Yan, Elizabeth

OBJECTIVE The objective of this study was to analyze the hemorrhagic risk of melanoma brain metastases after Gamma Knife radiosurgery (GKRS). METHODS A prospective institutional database was retrospectively queried to identify patients who underwent GKRS for melanoma brain metastases between 1990 and 2021. Lesional hemorrhage was defined as definite or possible based on radiologists’ readings, and severity was graded according to Common Terminology Criteria for Adverse Events. RESULTS Two hundred ninety-one patients with 1083 lesions treated in 419 sessions were identified. The mean (± SD) patient age was 60 ± 15 years, and 61% were male. The median follow-up period for overall survival (OS) was 11 (range 0–214) months with 581 patient-years. Definite/possible lesional hemorrhages occurred in 13% of lesions, with grade 3 hemorrhages observed in 4% of lesions. Surgical intervention was required in 2% of cases (5% of patients), and all resected lesions were pathologically consistent with melanoma. A decreased risk of definite/possible lesional hemorrhage was associated with a later time period between 2015 and 2021 (OR 0.45, 95% CI 0.266–0.75, p = 0.0021), increased marginal dose (OR 0.91, 95% CI 0.83–0.99, p = 0.037), antiplatelet use post-GKRS (OR 0.195, 95% CI 0.083–0.46, p < 0.001), and whole-brain radiotherapy (WBRT; OR 0.53, 95% CI 0.344–0.82, p = 0.0042). After 2015, more patients received anticoagulation, B-Raf proto-oncogene inhibitors, and immune checkpoint inhibitors, and fewer received bevacizumab (p < 0.001). The cumulative risk of lesional hemorrhage was 17%–20% at 36 months from GKRS, with 95%–96% of cases occurring within 12 months. The median patient OS was 11 (95% CI 9–13) months, and multivariate Cox regression analysis revealed that antiplatelet agents (hazard ratio [HR] 0.66, 95% CI 0.45–0.96, p = 0.031) and immune checkpoint inhibitors (HR 0.35, 95% CI 0.26–0.48, p < 0.001) were associated with longer OS, while WBRT (HR 1.36, 95% CI 1.02–1.81, p = 0.037) and definite/possible hemorrhage (HR 1.39, 95% CI 1.04–1.85, p = 0.024) were associated with shorter OS. CONCLUSIONS The definite hemorrhage risk of melanoma brain metastases after GKRS was 17% in the first 3 years and 95% of the lesional hemorrhage occurred within the 1st year. Surgical intervention was needed in 5% of patients. Antiplatelet agents and immune checkpoint inhibitors were associated with improved OS, while definite/possible hemorrhage was associated with worse OS.

