Faculty Bibliography

PURPOSE/OBJECTIVE(S)/OBJECTIVE:Radiation therapy (RT) positioning and planning are vital to minimizing toxicity in patients with synchronous bilateral breast cancer (SBBC). We studied clinical outcomes and setup reproducibility in SBBC patients treated in the prone position. MATERIALS/METHODS/METHODS:This retrospective study analyzed SBBC patients treated prone between 2012-2022. Demographics, clinical RT dose/field, dosimetry, on-treatment imaging, toxicity, and outcomes data were collected. RT delivery was standardized, with left breast treated first. After 2014, radiochromic (GaF) films were placed fractions 1-5 to evaluate field overlap, prompting re-simulation or re-planning if consistent overlap was detected. Positional shifts during setup were collected for bilateral whole breast irradiation (WBI) and partial breast irradiation (PBI). RESULTS:45 patients were included. Median age was 67 years old and median follow-up was 64 months. 35, 5, and 5 patients received bilateral WBI (1 with low axilla), bilateral PBI, a combination of WBI and PBI, respectively. The most common WBI dose was 40.5 Gy, with a simultaneous tumor bed boost to 48 Gy. PBI patients received 30 Gy in 5 fractions (n=4) or 40.05 Gy in 15 fractions (n=1). All patients who developed grade 2 (17.7%) and grade 3 (2%) dermatitis received bilateral WBI except for 1. 6 patients had acute dermatitis in the sternal area with overlap on GaF seen in 2 patients. Of 20 patients with late toxicity follow-up, 25% had late grade 1-2 dermatitis (20% received WBI). One patient recurred locally and distantly. Mean positional shifts were mostly sub-centimeter or sub-degree. Only 10% of patients had field overlap on GaF. CONCLUSION/CONCLUSIONS:To our knowledge, this is the first study examining patients treated for SBBC in the prone position. Prone bilateral RT is feasible with minimal shifts and overlap. However, higher rates of acute dermatitis occurred in bilateral WBI patients (vs. PBI), and overlap wasn't seen on GaF in all patients who developed midline dermatitis.

PURPOSE/OBJECTIVE:Intensity-modulated radiation therapy (IMRT) is increasingly used for total body irradiation (TBI) due to its ability to deliver myeloablative doses while sparing radiosensitive organs. To enable consistent evaluation in future National Clinical Trials Network (NCTN) studies, the xxx Hematologic Malignancies Working Group (HMWG) convened IMRT-TBI experts and NCTN leaders to develop consensus recommendations for standardized multi-institutional implementation. METHODS:A 47-question survey was distributed to NRG institutions utilizing IMRT-TBI to characterize current planning and delivery practices. Responses were analyzed for commonalities and variations. A multidisciplinary working group reviewed survey findings, developed consensus-based technical and clinical recommendations, and created a standardized template for IMRT-TBI integration into NCTN protocols. Topics included simulation, contouring, planning, organ-at-risk (OAR) constraints, quality assurance (QA), image-guided radiotherapy (IGRT), commissioning, credentialing, and safeguards for clinical trial conduct. RESULTS:Eight institutions with collective experience treating more than 750 patients with IMRT-TBI responded. Most centers used VMAT to the upper body with anteroposterior/posteroanterior (AP/PA) fields to the lower body, 3-9 isocenters, lower dose rates for lung fields (100-200 MU/min), and no physical bolus. Common OAR constraints included lungs mean dose <8 Gy, kidneys mean dose <6-8 Gy, and lenses maximum dose <90% of prescription. All respondents used auto-segmentation; 50% used auto-planning. QA practices varied, but patient-specific QA passing rates were high (>95% with 3%/2 mm gamma). Consensus recommendations for clinical trial use were established, including standardized PTV definitions, OAR sparing goals, dosimetric constraints, QA requirements, and credentialing processes. CONCLUSIONS:IMRT-TBI offers the potential for reduced toxicity and improved dose precision compared with 2D-TBI, but its complexity requires careful standardization in multi-institutional trials. The xxx HMWG and collaborating NCTN experts developed the consensus-based technical and clinical framework for incorporating IMRT-TBI into cooperative group protocols. Adoption of these recommendations will facilitate consistent implementation and enable rigorous evaluation of outcomes.

