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We compared the clinical outcomes of BM treated with mask immobilization with zero-SM (i.e., zero-PTV) to standard zero-SM frame immobilization SRS. Consecutive patients with BM, 0.5-2.0 cm in maximal diameter, treated with single-fraction SRS (22-24 Gy) during March 2019-February 2021 were included. Univariable and multivariable analysis were performed using the Kaplan-Meier method and Cox proportional hazards regression. A total of 150 patients with 453 BM met inclusion criteria. A total of 129 (28.5%) lesions were treated with a zero-SM mask immobilization and 324 (71.5%) with zero-SM frame immobilization. Frame immobilization treatments were associated with a higher proportion of gastrointestinal and fewer breast-cancer metastases (

Simple Summary In the multi-modal treatment of brain metastasis (BM), the role of systemic therapy has undergone a recent revolution. Due to the development of multiple agents with modest central nervous system penetration of the blood-brain barrier, targeted therapies and immune checkpoint inhibitors are increasingly being utilized alone or in combination with radiation therapy. However, the adoption of sequential or concurrent strategies varies considerably, and treatment strategies employed in clinical practice have rapidly outpaced evidence development. Therefore, this review critically analyzes the data regarding combinatorial approaches for a variety of systemic therapeutics with stereotactic radiosurgery and provides an overview of ongoing clinical trials. Abstract Brain metastasis (BM) represents a common complication of cancer, and in the modern era requires multi-modal management approaches and multi-disciplinary care. Traditionally, due to the limited efficacy of cytotoxic chemotherapy, treatment strategies are focused on local treatments alone, such as whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and resection. However, the increased availability of molecular-based therapies with central nervous system (CNS) penetration now permits the individualized selection of tailored systemic therapies to be used alongside local treatments. Moreover, the introduction of immune checkpoint inhibitors (ICIs), with demonstrated CNS activity has further revolutionized the management of BM patients. The rapid introduction of these cancer therapeutics into clinical practice, however, has led to a significant dearth in the published literature about the optimal timing, sequencing, and combination of these systemic therapies along with SRS. This manuscript reviews the impact of tumor biology and molecular profiles on the management paradigm for BM patients and critically analyzes the current landscape of SRS, with a specific focus on integration with systemic therapy. We also discuss emerging treatment strategies combining SRS and ICIs, the impact of timing and the sequencing of these therapies around SRS, the effect of corticosteroids, and review post-treatment imaging findings, including pseudo-progression and radiation necrosis.

We compared the clinical outcomes of BM treated with mask immobilization with zero-SM (i.e., zero-PTV) to standard zero-SM frame immobilization SRS. Consecutive patients with BM, 0.5–2.0 cm in maximal diameter, treated with single-fraction SRS (22–24 Gy) during March 2019–February 2021 were included. Univariable and multivariable analysis were performed using the Kaplan–Meier method and Cox proportional hazards regression. A total of 150 patients with 453 BM met inclusion criteria. A total of 129 (28.5%) lesions were treated with a zero-SM mask immobilization and 324 (71.5%) with zero-SM frame immobilization. Frame immobilization treatments were associated with a higher proportion of gastrointestinal and fewer breast-cancer metastases (p = 0.024), and a higher number of treated lesions per SRS course (median 7 vs. 3; p < 0.001). With a median follow up of 15 months, there was no difference in FFLF between the mask and frame immobilization groups on univariable (p = 0.29) or multivariable analysis (p = 0.518). Actuarial FFLF at 1 year was 90.5% for mask and 92% for frame immobilization (p = 0.272). Radiation necrosis rates at 1 year were 12.5% for mask and 4.1% for frame immobilization (p = 0.502). For BM 0.5–2.0 cm in maximal diameter treated with single-fraction SRS using 22–24 Gy, mask immobilization with zero SM produces comparable clinical outcomes to frame immobilization. The initial findings support omitting a SM when using mask immobilization with this treatment approach on a Gamma Knife® Icon™.

Purpose: The objective was to describe PRDR outcomes and report EQD2 OAR toxicity thresholds. Methods: Eighteen patients with recurrent primary CNS tumors treated with PRDR at a single institution between April 2017 and September 2021 were evaluated. The radiotherapy details, cumulative OAR doses, progression-free survival (PFS), overall survival (OS), and toxicities were collected. Results: The median PRDR dose was 45 Gy (range: 36–59.4 Gy); the median cumulative EQD2 prescription dose was 102.7 Gy (range: 93.8–120.4 Gy). The median cumulative EQD2 D0.03cc for the brain was 111.4 Gy (range: 82.4–175.2 Gy). Symptomatic radiation necrosis occurred in three patients, for which the median EQD2 brain D0.03cc was 115.9 Gy (110.4–156.7 Gy). The median PFS and OS after PRDR were 6.3 months (95%CI: 0.9–11.6 months) and 8.6 months (95%CI: 4.9–12.3 months), respectively. The systematic review identified five peer-reviewed studies with a median cumulative EQD2 prescription dose of 110.3 Gy. At a median follow-up of 8.7 months, the median PFS and OS were 5.7 months (95%CI: 2.1–15.4 months) and 6.7 months (95%CI: 3.2–14.2 months), respectively. Conclusion: PRDR re-irradiation is a relatively safe and feasible treatment for recurrent primary CNS tumors. Despite high cumulative dose to OARs, the risk of high-grade, treatment-related toxicity within the first year of follow-up remains acceptable.

