Adverse radiation effect versus tumor progression following stereotactic radiosurgery for brain metastases: Implications of radiologic uncertainty.

BACKGROUND: Adverse radiation effect (ARE) following stereotactic radiosurgery (SRS) for brain metastases is challenging to distinguish from tumor progression. This study characterizes the clinical implications of radiologic uncertainty (RU). METHODS: Cases reviewed retrospectively at a single-institutional, multi-disciplinary SRS Tumor Board between 2015-2022 for RU following SRS were identified. Treatment history, diagnostic or therapeutic interventions performed upon RU resolution, and development of neurologic deficits surrounding intervention were obtained from the medical record. Differences in lesion volume and maximum diameter at RU onset versus resolution were compared with paired t-tests. Median time from RU onset to resolution was estimated using the Kaplan-Meier method. Univariate and multivariate associations between clinical characteristics and time to RU resolution were assessed with Cox proportional-hazards regression. RESULTS: Among 128 lesions with RU, 23.5% had undergone ≥ 2 courses of radiation. Median maximum diameter (20 vs. 16 mm, p < 0.001) and volume (2.7 vs. 1.5 cc, p < 0.001) were larger upon RU resolution versus onset. RU resolution took > 6 and > 12 months in 25% and 7% of cases, respectively. Higher total EQD2 prior to RU onset (HR = 0.45, p = 0.03) and use of MR perfusion (HR = 0.56, p = 0.001) correlated with shorter time to resolution; larger volume (HR = 1.05, p = 0.006) portended longer time to resolution. Most lesions (57%) were diagnosed as ARE. Most patients (58%) underwent an intervention upon RU resolution; of these, 38% developed a neurologic deficit surrounding intervention. CONCLUSIONS: RU resolution took > 6 months in > 25% of cases. RU may lead to suboptimal outcomes and symptom burden. Improved characterization of post-SRS RU is needed.

Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.

Tungsten Filled 3-Dimensional Printed Lung Blocks for Total Body Irradiation.

PURPOSE: Lung blocks for total-body irradiation are commonly used to reduce lung dose and prevent radiation pneumonitis. Currently, molten Cerrobend containing toxic materials, specifically lead and cadmium, is poured into molds to construct blocks. We propose a streamlined method to create 3-dimensional (3D)-printed lung block shells and fill them with tungsten ball bearings to remove lead and improve overall accuracy in the block manufacturing workflow. METHODS AND MATERIALS: 3D-printed lung block shells were automatically generated using an inhouse software, printed, and filled with 2 to 3 mm diameter tungsten ball bearings. Clinical Cerrobend blocks were compared with the physician drawn blocks as well as our proposed tungsten filled 3D-printed blocks. Physical and dosimetric comparisons were performed on a linac. Dose transmission through the Cerrobend and 3D-printed blocks were measured using point dosimetry (ion-chamber) and the on-board Electronic-Portal-Imaging-Device (EPID). Dose profiles from the EPID images were used to compute the full-width-half-maximum and to compare with the treatment-planning-system. Additionally, the coefficient-of-variation in the central 80% of full-width-half-maximum was computed and compared between Cerrobend and 3D-printed blocks. RESULTS: The geometric difference between treatment-planning-system and 3D-printed blocks was significantly lower than Cerrobend blocks (3D: -0.88 ± 2.21 mm, Cerrobend: -2.28 ± 2.40 mm, P = .0002). Dosimetrically, transmission measurements through the 3D-printed and Cerrobend blocks for both ion-chamber and EPID dosimetry were between 42% to 48%, compared with the open field. Additionally, coefficient-of-variation was significantly higher in 3D-printed blocks versus Cerrobend blocks (3D: 4.2% ± 0.6%, Cerrobend: 2.6% ± 0.7%, P < .0001). CONCLUSIONS: We designed and implemented a tungsten filled 3D-printed workflow for constructing total-body-irradiation lung blocks, which serves as an alternative to the traditional Cerrobend based workflow currently used in clinics. This workflow has the capacity of producing clinically useful lung blocks with minimal effort to facilitate the removal of toxic materials from the clinic.

