Higgins, Kristin Ann

Background/Objectives: Proton therapy delivers highly conformal doses to the target area without producing an exit dose, minimizing cumulative doses to healthy liver tissue. This study aims to evaluate current practices, challenges, and variations in the implementation of proton stereotactic body radiation therapy (SBRT) and hypofractionated therapy for liver malignancies, with the goal of providing a technical assessment to promote broader adoption and support future clinical trials. Methods and Materials: An extensive survey was conducted by NRG Oncology across North American proton treatment centers to assess the current practices of proton liver SBRT and hypofractionated therapy. The survey focused on key aspects, including patient selection, prescription and normal tissue constraints, simulation and motion management, treatment planning, quality assurance (QA), treatment delivery, and the use of image-guided radiation therapy (IGRT). Results: This survey captures the current practice patterns and status of proton SBRT and hypofractionated therapy in liver cancer treatment. Proton therapy is increasingly preferred for treating inoperable liver malignancies due to its ability to minimize healthy tissue exposure. However, the precision required for proton therapy presents challenges, particularly in managing uncertainties and target motion during high-dose fractions and short treatment courses. Survey findings revealed significant variability in clinical practices across centers, highlighting differences in motion management, dose fractionation schedules, and QA protocols. Conclusion: Proton SBRT and hypofractionated therapy offer significant potential for treating liver malignancies. A comprehensive approach involving precise patient selection, treatment planning, and QA is essential for ensuring safety and effectiveness. This survey provides valuable insights into current practices and challenges, offering a foundation for technical recommendations to optimize the use of proton therapy and guide future clinical trials.

Abstract Background: The benefit of adjuvant regional nodal irradiation including the chest wall after mastectomy (CWI+RNI) and with whole breast irradiation (WBI+RNI) after breast conserving surgery (BCS) is well established in pts with pathologically positive axillary nodes (pN+). Pts who present with axillary node involvement (cN+), receive neoadjuvant chemotherapy (NC), and are found to be pathologically node-negative at surgery (ypN0), have lower loco-regional recurrence (LRR) rates compared to those who remain pathologically node-positive (ypN+). This phase III, randomized trial aimed to evaluate whether CWI+RNI after mastectomy or addition of RNI to WBI after BCS significantly improves invasive breast cancer recurrence-free interval (IBC-RFI) in cN+ pts found to be ypN0 after NC. Methods: Eligible pts had clinical cT1-3, N1, M0 invasive breast cancer (biopsy-proven N+ by FNA/core needle bx), completed ≥8 wks of NC (and anti-HER2 therapy if HER2+), and were ypN0 after mastectomy or BCS and sentinel node biopsy (SLNB, ≥2 nodes), axillary lymph node dissection (ALND), or both. Pts were randomized to “No RNI” (i.e., observation after mastectomy or WBI after BCS) vs. “RNI” (i.e., CWI+RNI after mastectomy or WBI+RNI after BCS). Primary endpoint was IBC-RFI. Secondary endpoints reported here: LRR-free interval (LRRFI), distant recurrence-free interval (DRFI), disease-free survival (DFS), and overall survival (OS). Study was designed to have 80% power to detect 35% reduction in annual rate of IBC-RFI for an absolute risk reduction of 4.6% (5-yr cumulative rate). Per protocol, final analysis was to occur after 172 events or 10 yrs after study initiation.Here we report the time-driven analysis prespecified in the protocol. Results: From 9/13-12/20, 1,641 pts were enrolled; 1,556 pts were available for primary event analysis; median f/u time 59.5 mos (IQR 40.7-74.1). Pt/tumor characteristics were well balanced between groups. Median age 52 yrs (range 21-84); 31% non-white; 21% cT1, 60% cT2, 19% cT3; 23% triple-negative, 21% HR+/HER2-, 56% HER2+; 58% BCS; 55% SLNB, 45% ALND+/-SLNB; and 78% had breast pathologic complete response. At the time of the analysis, 109 IBC-RFI events (63% of the planned 172) were confirmed (“No RNI”: 59, “RNI”: 50). There was no statistically significant difference between groups for IBC-RFI (HR=0.88, 95%CI 0.60-1.29; p=0.51), 5-yr point estimates: 91.8% for “No RNI” and 92.7% for “RNI.” There were no statistically significant differences between the treatment groups for secondary endpoints. There were no study-related deaths and no unexpected toxicities.Grade 4 toxicity was rare (0.1% with “No RNI”, 0.5% with “RNI”); 6.5% of pts developed grade 3 toxicity in “No RNI” and 10% in “RNI” group. Most common grade 3 toxicity was radiation dermatitis (3.3% in “No RNI,” 5.7% in “RNI”). Conclusion: In pts who present with biopsy-proven axillary node involvement and convert their axillary nodes to ypN0 after NC, CWI+RNI after mastectomy, or WBI+RNI after BCS, did not significantly improve IBC-RFI, LRRFI, DRFI, DFS, or OS. These findings suggest that downstaging involved axillary nodes with NC can result in optimization of adjuvant radiotherapy without adversely affecting oncologic outcomes. Follow-up of pts for long-term outcomes continues. NCT01872975 *EPM and JW are co-first authors. Table 1 Citation Format: Eleftherios Mamounas, Hanna Bandos, Julia White, Thomas Julian, Atif Khan, Simona Shaitelman, Mylin Torres, Frank Vicini, Patricia Ganz, Susan McCloskey, Nilendu Gupta, X. Allen Li, Peter Lucas, Nadeem Abu-Rustum, Saumil Gandhi, Rahul Tendulkar, Robert Coleman, Keiichi Fujiwara, Samantha Seaward, William Irvin, Kristin Higgins, Robert Mutter, Jean-Francois Boileau, Andrew Muskovitz, Reshma Jagsi, Anna Weiss, Curran Walter Jr., Norman Wolmark. Loco-Regional Irradiation in Patients with Biopsy-proven Axillary Node Involvement at Presentation Who Become Pathologically Node-negative After Neoadjuvant Chemotherapy: Primary Outcomes of NRG Oncology/NSABP B-51/RTOG 1304 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-07.