Abstract Purpose/Objectives: Proton therapy is under investigation in breast cancer as a strategy to reduce heart and lung exposure, which is associated with late cardiopulmonary adverse events and secondary malignancy. To date, studies investigating postmastectomy radiotherapy (PMRT) with protons have used conventional fractionation. We hypothesized that condensing treatment to 15 fractions would be safe based on evidence that breast cancer is more sensitive to higher dose fractions than surrounding normal tissues. Materials/Methods: We conducted a randomized non-inferiority phase II trial comparing conventional and hypofractionated proton PMRT with primary endpoint of 24-month complication rate (defined as grade 3 or higher late adverse events using CTCAE, v 4.0 and/or unplanned surgical intervention in patients undergoing mastectomy with reconstruction). With a 10% non-inferiority margin the study ensured 80% power and had a one sided-type I error rate of 0.05. Cardiotoxicity was assessed with serial transthoracic conventional and 2-dimensional speckle tracking echocardiography (2D-STE). Eligibility included age ≥ 18 years with non-inflammatory breast cancer resected by mastectomy with indications for PMRT. Assignment of treatments was balanced with respect to immediate breast reconstruction (IBR). Conventional fractionation group received 50 Gy in 25 fractions of 2 Gy, and hypofractionation group received 40.05 Gy in 15 fractions of 2.67 Gy (RBE 1.1). Target volume included the chest wall and axillary, supraclavicular, and internal mammary lymph nodes. All patients were treated with multi-field optimized pencil beam scanning (intensity modulated proton therapy). Results: Between 2016 and 2018, 82 patients were enrolled and randomized (41 conventional, 41 hypofractionation). Median patient age was 52 years. 32.9% were staged T3-T4 and 79.3% node positive at diagnosis. 57 of 82 patients (69.5%) elected IBR. The median mean heart dose was 0.49 Gy and the median ipsilateral lung volume receiving 40% of prescription or greater (V40%) was 13.6%. No significant changes on conventional or 2D-STE at end-of-treatment or 3-month follow-up compared to baseline were observed. The rate of ≥ grade 2 acute dermatitis was lower with hypofractionation (44% vs 15%, p = 0.006). Other ≥ grade 2 acute adverse events including esophagitis (0 vs 5%), infection (5% vs 2.4%) and skin hyperpigmentation (7.3% vs 4.8%) were not significantly different between the two arms. With a median follow-up of 38.3 months, the 24-month complication rate was conventional 14.6% vs hypofractionation 17.1% (absolute difference 2.4%, p=0.17, 95% CI [-, 15.7%]). In patients with IBR, 6 of 28 (21.4%) conventional and 7 of 29 (24.1%) hypofractionated patients developed complications (p =0.80). There was no significant difference in 3-year disease-free survival between the conventional (89.4%; 95% CI 80.0 – 99.8%) and hypofractionated (92.4%, 95% CI 84.5 – 100.0%) arms (p = 0.91). One local recurrence occurred in the hypofractionated arm simultaneous with regional and distant relapse. The remaining 6 recurrences were isolated distant events. Conclusions: Proton PMRT provided excellent locoregional control and normal tissue sparing. There were no subclinical echocardiographic changes indicative of radiation-induced cardiac dysfunction. Hypofractionation resulted in comparable disease control, tolerability and reconstruction outcomes as conventional fractionation. Although non-inferiority of hypofractionation could not be established based on the upper bound of the 95% confidence interval for complication rate being greater than 10%, both conventional and hypofractionation may be considered appropriate regimens for ongoing phase 3 randomized trials comparing photon and proton radiotherapy. Citation Format: Robert Mutter, Sharmila Giri, Briant Fruth, Nicholas Remmes, Aman Anand, Kathryn Ruddy, Hector Villarraga, Sebastian Santos Patarroyo, Elizabeth Yan, Kenneth Merrell, Lisa McGee, Tamara Vern-Gross, Bradley Stish, Robert Gao, Judy C. Boughey, Sean Park, Kimberly Corbin, Carlos Vargas. Phase II randomized trial of conventional versus hypofractionated post-mastectomy proton radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-05.

Abstract BACKGROUND Interpretation of serial magnetic resonance imaging (MRI) for glioblastoma following radiation therapy (RT) is complicated by difficulty differentiating tumor from treatment-related changes, even using updated RANO criteria. The incorporation of novel imaging such as 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) PET/CT to post-treatment serial imaging may improve prognostication and better facilitate future treatment decisions. METHODS The secondary analysis of a recent phase II prospective clinical trial of 18F-DOPA PET/CT-directed dose-escalated RT included patients with IDH-wildtype, MGMT-unmethylated glioblastoma who underwent post-treatment serial 18F-DOPA PET/CT surveillance. Quantitative features were extracted from pre-RT and post-RT serial PET/CT images, and robust prognostic features were selected using an in-house workflow. Both an automated machine learning (ML) algorithm and an interpretable ML algorithm were utilized to correlate surveillance PET image features with subsequent survival of greater than 12 months versus less than 12 months from the surveillance timepoint. Changes from pre-RT to post-RT PET/CT (delta model) were also assessed for association with post-RT survival and validated with a separate cohort. RESULTS Thirty-five patients with IDH-wildtype, MGMT-unmethylated glioblastoma who had at least one available (range: 1-14) post-treatment 18F-DOPA PET/CT were included. Twenty-four were used for model training, while 11 were used for validation. Ultimately, a five-feature post-RT model utilizing two shape, two texture, and one first-order radiomic feature was selected. For the delta model, five texture, two shape, and one first order radiomic feature were selected. The models show 90% accuracy in predicting survival &lt; 12 months post-surveillance on the training set, and 68%-73% accuracy (AUC 0.64-0.73) for the validation cohort. Delta features were significantly associated with overall survival (p &lt; 0.05). CONCLUSIONS Post-RT serial 18F-DOPA PET/CT imaging can help distinguish true tumor progression in patients with glioblastoma using a radiomics model. Tumor response evaluated for changes from pre-RT to post-RT 18F-DOPA PET/CT also predicted subsequent overall survival.