Modifiable Post-Mastectomy Radiation Therapy Factors and Impact on Implant-Based Breast Reconstruction Outcomes.

INTRODUCTION: Intensity modulated radiation therapy (IMRT) and other modifiable radiation factors have been associated with decreased radiation toxicity. These factors could allow for improved reconstructive outcomes in patients requiring post-mastectomy radiation therapy (PMRT). However, they have not yet been well-studied in implant-based breast reconstruction (IBBR). METHODS: We performed a retrospective chart review of patients who underwent mastectomy with immediate tissue expander placement followed by PMRT. Radiation characteristics were collected, including radiation technique, bolus regimen, X-ray energy, fractionation, maximum radiation hot spot (DMax), and tissue volume receiving >105% (V105%) or >107% (V107%) of the prescription dose. Reconstructive complications occurring after initiation of PMRT were analyzed with respect to these radiation characteristics. RESULTS: 68 patients (70 breasts) were included in this study. The overall complication rate was 28.6%, with infection being the most common complication (24.3%), requiring removal of the tissue expander or implant in greater than half of infections (15.7%). DMax was greater in patients who required explant after PMRT, and this approached statistical significance (114.5+/-7.2% v. 111.4+/-4.4%, p=0.059). V105% and V107% were also greater in patients who required explant after PMRT (42.1+/-17.1% v. 33.0+/-20.9% and 16.4+/-14.5% v. 11.3+/-14.6%, respectively), however this was not statistically significant (p=0.176 and p=0.313, respectively). There were no significant differences in complication rates between patients with respect to radiation technique or other radiation characteristics studied. CONCLUSIONS: Minimizing the radiation hot spots and volumes of tissue receiving greater than the prescription dose of radiation may improve reconstructive outcomes in patients undergoing IBBR followed by PMRT.

Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

Background: Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Recent studies have proposed prognostic meningioma classification systems using DNA methylation profiling, copy number variants, DNA sequencing, RNA sequencing, histology, or integrated models based on multiple combined features. Targeted gene expression profiling has generated robust biomarkers integrating multiple molecular features for other cancers, but is understudied for meningiomas. Methods: Targeted gene expression profiling was performed on 173 meningiomas and an optimized gene expression biomarker (34 genes) and risk score (0 to 1) was developed to predict clinical outcomes. Clinical and analytical validation was performed on independent meningiomas from 12 institutions across 3 continents (N = 1856), including 103 meningiomas from a prospective clinical trial. Gene expression biomarker performance was compared to 9 other classification systems. Results: The gene expression biomarker improved discrimination of postoperative meningioma outcomes compared to all other classification systems tested in the independent clinical validation cohort for local recurrence (5-year area under the curve [AUC] 0.81) and overall survival (5-year AUC 0.80). The increase in area under the curve compared to the current standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval [CI] 0.07-0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% CI 0.37-0.78, P = 0.0001) and re-classified up to 52.0% meningiomas compared to conventional clinical criteria, suggesting postoperative management could be refined for 29.8% of patients. Conclusions: A targeted gene expression biomarker improves discrimination of meningioma outcomes compared to recent classification systems and predicts postoperative radiotherapy responses.

Feasibility of accelerated image-guided high-dose-rate interstitial brachytherapy with inverse planning simulated annealing (IPSA-HDRBT) for post-operative treatment of pathologically node-negative squamous cell carcinomas of the oral tongue.

PURPOSE: Inverse planning simulated annealing (IPSA) produces highly conformal dose distributions and quick optimizations for high-dose-rate interstitial brachytherapy (HDRBT). We report our dosimetry and overall outcomes using this approach for the accelerated post-operative treatment of pathologically node-negative squamous cell carcinomas of the oral tongue (OTSCC) with high risk of local recurrence. METHODS: Patients with newly diagnosed pN0 OTSCC treated with partial glossectomy, neck dissection, and post-operative HDRBT alone from 2007 to 2021 were retrospectively reviewed. Patients received 30 Gy in 5 fractions over 2.5 days. Target volume and mandible dosimetry are reported. Actuarial rates of local control, regional control, disease-specific survival, and overall survival were estimated using the Kaplan-Meier method. Toxicity was categorized using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: 19 consecutive patients were reviewed. Median follow-up was 3.2 years (IQR 1.4-8.2 years) with a 3-year estimated local control rate of 81%. Target volumes were generally small, as the median volume was 12.66 cc. Median V150% and V200% were 52% and 24%, respectively. D1cc and D2cc to the mandible were 17.31 Gy and 14.42 Gy, respectively. CONCLUSIONS: IPSA-HDRBT is feasible and highly efficient for post-operative treatment of the primary tumor bed in patients with pathologically node-negative squamous cell carcinomas of the oral tongue. Further technical optimization and prospective clinical evaluation in a larger patient cohort are planned.