PURPOSE/OBJECTIVE:Improved communication by clinicians at initial consultation may reduce anxiety and psychological burden of cancer treatment. Based on our pilot qualitative study which involved semi-structured interviews with breast cancer patients, we developed Curietherapy User eXperience (CurieUx), an educational tool integrating augmented reality display technology into radiation oncology consultations. METHODS:We developed an interactive 3-dimensional hologram using an augmented reality desktop display. Animated modules on patient-specific anatomy (breast, regional lymph nodes, organs-at-risk), simulation, linear accelerator, and positioning (prone and breath holding techniques) were created. Patients with newly diagnosed breast cancer undergoing initial radiation oncology consult were prospectively enrolled. Likert scale surveys on anxiety (NIH PROMIS), radiation knowledge, and augmented reality experience (modified IBM technology usability survey) were administered to patients before and after consultation. RESULTS:A total of 40 newly diagnosed breast cancer patients were enrolled in this proof-of-concept study at a median age of 67 years. Patients reported decreases in multiple components of anxiety after consultation with the CurieUx platform, including in fearfulness (2.13 vs 1.78, p=0.003), uneasiness (2.28 vs. 1.82, p=0.008), nervousness (2.41 vs 2.06, p=0.005), and tenseness (2.28 vs 1.87, p=0.004). Patients reported significant increases in radiation knowledge across multiple domains, including treatment machine (2.35 vs 4.7, p<0.001), radiation (2.7 vs 4.58, p<0.001), positioning (2.49 vs 4.68, P<0.001), and confidence (2.4 vs 4.3, p<0.001). An overwhelming majority of patients had positive experiences (4 or 5 on Likert scale) using the CurieUx hologram display as part of consultation, including its ease of understanding (97%), clarity (93%), comfort (100%), value (97%), and satisfaction (97%). CONCLUSION/CONCLUSIONS:Curietherapy User eXperience is a valuable educational tool that reduces patient anxiety and promotes radiation knowledge. In this feasibility study, the vast majority of patients found the incorporation of CurieUx into the existing radiation oncology consultation practice to be a valuable addition to the process.

PURPOSE/OBJECTIVE:We present the preclinical rationale and clinical data from a phase 1b trial investigating the STING agonist dazostinag plus pembrolizumab following hypofractionated radiotherapy in patients with advanced non-small-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or squamous-cell carcinoma of the head and neck (SCCHN) whose disease had progressed on prior checkpoint inhibitors (CPIs) (NCT04879849). PATIENTS AND METHODS/METHODS:Eligible patients received radiation (8 Gy ×3 fractions) followed (≥40h) by pembrolizumab 200 mg every three weeks, and dazostinag in escalating doses (0.2-5.0 mg). Primary endpoints were safety and tolerability. Secondary endpoints included preliminary antitumor activity in irradiated and non-irradiated lesions, pharmacokinetics, and pharmacodynamic analyses. RESULTS:Preclinical studies demonstrated tumor control and enhanced intratumoral immune activation in mice treated with dazostinag plus radiation. Thirty-four patients (NSCLC: 15, SCCHN: 10, TNBC: 9) with a median number of six prior treatments were enrolled. Thirty-three (97.1%) patients reported treatment-emergent adverse events (TEAEs), none were dose-limiting toxicities; the most common were fatigue (52.9%), constipation (26.5%) and cough (20.6%). Dazostinag-related TEAEs occurred in 17 patients (50.0%); the most common were fatigue (26.5%), chills (8.8%), diarrhea, arthralgia, and myalgia (5.9% each). Antitumor activity, per RECIST v.1.1, was confirmed in two (7.1%) patients (one complete response and one partial response). Pharmacodynamic analyses indicated activation of STING and interferon-γ pathways across multiple dose levels, and induced immune responses, consistent with preclinical studies. CONCLUSIONS:Dazostinag, combined with pembrolizumab after radiotherapy, was well tolerated and demonstrated clinical activity in some patients with advanced/metastatic tumors whose disease had progressed on CPIs.

Clinicopathologic (CP) factors are used to estimate 10-year ipsilateral breast recurrence (IBR) risk and inform shared decision-making regarding post-operative radiation treatment (RT) for ductal carcinoma in situ (DCIS) patients. This study assesses the clinical value of the 7-gene biosignature (Lab-Location) compared to traditional CP definitions for predicting IBR rates and RT benefit. DCIS patients (n=926) treated with breast conserving surgery (BCS) ±RT were categorized as CP low-risk or high-risk based on established CP factors, study criteria, and nomograms. Women were classified as molecular Low Risk or High Risk by the biosignature. Ten-year IBR rates for CP risk groups were compared to and stratified by the biosignature. There were 37% of women classified as molecular Low Risk by the biosignature, while on average 47% were classified as low-risk by various CP definitions (range: 35-60%). Overall, CP low-risk groups had a mean absolute IBR benefit with RT of 6% (HR, 0.46; p<.001). The biosignature reclassified 53% of CP low-risk patients to molecular High Risk. These reclassified patients experienced higher IBR rates when RT was omitted and benefited from RT (HR, 0.30; p<.001) with an absolute reduction of 11.6% (17.7% vs. 6.1%). CP low-risk patients with concordant biosignature Low Risk demonstrated no significant RT benefit. On average, 28% of high-risk CP patients were reclassified as biosignature Low Risk and had no significant RT benefit (5.9% vs. 4.0%). This observational study supports optimizing de-escalation/escalation treatment strategies for DCIS, the 7-gene biosignature reliably discriminated a low-risk group without significant RT benefit compared to CP factors alone and an elevated risk group that benefitted from RT, facilitating improved shared decision making. A randomized clinical trial (NRG CC-016) will provide Level 1A evidence for the impact of RT treatment on IBR rates for patients in the 7-gene biosignature Low Risk group, including those with CP high-risk.