Abstract Medulloblastoma is a posterior fossa tumor rarely diagnosed in adults. Treatment includes craniospinal irradiation (CSI). Proton CSI is increasingly utilized to decrease radiation dose to normal tissues, despite the lack of randomized data demonstrating decreased toxicity compared to photon CSI. This single institution retrospective study of 39 adult medulloblastoma patients includes nineteen patients treated with photon CSI prior to 2015, and twenty treated with proton CSI thereafter. Median age was 28 years (range 18-66). Molecular subtype was most commonly sonic hedgehog (68%). The most common fractionation schedule was 36 Gy CSI in 20 fractions (85% of photon and 58% of proton patients) with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to the cochleae (median 32 Gy vs. 44 Gy), lacrimal glands (8 vs. 36 Gy), lens (2 vs. 28 Gy), parotid glands (3 vs. 26 Gy), pharyngeal constrictors (6 vs. 15 Gy), esophagus (2 vs. 29 Gy), heart (0 vs. 14 Gy), lungs (1 vs. 7 Gy), liver (0.1 vs. 7 Gy), and skin (38 vs. 51 Gy) (all p&lt; 0.001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% vs. 35%, p= 0.044) and decreased median weight loss during radiation (+1.0 vs. -2.8 kg, p= 0.011). Acute hospitalization was associated with increased weight loss (p= 0.009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At last follow-up five photon patients had died (two of progressive disease, three without recurrence ages 41-63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. In conclusion, this study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.

Abstract While dose escalation of radiotherapy (DERT) has failed to improve overall survival (OS) or progression-free survival (PFS) for glioblastoma in previous studies, a recent phase II clinical trial utilizing 18F-DOPA-PET-directed DERT demonstrated improved PFS in MGMT-unmethylated patients and OS in MGMT-methylated patients compared to historical controls. This planned secondary analysis sought to determine 1) how 18F-DOPA-PET changes RT volumes beyond standard MRI-planning, 2) which patients benefit most and least from this protocol, 3) which are mostly likely to experience clinically significant radionecrosis after DERT, and 4) patterns of failure after DERT. For 69 evaluable patients, median MRI-defined, PET-defined, and combined low-dose gross tumor volumes (GTV51) were 54 cc (range 9-248), 23 cc (0.4-179), and 62 cc (10-260), respectively. Median MRI-defined, PET-defined, and combined high-dose GTVs (GTV76) were 32 cc (range 4-136), 6 cc (0.1-138), and 34 cc (4-162), respectively. 18F-DOPA-PET resulted in a median volumetric expansion of 13% (0-243%) and 5% (0-217%) from MRI-defined low-dose and high-dose GTV’s, respectively. Central failures ( &gt;95% of recurrence tumor volume) occurred within the 76 Gy, 60 Gy, and 51 Gy isodose lines in 32 (46%), 60 (87%), and 64 (93%) patients, respectively. Recursive partitioning analysis stratified patients by OS and PFS. Patients with 18F-DOPA-PET-defined GTV76 &gt; 7.8cc, MRI-defined GTV76 &gt; 42.7cc, and MGMT promotor-unmethylated tumors had the shortest OS, while patients with smaller PET and MRI-defined tumors had the longest OS (median 10.4 vs. 64.6 months, p&lt; 0.001). Similarly, PFS was worst in patients with 18F-DOPA-PET-defined GTV76 &gt; 2.17 cc who had biopsy only (median PFS 3.2 months, p&lt; 0.001). Patients with 18F-DOPA-PET-defined GTV51 &gt; 50 cc had the highest risk of grade 3+ radionecrosis (p&lt; 0.001). In conclusion, larger 18F-DOPA-PET and MRI-defined tumor volumes were associated with worse outcomes, and 18F-DOPA-PET-directed DERT appears to reduce risk of central recurrence in high-dose volumes.