Recurrent Radiation-Induced Cavernous Malformation After Gamma Knife Stereotactic Radiosurgery for Brain Metastasis.

Cavernous malformations are a rare complication of radiation therapy reported most commonly as a late complication after cranial irradiation for pediatric malignancies. However, cavernous malformations after stereotactic radiosurgery in adult patients are not well characterized. We present a case of a 67-year-old female with metastatic breast cancer who received Gamma Knife stereotactic radiosurgery for brain metastases and developed a cavernous malformation at the site of a treated metastasis 30 months after treatment. She underwent resection and did well until 55 months later, when she developed symptomatic recurrence of cavernous malformation without evidence of tumor recurrence, requiring repeat resection. This represents the first reported case of radiation-induced cavernous malformation treated with stereotactic radiosurgery for brain metastases, who later developed a recurrence of the cavernous malformation. As patients with brain metastases are living longer and are increasingly treated with stereotactic radiosurgery, awareness of cavernous malformation as a potential complication and the risk of recurrence is critical to ensure appropriate diagnosis and management.

Frameworks for Radiation Oncology Global Health Initiatives in US Residency Programs.

PURPOSE: To understand trends, pathways, and experiences and to establish a framework for radiation oncology (RO) programs interested in developing global health (GH) initiatives. METHODS: An in-depth interview was conducted of all US RO programs with established GH initiatives. Programs were identified by reviewing results of the 2018 Association of Residents in Radiation Oncology Global Health Resident Survey and individualized outreach to screen for additional programs meeting the following criteria: (1) active resident involvement in RO-specific GH opportunities, (2) active faculty involvement in these initiatives, and (3) department chair or program director awareness and support for ongoing opportunities. Among 88 residency programs, 11 were identified. Standardized questions explored the type of initiative, planning, staff and resident involvement, challenges, components to success, and history of programs through December 2018. RESULTS: Between 2010 and 2018, 11 programs started initiatives. Total resident participants ranged from one to 13 (median = 3) in each program's history. Initiatives spanned education (n = 9 [82%]), clinical mentorship (73%), innovative technology (55%), bilateral hosting programs (45%), clinical development and equipment (45%), promotion of local research (36%), clinical care (36%), industry partnerships (27%), and remote tumor board (18%). Faculty involvement included radiation oncologists (91%), medical physicists (55%), and non-RO department faculty (27%). Six programs (55%) had faculty with prior GH experience. Four (36%) programs reported medical student involvement in projects. Barriers included international communication (36%), time for faculty (18%), funding (9%), and legal (9%) concerns. Commonest components of success included fostering relationships with international sites and identifying needs before solutions. CONCLUSION: RO GH initiatives were reported as positive, educational, and feasible across 11 US residency programs. Growth is expected, representing opportunities for innovation and service among US programs.

Hypofractionated Whole-Breast Irradiation in Women Less Than 50 Years Old Treated on 4 Prospective Protocols.