Purpose: The objectives of this study were to evaluate the implementation, device usage rates, clinical outcomes, and treatment-related toxicities associated with TTFields and pemetrexed plus platinum-based chemotherapy in patients with unresectable MPM, outside the initial trial results. Methods: Consecutive patients with unresectable MPM were enrolled onto an FDA-required HDE protocol from 2019 to 2021. All patients were treated with a protocol-defined regimen of continuous TTFields (150 kHz) and pemetrexed plus platinum-based chemotherapy. Results: Five patients with unresectable MPM were enrolled. The median number of 4-week TTFields cycles was 5 (range: 2–7 cycles). Median TTFields device usage in the first 3 months was 12.5 h per day (range: 5–16.8 h), representing 52% (21–70%) of the potential daily duration. The median follow-up was 5.4 months (range: 1.1–20.9 months). Treatment-related dermatitis was the only side effect associated with TTFields and was reported as grade 1–2 in all patients; no patient had grade 3+ device-related toxicities. Conclusions: This study represents the first results of real-world implementation of TTFields for MPM. In comparison to the initial clinical trial (STELLAR), compliance rates were lower, although skin-related toxicities appeared similar. Further initiatives and guidelines should be developed to manage treatment-related dermatitis and improve device usage.

Simple Summary Malignant pleural mesothelioma (MPM) is a rare cancer with an aggressive disease course. For patients who are medically inoperable or surgically unresectable, multi-agent systemic therapy remains an accepted standard-of-care around the world. Given the rare incidence of MPM and the disease’s aggressive nature, novel clinical trial designs are required. The purpose of this meta-analysis is to provide baseline summative survival estimates as well as evaluate the influence of prognostic variables to provide comparative estimates for future trial designs. In this study, a nomogram model was created to estimate survival with treatment with platinum-pemetrexed using covariates known to be associated with survival, including median age, gender, ECOG performance status, tumor stage, and tumor pathology subtype. Collaborative efforts can drive the change in the right direction, and appreciable progress has to be facilitated and newer trial designs may need to pave the way for future innovations in this rare disease. Abstract (1) Purpose: Malignant pleural mesothelioma (MPM) is a rare cancer with an aggressive course. For patients who are medically inoperable or surgically unresectable, multi-agent systemic chemotherapy remains an accepted standard-of-care. The purpose of this meta-analysis is to provide baseline summative survival estimates as well as evaluate the influence of prognostic variables to provide comparative estimates for future trial designs. (2) Methods: Using PRISMA guidelines, a systematic review and meta-analysis was performed of MPM studies published from 2002–2019 obtained from the Medline database evaluating systemic therapy combinations for locally advanced or metastatic disease. Weighted random effects models were used to calculate survival estimates. The influence of proportions of known prognostic factors on overall survival (OS) were evaluated in the creation of a prognostic nomogram to estimate survival. The performance of this model was evaluated against data generated from one positive phase II study and two positive randomized trials. (3) Results: Twenty-four phase II studies and five phase III trials met the eligibility criteria; 2534 patients were treated on the included clinical studies. Ten trials included a platinum-pemetrexed-based treatment regimen, resulting in a pooled estimate of progression-free survival (PFS) of 6.7 months (95% CI: 6.2–7.2 months) and OS of 14.2 months (95% CI: 12.7–15.9 months). Fifteen experimental chemotherapy regimens have been tested in phase II or III studies, with a pooled median survival estimate of 13.5 months (95% CI: 12.6–14.6 months). Meta-regression analysis was used to estimate OS with platinum-pemetrexed using a variety of features, such as pathology (biphasic vs. epithelioid), disease extent (locally advanced vs. metastatic), ECOG performance status, age, and gender. The nomogram-predicted estimates and corresponding 95% CIs performed well when applied to recent randomized studies. (4) Conclusions: Given the rarity of MPM and the aggressive nature of the disease, innovative clinical trial designs with significantly greater randomization to experimental regimens can be performed using robust survival estimates from prior studies. This study provides baseline comparative values and also allows for accounting for differing proportions of known prognostic variables.