Chicoine, Michael

2015 Background: Effective treatments for recurrent meningiomas following radiation therapy (RT) are limited. Inhibitors of the programmed-death-1 (PD-1) or programmed-death ligand-1 (PD-L1) pathway have shown modest activity for these tumors in single-arm phase 2 studies. This study aims to evaluate the immunological effects of combining anti-PD-L1 (avelumab) with proton beam therapy (PBT) for recurrent radiation-relapsed meningiomas. Methods: Recurrent grade 1-3 meningiomas that failed prior surgery and RT were treated with neoadjuvant avelumab (10 mg/kg IV biweekly for 6 doses) plus hypofractionated PBT (20 Gy over 5 fractions), followed by surgery and additional adjuvant avelumab (up to 6 doses). Blood samples were collected pre-avelumab, at week 4, and before surgery. Eligibility criteria include age ≥ 18 years, KPS ≥ 60, surgery suitability, dexamethasone dose ≤ 4mg daily, normal organ function; no prior anti-PD1/PDL1 therapy, and absence of autoimmunity. RNA-sequencing (RNAseq) and multiplex immunofluorescence (MxIF) were performed on pre- and post-avelumab tumor tissues; blood samples underwent multiplex flow cytometry (MxFC). Results: Between March 2018 to March 2023, 9 patients (22% grade 1, 56% grade 2, and 22% grade 3) were enrolled in the study. All completed neoadjuvant therapy, one forwent surgery due to dramatic radiological response, and two did not complete adjuvant avelumab (due to patient preference and infusion reaction). There was no dose-limiting toxicity or unexpected toxicity. After a median follow-up of 43.0 month and a minimum follow-up of 21.7 months, 8 patients have progressed, and 2 patients with progression have died. The median progression-free survival (PFS) was 19.1 months (95% CI: 15.2-23.0), with the median overall survival not yet reached. Three patients demonstrated notably prolonged PFS (37.7, 58.5 months, and ongoing). RNAseq showed significant increase in T-cell and macrophage gene expression in post-treatment tissues compared to pre-treatment. MxIF revealed a marked increase in T-cell and CD68+ macrophage infiltration in the long-PFS patients’ post-treatment tissues, a pattern not observed in the short-PFS patients. Particularly, the long-PFS patients’ post-treatment tissues displayed increased infiltration of CD68+HLADR+ macrophages, likely of M1-phenotype. In contrast, the pre- and post-treatment tissues from the short-PFS patients predominantly featured CD206+ macrophages, likely of M2-phenotype. A trend towards increased number of primed T cells in the peripheral blood was observed in the long-PFS patients at week 4. Conclusions: Avelumab combined with RT may induce an immunological response in some radiation-relapsed meningioma patients, leading to prolonged remission. Further investigations with larger prospective studies and predictive biomarkers are warranted. Clinical trial information: NCT03267836 .

OBJECTIVE The internal high-dose volume varies widely for a given prescribed dose during stereotactic radiosurgery (SRS) to treat brain metastases (BMs). This may be altered during treatment planning, and the authors have previously shown that this improves local control (LC) for non–small cell lung cancer BMs without increasing toxicity. Here, they seek to identify potentially actionable dosimetric predictors of LC after SRS for melanoma BM. METHODS The records of patients with unresected melanoma BM treated with single-fraction Gamma Knife RS between 2006 and 2017 were reviewed. LC was assessed on a per-lesion basis, defined as stability or a decrease in lesion size. Outcome-oriented approaches were utilized to determine optimal dichotomization for dosimetric variables relative to LC. Univariable and multivariable Cox regression analysis was implemented to evaluate the impact of collected parameters on LC. RESULTS Two hundred eighty-seven melanoma BMs in 79 patients were identified. The median age was 56 years (range 31–86 years). The median follow-up was 7.6 months (range 0.5–81.6 months), and the median survival was 9.3 months (range 1.3–81.6 months). Lesions were optimally stratified by volume receiving at least 30 Gy (V30) greater than or equal to versus less than 25%. V30 was ≥ and < 25% in 147 and 140 lesions, respectively. For all patients, 1-year LC was 83% versus 66% for V30 ≥ and < 25%, respectively (p = 0.001). Stratifying by volume, lesions 2 cm or less (n = 215) had 1-year LC of 82% versus 70% (p = 0.013) for V30 ≥ and < 25%, respectively. Lesions > 2 to 3 cm (n = 32) had 1-year LC of 100% versus 43% (p = 0.214) for V30 ≥ and < 25%, respectively. V30 was still predictive of LC even after controlling for the use of immunotherapy and targeted therapy. Radionecrosis occurred in 2.8% of lesions and was not significantly associated with V30. CONCLUSIONS For a given prescription dose, an increased internal high-dose volume, as indicated by measures such as V30 ≥ 25%, is associated with improved LC but not increased toxicity in single-fraction SRS for melanoma BM. Internal dose escalation is an independent predictor of improved LC even in patients receiving immunotherapy and/or targeted therapy. This represents a dosimetric parameter that is actionable at the time of treatment planning and warrants further evaluation.

Abstract BACKGROUND Perioperative steroid protocols for patients undergoing transsphenoidal surgery (TSS) for pituitary pathology vary by institution. OBJECTIVE To assess the safety of withholding glucocorticoids in patients undergoing TSS. METHODS Patients with an intact hypothalamic-pituitary-adrenal (HPA) axis undergoing TSS for a pituitary tumor at the same academic institution between 2012 and 2015 were randomized to either receive 100 mg of intravenous hydrocortisone followed by 0.5 mg of intravenous dexamethasone every 6 h for 4 doses (STER, n = 23) or to undergo surgery without steroids (NOSTER, n = 20). Postoperative cortisol levels were then used to determine the need for glucocorticoids after surgery. Data regarding postoperative cortisol levels, hospital stay length, and complications were collected. RESULTS Mean postoperative 8 am cortisol levels were higher in the NOSTER group compared to the STER group (745 ± 359 nmol/L and 386 ± 193 nmol/L, respectively, P = .001) and more patients were discharged on glucocorticoids in the STER group (42% vs 12%, P = .07). There was no difference in the incidence of postoperative complications, including hyperglycemia, diabetes insipidus, or permanent adrenal insufficiency. Permanent adrenal insufficiency occurred in 8% of patients. CONCLUSION Perioperative steroids can be safely withheld in patients with an intact HPA axis undergoing TSS. Although administration of perioperative glucocorticoids does not appear to increase the risk of complications, it may interfere with assessment of the HPA axis after surgery.