another tumor. The aim of this study was to evaluate tumor responses to this combination in a clinical setting. METHODS: A post-hoc analysis of 3 ongoing immunoradiation trials was performed. Twenty-six (of 155) patients received low-dose radiation (1-20 Gy total), either as scatter from high-dose radiation or from intentional treatment of a second isocenter with low-dose radiation, were evaluated for response. The low-dose lesions were compared to lesions that received no radiation (< 1 Gy total). Response rates, both defined as complete and partial responses as defined by RECIST criteria were used to compare lesion types. RESULTS: The 26 patients had a total of 83 lesions for comparison (38 receiving low-dose, 45 receiving no-dose). The average dose given to low-dose lesions was 7.3 Gy (1.1-19.4 Gy), and the average time to response was 56 days. Twenty-two out of 38 (58%) low-dose lesions met the PR/CR criteria for RECIST compared with 8 out of 45 (18%) no-dose lesions (P = 0.0001). The median change for longest diameter size for low-dose lesions was - 38.5% compared to 8% in no-dose lesions (P < 0.0001). Among the low-dose lesions that had at least one no-dose lesion within the same patient as a control (33 and 45 lesions respectively), 12 low-dose lesions (36%) responded without a corresponding response in their no-dose lesions; Conversely, two (4%) of the no-dose lesions responded without a corresponding response in their low-dose lesion (P = 0.0004). CONCLUSIONS: Low-dose radiation may increase systemic response rates of metastatic disease treated with high-dose radiation and immunotherapy.

Role of Radiation Therapy in Modulation of the Tumor Stroma and Microenvironment.

In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has been the cross-talk between tumor cells and the surrounding environment or stroma. This tumor stroma, comprised of various cells, and extracellular matrix (ECM), has been shown to aid in suppressing host immune responses against tumor cells. Through immunosuppressive cytokine secretion, metabolic alterations, and other mechanisms, the tumor stroma provides a complex network of safeguards for tumor proliferation. With recent advances in more effective, localized treatment, radiation therapy (XRT) has allowed for strategies that can effectively alter and ablate tumor stromal tissue. This includes promoting immunogenic cell death through tumor antigen release to increasing immune cell trafficking, XRT has a unique advantage against the tumoral immune evasion mechanisms that are orchestrated by stromal cells. Current studies are underway to elucidate pathways within the tumor stroma as potential targets for immunotherapy and chemoradiation. This review summarizes the effects of tumor stroma in tumor immune evasion, explains how XRT may help overcome these effects, with potential combinatorial approaches for future treatment modalities.

Phase II Trial of Ipilimumab with Stereotactic Radiation Therapy for Metastatic Disease: Outcomes, Toxicities, and Low-Dose Radiation-Related Abscopal Responses.

Ipilimumab is effective for patients with melanoma, but not for those with less immunogenic tumors. We report a phase II trial of ipilimumab with concurrent or sequential stereotactic ablative radiotherapy to metastatic lesions in the liver or lung (NCT02239900). Ipilimumab (every 3 weeks for 4 doses) was given with radiotherapy begun during the first dose (concurrent) or 1 week after the second dose (sequential) and delivered as 50 Gy in 4 fractions or 60 Gy in 10 fractions to metastatic liver or lung lesions. In total, 106 patients received ≥1 cycle of ipilimumab with radiation. Median follow-up was 10.5 months. Median progression-free survival time was 2.9 months (95% confidence interval, 2.45-3.40), and median overall survival time was not reached. Rates of clinical benefit of nonirradiated tumor volume were 26% overall, 28% for sequential versus 20% for concurrent therapy (P = 0.250), and 31% for lung versus 14% for liver metastases (P = 0.061). The sequential lung group had the highest rate of clinical benefit at 42%. There were no differences in treatment-related adverse events between groups. Exploratory analysis of nontargeted lesions revealed that lesions receiving low-dose radiation were more likely to respond than those that received no radiation (31% vs. 5%, P = 0.0091). This phase II trial of ipilimumab with stereotactic radiotherapy describes satisfactory outcomes and low toxicities, lending support to further investigation of combined-modality therapy for metastatic cancers.

The effect of early versus delayed radiation therapy on length of hospital stay in the palliative setting.

BACKGROUND: Radiation therapy (RT) can offer timely and effective treatment to oncology patients in the palliative setting. To date, there is sparse evidence investigating temporal relationships regarding the initiation of RT and subsequent hospital stay in the inpatient palliative setting. We aimed to assess whether times between admission, consultation, and initiation of treatment effected the length of hospital stay for patients receiving palliative radiation therapy (PRT). METHODS: This was a retrospective chart review of patients who received a consult for PRT from August 2014 to October 2016. All data was collected from a single community cancer center. Data including demographics, radiation treatment details, and temporal data (e.g., length of stay, time from admission to consult, etc.) were recorded. RESULTS: Of the 135 patients that received PRT, 60 of them were treated in the inpatient setting. The most common indications for PRT were pain (37%) and non-pain related neurologic symptoms (37%). The most common treatment sites were bone (58%), brain (22%), and lung (17%). There was a significant difference in duration of hospital stay between patients who were seen by palliative radiation oncology within two days versus greater than 2 days (P=0.02); and patients who were treated within 2 days of admission versus greater than 2 days (P=0.03). CONCLUSIONS: Further research is needed to establish causal temporal relationships in palliative radiation oncology. However, this data suggests that early involvement of the radiation oncology team is associated with a reduced length of hospital stay.