Abstract The CD8 + T-cell response is prognostic for survival outcomes in several tumor types. However, whether this extends to tumors in the brain, an organ with barriers to T cell entry, remains unclear. Here, we analyzed immune infiltration in 67 brain metastasis (BrM) and found high frequencies of PD1 + TCF1 + stem-like CD8 + T-cells and TCF1- effector-like cells. Importantly, the stem-like cells aggregate with antigen presenting cells in immune niches, and niches were prognostic for local disease control. Standard of care for BrM is resection followed by stereotactic radiosurgery (SRS), so to determine SRS’s impact on the BrM immune response, we examined 76 BrM treated with pre-operative SRS (pSRS). pSRS acutely reduced CD8 + T cells at 3 days. However, CD8 + T cells rebounded by day 6, driven by increased frequency of effector-like cells. This suggests that the immune response in BrM can be regenerated rapidly, likely by the local TCF1 + stem-like population.

PURPOSE The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on radiation therapy (RT) for small-cell lung cancer (SCLC). Because of the relevance of this topic to ASCO membership, ASCO reviewed the guideline, applying a set of procedures and policies used to critically examine guidelines developed by other organizations. METHODS The ASTRO guideline on RT for SCLC was reviewed for developmental rigor by methodologists. Then, an ASCO Expert Panel reviewed the content and the recommendations. RESULTS The ASCO Expert Panel determined that the recommendations from ASTRO guideline on RT for SCLC, published in June 2020, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed ASTRO guideline on RT for SCLC with a few discussion points. RECOMMENDATIONS Recommendations addressed thoracic radiotherapy for limited-stage SCLC, role of stereotactic body radiotherapy in stage I or II node-negative SCLC, prophylactic cranial radiotherapy, and thoracic consolidation for extensive-stage SCLC. Additional information is available at www.asco.org/thoracic-cancer-guidelines .

TPS9082 Background: Limited stage small cell lung cancer (LS-SCLC) is treated with standard of care platinum/etoposide (EP) and thoracic radiation therapy (TRT) with curative intent, however the majority of patients are not cured and median overall survival is approximately 30 months. Addition of atezolizumab to chemotherapy in extensive stage SCLC has improved progression free and overall survival in a non-curative setting leading to hope that addition of an immune checkpoint inhibitor to standard chemoradiotherapy could benefit LS-SCLC patients. LU005 is a randomized phase II/III trial of standard concurrent chemoradiation with or without atezolizumab for patients with LS-SCLC. Methods: Patients are randomly assigned in a 1:1 ratio to standard EP chemotherapy with concurrent TRT (45 Gy BID or 66 Gy QD) with or without atezolizumab beginning concurrently with TRT, and continued every 3 weeks for up to 12 months. Eligible patients have LS-SCLC, PS 0-2, adequate organ function, no concerning comorbidities (including no active autoimmune disease) and are eligible for TRT. Patients are randomized prior to their second cycle of EP and thoracic radiation begins with the second overall cycle of chemotherapy (first cycle of study therapy) in both treatment arms. Prophylactic cranial radiation (PCI) is recommended for patients who respond to treatment. The phase II/III primary endpoints are progression free (PFS) and overall survival (OS) respectively. Secondary endpoints include objective response rates, local and distant disease control, and quality of life/patient reported outcomes assessment. Translational science component includes blood and tissue based immune related assays. This study activated in May 2019. 50 of 506 planned patients have been accrued as of 2/1/2020. Supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U23CA180803 (IROC) from the National Cancer Institute (NCI) and Genentech. *Authors Ross and Higgins are co-first authors and contributed equally to this work. Clinical trial information: NCT03811002.