PURPOSE: Hypofractionated whole-breast radiation therapy (RT) has proved to be equivalent to conventionally fractionated RT in multiple randomized trials. There is controversy regarding its use in younger women because of their underrepresentation in trials and the concern for late toxicity. We evaluated disease control and cosmetic outcomes in patients aged <50 years treated with hypofractionated RT in 4 prospective single-institutional trials. METHODS AND MATERIALS: From 2003 to 2015, 1313 patients were enrolled in 4 prospective protocols investigating the use of adjuvant hypofractionated RT after breast-conserving surgery with a daily or weekly concomitant boost. We identified the records of 348 patients aged <50 years at consultation for this analysis. Overall survival, disease-free survival, and local recurrence-free survival were estimated using the Kaplan-Meier method by study and across studies using meta-analytic methods. The late effects of RT, clinician-rated cosmesis, and patient-rated cosmesis were also evaluated. RESULTS: With a median follow-up period of 66.9 months, the overall survival rate was 99.6%, the disease-free survival rate was 96.3%, and the local recurrence-free survival rate was 97.7% at 3 years. Clinician-rated cosmesis (n = 242) was excellent or good in 93.4% of cases and fair or poor in 6.6%. Patient-rated cosmesis (n = 259) was excellent or good in 86.1% and fair or poor in 13.9%. When patients rated themselves differently than their physicians, patients more often rated themselves poorly compared with their physicians (P = .0044, Cochran-Mantel-Haenszel test). CONCLUSIONS: At a median follow-up of 5 years, an analysis of patients aged <50 years demonstrated that hypofractionated RT was safe and effective, with good to excellent cosmesis as assessed by both clinicians and patients.

Five-Fraction Stereotactic Body Radiation Therapy (SBRT) and Chemotherapy for the Local Management of Metastatic Pancreatic Cancer.

BACKGROUND: The majority of patients with pancreatic cancer are diagnosed with metastatic disease at presentation. Nevertheless, local progression is responsible for up to 30% of deaths and can lead to significant morbidity. As a consequence, further exploration of effective methods of local control and palliation is essential. Stereotactic body radiation therapy (SBRT) is a widely utilized technique for the treatment of localized pancreatic cancer. Here, we report our experience with SBRT and chemotherapy for the local treatment of the metastatic patient population. METHODS: This single institution retrospective review analyzed 20 patients with pathologically diagnosed metastatic adenocarcinoma of the pancreas. All patients underwent fiducial placement under endoscopic ultrasound (EUS) guidance. SBRT was delivered in five fractions to a total dose of 25 to 30 Gy. Patients received concurrent (given within 1 week of the start of SBRT) or sequential chemotherapy. Local tumor control was evaluated using Response Evaluation Criteria in Solid Tumors. Toxicity was graded using Common Terminology Criteria for Adverse Events version 4.03. Local control and overall survival were reported using the Kaplan-Meier method. RESULTS: Patient median age was 64 years, and the median pre-treatment Eastern Cooperative Oncology Group performance status was 1. All patients received chemotherapy and half of the patients (10 of 20) received concurrent chemotherapy with folinic acid, fluorouracil, and oxaliplatin or fluorouracil, leucovorin, irinotecan, and oxaliplatin. Nearly all patients (19 of 20) received post-SBRT chemotherapy. Median time from pathological diagnosis to SBRT was 3.9 months. The twelve-month local control and overall survival were 43 and 53%, respectively. However, in patients with planning target volume (PTV) targets smaller than the population median, the 12-month local control was 78%. Median time to local progression (17.8 vs. 3.0 months, p = 0.02) and overall survival (24.9 vs. 8.8, p = 0.001) were also significantly improved in this smaller PTV cohort. Though not statistically significant, there was a trend towards improvement in local control (17.8 vs. 4.3 months, p = 0.17) and overall survival (16.7 vs. 9.7 months, p = 0.087) for those who received concurrent versus sequential chemotherapy, respectively. Lastly, there were no reported grade 3-5 late toxicities. CONCLUSIONS: As systemic therapies improve, the local management of pancreatic cancer will become increasingly important. Here, we report significantly improved local control with SBRT of smaller PTV tumors with concurrent chemotherapy. Five-fraction SBRT offers a quick and effective modality of local tumor control with minimal toxicity in the metastatic pancreatic cancer population.

FDG-PET in early AD diagnosis.

FDG-PET is a valuable tool that will continue to aid in identifying AD in its prodromal and early dementia stages, distinguishing it from other causes of dementia, and tracking progression of the disease. As brain FDG-PET scans and well-trained readers of these scans are becoming more widely available to clinicians who are becoming more informed about the role FDG-PET can play in early AD diagnosis, its use is expected to increase.