STING Agonists in Head and Neck Squamous Cell Carcinoma.

ABSTRACT: Despite the development of new treatment paradigms and improved biologic understanding of head and neck squamous cell carcinoma (HNSCC), therapeutic resistance remains a substantial problem, and novel treatment approaches are needed. Stimulator of interferon genes (STING) is a critical regulator of the antitumor response through regulation of both immune-dependent and tumor-intrinsic mechanisms. As such, the STING pathway has emerged as a rational pharmacologic target leading to the development of multiple STING agonists. These compounds have impressive preclinical efficacy as single agents and with PD-1 (programmed death-1) axis agents. However, clinical evaluation in this context has yet to show substantial efficacy. In contrast to monotherapy approaches, activation of STING in combination with DNA-damaging agents has been shown to enhance the effect of these agents in preclinical models and represents a promising approach to improve outcomes in patients with HNSCC. In this review, we will discuss the preclinical and clinical data supporting the use of STING agonists and highlight potential avenues of exploration to unlock the potential of these agents in HNSCC.

Geographic Access to Radiation Therapy Facilities in the United States.

PURPOSE: The current distribution of radiation therapy (RT) facilities in the United States is not well established. A comprehensive inventory of U.S. RT facilities was last assessed in 2005, based on data from state regulatory agencies and dosimetric quality assurance bodies. We updated this database to characterize population-level measures of geographic access to RT and analyze changes over the past 15 years. METHODS AND MATERIALS: We compiled data from regulatory and accrediting organizations to identify U.S. facilities with linear accelerators used to treat humans in 2018 to 2020. Addresses were geocoded and analyzed with Geographic Information Services software. Geographic access was characterized by assessing the Euclidian distance between ZIP code tabulation areas/county centroids and RT facilities. Populations were assigned to each county to estimate the effect of facility changes at the population level. Logistic regressions were performed to identify features associated with increased distance to RT and associated with regions that gained an RT facility between the 2 time points studied. RESULTS: In 2020, a total of 2313 U.S. RT facilities were reported, compared with 1987 in 2005, representing a 16.4% growth in facilities over nearly 15 years. Based on population attribution to the centroids of ZIP Code Tabulation Areas, 77.9% of the U.S. population lives within 12.5 miles of an RT facility, and 1.8% of the U.S. population lives more than 50 miles from an RT facility. We found that increased distance to RT was associated with nonmetro status, less insurance, older median age, and less populated regions. Between 2005 and 2020, the population living within 12.5 miles from an RT facility increased by 2.1 percentage points, whereas the population living furthest from RT facilities decreased 0.6 percentage points. Regions with improved geographic RT access are more likely to be higher income and better insured. CONCLUSIONS: The percentage of the U.S. population with limited geographic access to RT is 1.8%. We found that people benefiting from improved access to RT facilities are more economically advantaged, suggesting disparities in geographic access may not improve without intervention.

Preparing Patients for Sexual Dysfunction After Radiation for Anorectal Cancers: A Systematic Review.

PURPOSE: Successful multimodality treatment of anorectal cancers has led to increased numbers of survivors who experience permanent, life-changing side effects of treatment. Little is known about sexual dysfunction (SD) in this population. The etiology of SD after anorectal cancer treatment is complex and multifactorial. However, pelvic radiation plays a significant negative role in anatomic, hormonal, and physiological aspects of sexual function. METHODS AND MATERIALS: A systematic literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. Information was organized by key concepts useful for patient education, including (1) rates of SD after pelvic radiation for rectal cancer, (2) rates of SD after pelvic radiation for anal cancer, (3) mechanisms of SD and methods to reduce rates of SD, and (4) issues and opportunities related to patient education and discussion of SD after pelvic radiation. RESULTS: SD after pelvic radiation for anorectal cancers is common in both men and women. Higher radiation doses may increase the risk for vaginal stenosis; however, it is unclear whether there are similar dose-volume relationships for men. Vaginal dilators and advanced radiation techniques can reduce the radiation dose to sexual organs at risk. Improvement is needed regarding counseling and education of patients about SD. CONCLUSIONS: This review provides information from previously published studies that clinicians may use in their discussions with patients embarking on pelvic radiation for anorectal cancers. More modern, standardized, and complete data are needed to quantify the risk of SD after treatment. Some methods of sexual toxicity reduction have been studied, but further study into interventions aimed at treating postradiation sexual function are needed.

Changing Therapeutic Landscape for Melanoma With Multiple Brain Metastases.

Over 90 000 people are expected to be diagnosed with melanoma in the United States this year. The development of brain metastases is particularly difficult to manage. Over the past few years, melanoma patients with multiple unresectable brain metastases for which stereotactic surgery might also not be a viable option have fortunately experienced a dramatic expansion in available management options given improvements made to targeted agents, immunotherapy, and radiotherapy. Whole-brain radiation therapy (WBRT) is a long-standing radiation technique that has become increasingly sophisticated. In this review, we summarize retrospective and prospective studies on individual advances in targeted agents, immunotherapy, and WBRT, highlighting important variables such as overall survival, intracranial progression-free survival, control and response rates, and toxicities. We also discuss the recent integration of these therapies into a multimodality approach, which has shown promise in the clinical setting although toxicities have not been insignificant. Finally, we describe ongoing prospective trials relevant to melanoma with brain metastases, and we conclude with our own thoughts on the optimal approach for these patients.

