RTOG Foundation

Objective: To understand the dynamics of vaccination conversations between obstetrician/gynecologists and pregnant women and the factors influencing vaccine acceptance and differences by patient race and ethnicity. Methods: In this qualitative study we used linguistic analysis to analyze vaccination conversations between 40 unique patients and 10 unique providers from the 2020 to 2021 influenza season. The results were stratified for non-Hispanic White (“White”) patients compared to non-Hispanic Black and Hispanic patients (“patients of color/POC”) to assess differences in the strength of provider vaccine recommendations, initiation of vaccination conversation, the patient reaction to vaccination prompts, and association of these factors with vaccination intent as the primary outcome. Results: The linguistic analysis demonstrated that 22 (55%) out of 40 patients intended to get vaccinated. More POC delayed or refused influenza vaccination (3/6) than White patients (2/10), while more White patients (5/5) than POC demonstrated intent to get the Tdap vaccine (6/10). While providers consistently explained the value of vaccination, greater emphasis was placed on communicating the benefits of Tdap compared with influenza vaccination to POC. Providers used fewer techniques indicative of strong vaccine recommendations when recommending influenza vaccination to POC compared with White patients. Conclusion: This hypothesis-generating study suggests some aspects of provider communication about prenatal vaccination may differ by patients’ race and ethnicity. Provider-based interventions to improve communication with pregnant women about prenatal vaccines may improve vaccine uptake and reduce racial and ethnic disparities.

Hypoxia-inducible factor (HIF)-1α is continuously synthesized and degraded in normoxia. During hypoxia, HIF1α stabilization restricts cellular/mitochondrial oxygen utilization. Cellular stressors can stabilize HIF1α even during normoxia. However, less is known about HIF1α function(s) and sex-specific effects during normoxia in the basal state. Since skeletal muscle is the largest protein store in mammals and protein homeostasis has high energy demands, we determined HIF1α function at baseline during normoxia in skeletal muscle. Untargeted multiomics data analyses were followed by experimental validation in differentiated murine myotubes with loss/gain of function and skeletal muscle from mice without/with post-natal muscle-specific Hif1a deletion (Hif1amsd). Mitochondrial oxygen consumption studies using substrate, uncoupler, inhibitor, titration protocols; targeted metabolite quantification by gas chromatography-mass spectrometry; and post-mitotic senescence markers using biochemical assays were performed. Multiomics analyses showed enrichment in mitochondrial and cell cycle regulatory pathways in Hif1a deleted cells/tissue. Experimentally, mitochondrial oxidative functions and ATP content were higher with less mitochondrial free radical generation with Hif1a deletion. Deletion of Hif1a also resulted in higher concentrations of TCA cycle intermediates and HIF2α proteins in myotubes. Overall responses to Hif1amsd were similar in male and female mice, but changes in complex II function, maximum respiration, Sirt3 and HIF1β protein expression and muscle fibre diameter were sex-dependent. Adaptive responses to hypoxia are mediated by stabilization of constantly synthesized HIF1α. Despite rapid degradation, the presence of HIF1α during normoxia contributes to lower mitochondrial oxidative efficiency and greater post-mitotic senescence in skeletal muscle. In vivo responses to HIF1α in skeletal muscle were differentially impacted by sex. KEY POINTS: Hypoxia-inducible factor -1α (HIF1α), a critical transcription factor, undergoes continuous synthesis and proteolysis, enabling rapid adaptive responses to hypoxia by reducing mitochondrial oxygen consumption. In mammals, skeletal muscle is the largest protein store which is determined by a balance between protein synthesis and breakdown and is sensitive to mitochondrial oxidative function. To investigate the functional consequences of transient HIF1α expression during normoxia in the basal state, myotubes and skeletal muscle from male and female mice with HIF1α knockout were studied using complementary multiomics, biochemical and metabolite assays. HIF1α knockout altered the electron transport chain, mitochondrial oxidative function, signalling molecules for protein homeostasis, and post-mitotic senescence markers, some of which were differentially impacted by sex. The cost of rapid adaptive responses mediated by HIF1α is lower mitochondrial oxidative efficiency and post-mitotic senescence during normoxia.

131 Background: Patients with high-risk features who experience biochemical relapse (BCR) after radical prostatectomy (RP) benefit from the addition of androgen deprivation therapy (ADT) to salvage radiotherapy (SRT). We hypothesized that intensification of androgen receptor (AR) blockade with enzalutamide would improve SRT outcomes for high-risk patients. Methods: Post prostatectomy prostate cancer patients who have had BCR (PSA ≥ 0.2 ng/mL) with at least 1 high-risk feature (Gleason 8-10, seminal vesicle invasion, pN1, persistent PSA >0.1 ng/mL after RP, and PSA ≥ 0.7 ng/mL) were eligible. Patients were randomized 1:1 to 24 months of ADT with an LHRH analog (LHRHa) or intensified ADT comprised of LHRHa + enzalutamide. The primary endpoint was progression free survival (PFS) with progression defined as PSA ≥ 0.05 ng/mL or initiation of new therapy following SRT. The target accrual of 170 patients provided 80% power to detect a HR=0.65 using a one-sided logrank test with a type I error of 0.10. Results: Between April 2019 and August 2022, 188 patients were enrolled. The patient characteristics were well balanced between the two arms. Median age was 64 years. Nodal involvement (pN1), pT3a-b, and Gleason 9 were noted in 22%, 77%, and 52% of patients, respectively. Over 70% had > 1 aggressive feature. Median follow-up time at the time of this report was 15.8 months. Prostatic fossa and pelvic SRT were mandatory. Para-aortic radiotherapy (RT), and lymph node and prostatic fossa lesion RT boosts were left at the discretion of the radiation oncologist. PFS favored the enzalutamide-intensified arm (HR=0.72, 80% confidence interval [CI]:0.56-0.94, one-sided p=0.14). Grade 3 adverse events (AEs) related to treatment in the standard versus enzalutamide arms were 11 vs. 23%, while Grade 4 AEs were 4% vs. 1%, respectively. The most common AEs (all grades, >15%) included hot flashes, fatigue, diarrhea, and decreased lymphocytes. The grade 3+ AEs (>3%) included decreased lymphocytes and hypertension. The largest differences (>7%) in AEs included insomnia, decreased lymphocytes. Diarrhea was less frequent with enzalutamide (40% vs 54%). Conclusions: The addition of enzalutamide to standard ADT did not meaningfully increase toxicity. While there was a trend toward PFS benefit from intensification, it has not yet met statistical significance. Updates on PFS and other clinical endpoints including quality of life will be reported with longer follow-up. Clinical trial information: NCT03809000 .