Safety of Combined Immunotherapy and Thoracic Radiation Therapy: Analysis of 3 Single-Institutional Phase I/II Trials.

PURPOSE: The safety of combined immunotherapy and thoracic radiation therapy (iRT) has been understudied. We evaluated toxicities in patients receiving iRT from 3 single-institutional phase 1/2 trials. METHODS AND MATERIALS: Clinical/treatment characteristics and toxicities (per the Common Toxicity Criteria for Adverse Events, version 4.0) were extracted. For purposes of this analysis, groupings were made into (1) patients receiving immunotherapy plus stereotactic body radiation therapy (50 Gy/4 fractions or 60 Gy/10 fractions), (2) immunotherapy plus 45 Gy/15 fractions, and (3) twice-daily chemoimmunoradiotherapy (45 Gy in twice-daily fractions). RESULTS: None of the 60 patients undergoing immunotherapy plus stereotactic body radiation therapy (50 Gy, n = 49; 60 Gy, n = 11) experienced grade ≥4 events. There were 34 instances of any grade 3 event (in 15 total patients), with 9 pulmonary specific grade 3 events (in 4 patients). In the patients receiving 45 Gy/15 fractions (small cell lung cancers, n = 26; non-small cell lung cancers, n = 27), there were 2 grade 4 events (in the same patient), along with 17 grade 3 toxicities experienced by 10 total patients (2 pulmonary specific). Lastly, in the twice-daily cohort (n = 22), there were 5 grade 4 events (3 of which occurred in 1 patient) and 16 grade 3 toxicities occurring in 8 total patients (half of which were hematologic). CONCLUSIONS: Administration of combined iRT is safe in the short term. Toxicities did not appreciably associate with demographics or dosimetry.

Toxicity of radiation and immunotherapy combinations.

PURPOSE: Although immunotherapy is a rapidly emerging modality for cancer care, there have been multiple reports of fatal toxicities. There have also been cases of treatment-related deaths with combined non-immunotherapeutic biologic compounds with radiation therapy. Thus, provision of summative information appraising the safety of combinatorial immunotherapy and radiation therapy (iRT) is imperative. Because this has not been well characterized, this review summarizes the available evidence to date. METHODS AND MATERIALS: Owing to the heterogeneity and relatively low quantity of published reports, this review was conducted in a narrative rather than systematic format. RESULTS: The results of combined iRT, both concurrent and sequential, are discussed for oncologic therapy of the brain, lung, liver, and prostate. Most evidence is from small samples and shorter follow-up but does consist of multiple prospective publications. Most data exist for ipilimumab, with programmed cell death -1 inhibitors emerging in more recent years. With 2 large phase 3 trials as exceptions, there were no instances of iRT-related deaths across all discussed studies. Altogether, grade 3 to 4 toxicities were relatively low in frequency; of the studies that compared iRT with an "immunotherapy only" or "RT only" cohort, none documented a clear increase in high-grade adverse events with combined-modality management. CONCLUSIONS: Despite the low quantity of data, combined iRT offers encouraging safety profiles. There is no evidence that iRT produces an overt increase in high-grade toxicities. Further data, especially on concurrent iRT, are anticipated from numerous iRT trials that are currently ongoing worldwide.

Overview of ongoing clinical trials investigating combined radiotherapy and immunotherapy.

Given the unprecedentedly rapid progression of clinical immuno-oncology, evaluation of currently ongoing and upcoming clinical trials is essential to address potential deficiencies for future trial design. This observational study examined trends in the current landscape of clinical trials investigating immunotherapy with radiotherapy (iRT). The National Institute of Health's clinicaltrials.gov database was queried for trials including radiation and one of the six currently US FDA approved immunotherapy drugs: ipilimumab, nivolumab, pembrolizumab, durvalumab, atezolizumab and avelumab. This study highlights that the construction of prospective iRT trials is rapidly escalating. This study provides a framework to not only understand ongoing multidisciplinary trials, but also for prudent iRT trial design in the future.

Utilization of Neoadjuvant Intensity-modulated Radiation Therapy for Rectal Cancer in the United States.

BACKGROUND/AIM: Advances in technology have expanded the use of intensity-modulated radiotherapy (IMRT). The goal of this study was to investigate trends in the utilization of IMRT for rectal cancer (RC) in USA. MATERIALS AND METHODS: The National Cancer Database was queried for RC patients receiving neoadjuvant chemoradiotherapy with either IMRT or three-dimensional conformal radiation therapy (3DCRT). Differences in factors associated with receipt of 3DCRT versus IMRT were determined and temporal trends were analyzed. RESULTS: From 2005 to 2009, IMRT utilization increased, but remained constant and roughly equivalent to 3DCRT from 2010 to 2014. Patients who received IMRT were more likely to have T4 disease (p=0.014), while patients diagnosed in 2004-2006 (p<0.0001) and 2007-2008 (p=0.015) were less likely to receive IMRT. There were no significant differences in postoperative outcomes between patients receiving 3DCRT and IMRT. CONCLUSION: IMRT utilization initially increased, but is now used at similar frequencies to 3DCRT and offers similar short-term postoperative outcomes.