Association of Presalvage Radiotherapy PSA Levels After Prostatectomy With Outcomes of Long-term Antiandrogen Therapy in Men With Prostate Cancer.

Importance: In men with recurrent prostate cancer, addition of long-term antiandrogen therapy to salvage radiotherapy (SRT) was associated with overall survival (OS) in the NRG/RTOG 9601 study. However, hormone therapy has associated morbidity, and there are no validated predictive biomarkers to identify which patients derive most benefit from treatment. Objective: To examine the role of pre-SRT prostate-specific antigen (PSA) levels to personalize hormone therapy use with SRT. Interventions: Men were randomized to SRT plus high-dose nonsteroidal antiandrogen (bicalutamide, 150 mg/d) or placebo for 2 years. Design, Setting, and Participants: In this secondary analysis of the multicenter RTOG 9601 double-blind, placebo-controlled randomized clinical trial conducted from 1998 to 2003 by a multinational cooperative group, men with a positive surgical margin or pathologic T3 disease after radical prostatectomy with pre-SRT PSA of 0.2 to 4.0 ng/mL were included. Analysis was performed between March 4, 2019, and December 20, 2019. Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary end points included distant metastasis (DM), other-cause mortality (OCM), and grades 3 to 5 cardiac and neurologic toxic effects. Subgroup analyses were performed using the protocol-specified PSA stratification variable (1.5 ng/mL) and additional PSA cut points, including test for interaction. Competing risk analyses were performed for DM and other-cause mortality (OCM). Results: Overall, 760 men with PSA elevation after radical prostatectomy for prostate cancer were included. The median (range) age of particpants was 65 (40-83) years. Antiandrogen assignment was associated with an OS benefit in the PSA stratum greater than 1.5 ng/mL (n = 118) with a 25% 12-year absolute benefit (hazard ratio [HR], 0.45; 95% CI, 0.25-0.81), but not in the PSA of 1.5 ng/mL or less stratum (n = 642) (1% 12-year absolute difference; HR, 0.87; 95% CI, 0.66-1.16). In a subanalysis of men with PSA of 0.61 to 1.5 (n = 253), there was an OS benefit associated with antiandrogen assignment (HR, 0.61; 95% CI, 0.39-0.94). In those receiving early SRT (PSA ≤0.6 ng/mL, n = 389), there was no improvement in OS (HR, 1.16; 95% CI, 0.79-1.70), an increased OCM hazard (subdistribution HR, 1.94; 95% CI, 1.17-3.20; P = .01), and an increased odds of late grades 3 to 5 cardiac and neurologic toxic effects (odds ratio, 3.57; 95% CI, 1.09-15.97; P = .05). Conclusions and Relevance: These results suggest that pre-SRT PSA level may be a prognostic biomarker for outcomes of antiandrogen treatment with SRT. In patients receiving late SRT (PSA >0.6 ng/mL, hormone therapy was associated with improved outcomes. In men receiving early SRT (PSA ≤0.6 ng/mL), long-term antiandrogen treatment was not associated with improved OS. Future randomized clinical trials are needed to determine hormonal therapy benefit in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT00002874.

Correlation between cribriform/intraductal prostatic adenocarcinoma and percent Gleason pattern 4 to a 22-gene genomic classifier.

BACKGROUND: The Decipher test measures expression of 22 RNA biomarkers associated with aggressive prostate cancer used to improve risk stratification of patients to help guide management. To date, Decipher's genomic classification has not been extensively correlated with specific histologic growth patterns in prostatic adenocarcinoma. With a growing understanding of the clinical aggressiveness associated with cribriform growth pattern (CF), intraductal carcinoma (IDC), and percent Gleason pattern 4 (G4%), we sought to determine if their presence was associated with an increased genomic risk as measured by the Decipher assay. DESIGN: Clinical use of the Decipher assay was performed on the highest Gleason score (GS) tumor nodule of prostatectomy specimens from a prospective cohort of 48 patients, with GS varying from 7 through 9 to help guide clinical risk stratification. The tumors were reviewed for CF, IDC, and G4%, which were then compared to the Decipher score (0-1) and risk stratification (high vs not high). RESULTS: The presence of CF/IDC was significantly associated with Decipher risk score (P = .007), with a high-risk Decipher score in 22% vs 56% of patients without or with CF/IDC. On binary logistic regression analysis, G4% (odds ratio [OR] 1.04 per percent increase [95% confidence interval [CI], 1.02-1.06]; P = .0004) and CF predominant (OR, 9.60 [95%CI, 1.48-62.16]; P = .02) were significantly associated with a high-risk GC score. IDC did not reach significance (OR, 1.92 [95%CI, 0.65-5.67]; P = .24). CONCLUSIONS: Our findings add to an expanding knowledge base that supports G4% and CF/IDC as molecularly unique and clinically relevant features in prostatic adenocarcinoma. These histologic features should be standardly reported as they are associated with more aggressive prostate cancer. Future work should determine the independent information of these histologic findings that are relative to genomic assessment on long-term outcomes.