Clinical trials have become the primary mechanism to validate process improvements in oncology clinical practice. Over the past two decades there have been considerable process improvements in the practice of radiation oncology within the structure of a modern department using advanced technology for patient care. Treatment planning is accomplished with volume definition including fusion of multiple series of diagnostic images into volumetric planning studies to optimize the definition of tumor and define the relationship of tumor to normal tissue. Daily treatment is validated by multiple tools of image guidance. Computer planning has been optimized and supported by the increasing use of artificial intelligence in treatment planning. Informatics technology has improved, and departments have become geographically transparent integrated through informatics bridges creating an economy of scale for the planning and execution of advanced technology radiation therapy. This serves to provide consistency in department habits and improve quality of patient care. Improvements in normal tissue sparing have further improved tolerance of treatment and allowed radiation oncologists to increase both daily and total dose to target. Radiation oncologists need to define a priori dose volume constraints to normal tissue as well as define how image guidance will be applied to each radiation treatment. These process improvements have enhanced the utility of radiation therapy in patient care and have made radiation therapy an attractive option for care in multiple primary disease settings. In this chapter we review how these changes have been applied to clinical practice and incorporated into clinical trials. We will discuss how the changes in clinical practice have improved the quality of clinical trials in radiation therapy. We will also identify what gaps remain and need to be addressed to offer further improvements in radiation oncology clinical trials and patient care.

The standard of care for locally advanced head and neck cancer is concurrent chemoradiation or postoperative irradiation with or without chemotherapy. Surgery may not be an option for older patients (70 years old or above) due to multiple co-morbidities and frailty. Additionally, the standard chemotherapy of cisplatin may not be ideal for those patients due to oto- and nephrotoxicity. Though carboplatin is a reasonable alternative for cisplatin in patients with a pre-existing hearing deficit or renal dysfunction, its efficacy may be inferior to cisplatin for head and neck cancer. In addition, concurrent chemoradiation is frequently associated with grade 3-4 mucositis and hematologic toxicity leading to poor tolerance among older cancer patients. Thus, a new algorithm needs to be developed to provide optimal local control while minimizing toxicity for this vulnerable group of patients. Recently, immunotherapy with check point inhibitors (CPI) has attracted much attention due to the high prevalence of program death-ligand 1 (PD-L1) in head and neck cancer. In patients with recurrent or metastatic head and neck cancer refractory to cisplatin-based chemotherapy, CPI has proven to be superior to conventional chemotherapy for salvage. Those with a high PD-L1 expression defined as 50% or above or a high tumor proportion score (TPS) may have an excellent response to CPI. This selected group of patients may be candidates for CPI combined with modern radiotherapy techniques, such as intensity-modulated image-guided radiotherapy (IM-IGRT), volumetric arc therapy (VMAT) or proton therapy if available, which allow for the sparing of critical structures, such as the salivary glands, oral cavity, cochlea, larynx and pharyngeal muscles, to improve the patients' quality of life. In addition, normal organs that are frequently sensitive to immunotherapy, such as the thyroid and lungs, are spared with modern radiotherapy techniques. In fit or carefully selected frail patients, a hypofractionated schedule may be considered to reduce the need for daily transportation. We propose a protocol combining CPI and modern radiotherapy techniques for older patients with locally advanced head and neck cancer who are not eligible for cisplatin-based chemotherapy and have a high TPS. Prospective studies should be performed to verify this hypothesis.

SummaryPatients who are severely affected by coronavirus disease 2019 (COVID‐19) may develop a delayed onset ‘cytokine storm’, which includes an increase in interleukin‐6 (IL‐6). This may be followed by a pro‐thrombotic state and increased D‐dimers. It was anticipated that tocilizumab (TCZ), an anti‐IL‐6 receptor monoclonal antibody, would mitigate inflammation and coagulation in patients with COVID‐19. However, clinical trials with TCZ have recorded an increase in D‐dimer levels. In contrast to TCZ, colchicine reduced D‐dimer levels in patients with COVID‐19. To understand how the two anti‐inflammatory agents have diverse effects on D‐dimer levels, we present data from two clinical trials that we performed. In the first trial, TCZ was administered (8 mg/kg) to patients who had a positive polymerase chain reaction test for COVID‐19. In the second trial, colchicine was given (0·5 mg twice a day). We found that TCZ significantly increased IL‐6, α‐Defensin (α‐Def), a pro‐thrombotic peptide, and D‐dimers. In contrast, treatment with colchicine reduced α‐Def and Di‐dimer levels. In vitro studies show that IL‐6 stimulated the release of α‐Def from human neutrophils but in contrast to colchicine, TCZ did not inhibit the stimulatory effect of IL‐6; raising the possibility that the increase in IL‐6 in patients with COVID‐19 treated with TCZ triggers the release of α‐Def, which promotes pro‐thrombotic events reflected in an increase in D‐dimer levels.