Abstract PurposeTo clarify the role of stereotactic radiosurgery (SRS) for atypical meningiomas (AM).MethodsA retrospective analysis of 68 patients with AM having SRS from 1995 until 2019. Nineteen patients (28%) had undergone prior external beam radiation therapy (EBRT) (median dose, 54 Gy). The median follow-up period was 52 months.ResultsEighteen (26%), 17 (25%), and 33 (49%) patients received SRS as an upfront adjuvant (≤ 6 months), early salvage (7-18 months), or late salvage treatment (> 18 months), respectively. The 3-, 5-, and 10-year progression-free survivals (PFSs) were 52%, 35%, and 25%, respectively. The 3-, 5-, and 10-year disease-specific survivals (DSSs) were 85%, 78%, and 61%, respectively. Adverse radiation events (AREs) were observed in 12 patients (18%), with increased or new seizures being the most frequent complication (n=7). Prior EBRT was associated with reduced PFS (HR = 5.92, P <0.01), reduced DSS (HR = 5.84, P <0.01), and an increased risk of ARE (HR = 3.31, P = 0.04). Timing of SRS was correlated with reduced PFS for patients having early salvage treatment compared to upfront adjuvant (HR = 3.17, P = 0.01) or late salvage treatment (HR = 4.39, P <0.01). ConclusionPFS for patients with residual/recurrent AM remains poor despite SRS. Prior EBRT was associated with worse tumor control, higher tumor-related mortality, and an increased risk of ARE. Further study on the timing of SRS is needed to determine if upfront adjunctive SRS improves tumor control compared to salvage SRS.

Background: Contemporary breast cancer radiotherapy (RT) results in variable cardiac radiation exposure. While cardiomyocytes are radio-resistant, radiation induces coronary microvascular endothelial damage and inflammation which may ultimately lead to myocardial inflammation, ischemia and fibrosis and put patients at risk for heart failure (HF) and particularly, HF with preserved ejection fraction (HFpEF). Methods: Community based (Olmsted County, MN), HF case-control study of contemporary (1999-2014) breast cancer RT patients with CT-based RT planning for precise mean cardiac radiation dose (MCRD) calculation. HF cases (n=66) and controls (n=129) were matched (1:2) for age at RT, HF risk factors, tumor side and chemotherapy use. Matched controls and cases had identical follow-up (index interval). Proportion of HF and clinical characteristics in categories of MCRD were reported (table) and conditional logistic regression was used to estimate the HF odds ratio (OR) associated with MCRD as a continuous variable. Results: Of the 66 HF cases, 46 (70%) had HFpEF and 20 (30%) had HF with reduced ejection fraction (HFrEF). The proportion of patients with HF (any) or HFpEF increased and proportion with HFrEF tended to increase with increasing MCRD. The prevalence of HF risk factors (hypertension, diabetes, coronary disease) at time of RT did not vary by MCRD while left sided tumor, cancer stage and adriamycin use increased with increasing MCRD. The OR per 1 unit increase in log MCRD was 3.71 (1.98, 6.94) for total HF (p<0.001), 4.91 (1.93, 9.09) for HFpEF (p<0.001) and 2.78 (0.91, 8.47) for HFrEF (p=0.07). The mean index interval was 5.0±3.2 years. Conclusion: Cardiac radiation incident to contemporary breast RT increases the risk of HF, and particularly HFpEF over a short post-RT interval. These data may guide use of proton beam therapy in breast cancer. These data also provide support for the role of coronary microvascular compromise in the pathophysiology of HFpEF.