The overall number of breast cancer patients at risk of developing local-regional disease recurrence has been increasing due to long-term survivorship from improvements in multimodality breast cancer treatment and a steady increase in breast cancer incidence. Many patients receive radiotherapy as part of definitive multidisciplinary breast cancer treatment, and to date, practitioners have approached reirradiation delivery with reticence due to concern for serious toxicities that may be incurred with high cumulative radiation doses. However, a subset of patients with breast cancer recurrence may benefit from reirradiation for improved locoregional tumor control. An emerging body of evidence has demonstrated promising efficacy and safety of breast cancer reirradiation that are gradually redefining the treatment paradigm. In addition, an increase in systemic therapy options has further optimized the opportunity for successful salvage of breast cancer recurrence. In this critical review, we review breast cancer radiation and systemic therapy salvage options, available data, ongoing studies, and treatment delivery considerations.

PURPOSE/OBJECTIVE:The recently published results of the National Surgical Adjuvant Breast and Bowel Project B51 trial suggest that regional nodal irradiation may be safely omitted in patients with cT1-3N1 breast cancer treated with either lumpectomy or mastectomy, and achieve a pathologic complete response (pCR) in the regional nodes. Of note, almost 80% of patients on the trial demonstrated breast pCR. The goal of our study was to compare clinical outcomes between patients with breast pCR versus not. METHODS AND MATERIALS/METHODS:We included all patients treated at a single institution between 2010 and 2021 with cT1-3N1 breast cancer (pathologically proven via fine needle aspiration) who completed neoadjuvant chemotherapy and had axillary nodal pCR. Patients could undergo breast-conserving surgery or mastectomy. Univariate and multivariate logistic models were used to identify factors associated with breast pCR. Cox proportional hazard model was used to find independent prognostic variables associated with disease-free survival (DFS). RESULTS:We identified 124 patients meeting eligibility criteria. Of those, 72 patients (58%) achieved a breast pCR. On multivariate analysis, patients with human epidermal growth factor receptor (HER2)-positive breast cancer were more likely to develop breast pCR than patients with HER2-negative disease (odds ratio = 15.3; CI, 2.9-156.6; P = .001). At a median follow-up of 5 years, our study showed an overall low rate of local recurrence or distant metastasis with 5-year DFS of 92.3%. There was a numerically higher disease recurrence rate in patients without a breast pCR compared to those with a breast pCR, though this difference was not statistically significant (4.2% vs 12%; hazard ratio = 3.41; 95% CI, 0.53-22.1; P = .2). CONCLUSIONS:Our study showed that of the 124 patients who had pCR in the nodes, only 58% had a pCR in the breast, which is lower than the 80% rate seen in National Surgical Adjuvant Breast and Bowel Project B51. While our study found no significant difference in 5-year DFS between those with breast pCR versus not, given that patients with ER/PR+/HER2- disease are less likely to achieve breast pCR and tend to recur at later timepoints, further research is needed to evaluate the benefit of regional nodal irradiation in patients with a pCR in the axilla without a pCR in the breast.

Outcomes for patients with early breast cancer have improved in recent years as detection and treatments have improved. The goal of many recent trials has therefore been to identify patients in whom de-intensification of therapy may be appropriate, thereby maximizing the therapeutic ratio of breast cancer treatments. In each discipline within breast cancer, surgery, radiation oncology, and medical oncology, trials have explored treatment de-escalation. In surgery, studies evaluate the omission of surgery to the breast or axilla; in radiation oncology, studies evaluate reduced dose and/or number of fractions (hypofractionation), reduced target [partial breast irradiation (PBI)], and omission of RT altogether; in medical oncology, studies evaluate reduced duration, alternate forms, and omission of ET altogether. In many cases, these studies have shown that targeted omission or de-intensification does not compromise outcomes. The challenge in multidisciplinary care is how to implement these deintensification strategies for a particular patient in relation to other aspects of the overall treatment plan. In this critical review, we review the data in support of omission or de-intensification of surgical, radiation, and endocrine therapies in patients with low risk breast cancer, and consider these approaches in relation to one another.