Abstract Background Patterns of recurrence and survival with different surgical and radiotherapy (RT) techniques were evaluated to guide RT target volumes for patients with temporal lobe glioma. Methods and Materials This retrospective cohort study included patients with World Health Organization grades II to IV temporal lobe glioma treated with either partial (PTL) or complete temporal lobectomy (CTL) followed by RT covering both the parenchymal and dural resection bed (whole-cavity radiotherapy [WCRT]) or the parenchymal resection bed only (partial-cavity radiotherapy [PCRT]). Patterns of recurrence, progression-free survival (PFS) and overall survival (OS) were evaluated. Results Fifty-one patients were included and 84.3% of patients had high-grade glioma (HGG). CTL and PTL were performed for 11 (21.6%) and 40 (78.4%) patients, respectively. Median RT dose was 60 Gy (range, 40-76 Gy). There were 82.4% and 17.6% of patients who received WCRT and PCRT, respectively. Median follow-up time was 18.4 months (range, 4-161 months). Forty-six patients (90.2%) experienced disease recurrence, most commonly at the parenchymal resection bed (76.5%). No patients experienced an isolated dural recurrence. The median PFS and OS for the PCRT and WCRT cohorts were 8.6 vs 10.8 months (P = .979) and 19.9 vs 18.6 months (P = .859), respectively. PCRT was associated with a lower RT dose to the brainstem, optic, and ocular structures, hippocampus, and pituitary. Conclusion We identified no isolated dural recurrence and similar PFS and OS regardless of postoperative RT volume, whereas PCRT was associated with dose reduction to critical structures. Omission of dural RT may be considered a reasonable alternative approach. Further validation with larger comparative studies is warranted.

Contralateral axillary metastasis (CAM) in breast cancer is presently treated as a stage IV disease. We hypothesized that this disease pattern is a manifestation of direct aberrant lymphatic drainage and would behave more similar to advanced locoregional disease. This is a single-site, retrospective review of patients with biopsy-proven CAM from 2008–2017. Descriptive analysis was performed. Twenty-three patients met the inclusion criteria. The median disease-free interval from primary tumor treatment to diagnosis of CAM was 68 months (range, 36–155 months). This population had aggressive disease (74% local recurrences and 61% clinical evidence of cutaneous or underlying muscular invasion) and extensive locoregional therapy (70% radiated, 57% mastectomy, and 65% axillary lymph node dissection) before their presentation with CAM. Fifteen (65.2%) patients recurred after treatment of CAM; the median recurrence-free interval was 11 months (range, 5–23 months), and 12 (52.2%) patients developed distant metastases. The median distant metastasis-free survival was 14 months (range, 11–23 months), and the median overall survival was 31 months (range, 22–67.5 months). Development of CAM is associated with aggressive disease and extensive prior locoregional surgery and/or radiation. The short recurrence-free interval and high progression to additional stage IV disease suggest these patients behave similar to traditional stage IV patients with resected oligometastatic disease.

Abstract BACKGROUND Treatment of temporal lobe glioma (TLG) frequently includes partial or complete temporal lobectomy (TL) followed by radiotherapy (RT). However, there are two approaches for temporal resection cavity RT, 1) standard target volumes (STV) targeting the entire TL resection cavity, dura, and peri-tumoral brain parenchyma or 2) modified target volumes (MTV) targeting only the adjacent peri-tumoral brain parenchyma. We report patterns of failure and a dosimetric comparison of these approaches. MATERIALS AND METHODS This was a retrospective review of 49 patients with WHO grade II-IV TLG who underwent partial or complete TL and post-operative RT between 1998 and 2018. Progression-free survival (PFS) was estimated using the Kaplan-Meier method. RESULTS The median patient age was 56 years (range,21–76). Patients were diagnosed with glioblastoma (n=32,65%), anaplastic glioma (n=10,20%) and low-grade glioma (n=7,14%). Treatment included partial TL with STV (n=33,67%), partial TL with MTV (n=5,10%), complete TL with STV (n=8,16%) and complete TL with MTV (n=3,6%). Mean RT dose was 60 Gy (range,40–76) in 30 fractions (range,15–39). At median follow-up time of 18 months (range, 3–161), 44 patients (90%) experienced recurrence: 34 (77%) in-field, 5 (11%) out-of-field, and 5 (11%) both in- and out-of-field. Among the 39 in-field failures, the location of recurrence included brain parenchyma (n=38,97%), ventricle (n=6,15%), and dura (n=5,13%). No patient experienced isolated dural recurrence regardless of tumor grade, extent of TL, or radiation volume. Median PFS was 20 months (95% confidence interval [CI]: 15–24). RT volume (STV vs. MTV) was not associated with worsened PFS (hazard ratio: 1.1, 95% CI: 0.5–2.6). MTV was associated with significant reductions in mean or max doses to brain stem, optic chiasm, optic nerves, hippocampus, and pituitary compared to STV. CONCLUSION Omitting RT to the entire TL cavity may reduce dose to multiple normal tissues with no detriments in dural recurrence or PFS.