Kari Jacobsen

Low incidence of melanoma brain metastasis in the hippocampus.

AIMS ANZMTG 01.07 WBRTMel is a phase 3 randomized trial to address the role of whole brain radiation therapy (WBRT) after local treatment of 1-3 melanoma brain metastases. Modern radiation therapy technologies can now conformally spare the hippocampus during WBRT and therefore potentially reduce the risk of neurocognitive deficit. The aims of this study were to report the prevalence of melanoma metastases within the hippocampal sparing region and to identify variables that correlate with the presence of metastases within the hippocampal sparing region. METHODS The pre-local treatment MRI scans of 77 eligible WBRTMel patients were used to contour the individual metastasis and the hippocampus. The volume, location and closest distance of each metastasis to the hippocampus were recorded. Binary logistic regression was performed to assess the influence of factors on the location of a metastasis within 5mm of the hippocampus. RESULTS The median age was 61 and 66% were male. The distribution of the 115 metastases was frontal (50, 43.5%), parietal (23, 20.0%), temporal (13, 11.2%), occipital (18, 15.7%), cerebellum (10, 8.6%) and pineal gland (1, 1.0%). The median aggregate volume of the metastasis was 3516mm(3). None of the metastases were within the hippocampus. Four patients (5.2%) had metastases within 5mm of the hippocampus. The median distance from metastasis to the nearest hippocampus was 37.2mm. Only the total volume of metastases was a significant predictor for the risk of a metastasis within the hippocampal sparing region (OR 1.071, 95% CI: 1.003-1.144, p=0.040). CONCLUSIONS This study confirmed a low incidence of melanoma metastasis in the hippocampal sparing region at diagnosis. Given the lack of randomized data on the safety and benefit of hippocampal sparing WBRT, the current WBRTMel trial provides the opportunity to explore the feasibility of this technique.

Melanoma staging: Varying precision and terminal digit clustering in Breslow thickness data is evident in a population-based study

Background: Errors in Breslow thickness reporting can give misclassification of T category, an important classifier in melanoma staging. Objective: We sought to investigate precision (number of digits) and terminal digit clustering in Breslow thickness and potential consequences for T category. Methods: All first primary and morphologically verified invasive melanomas in Norway between 2008 and 2015 were included. A smoothing model was fitted to estimate the underlying Breslow thickness distribution without digit clustering. Results: Thickness was reported for 13,057 (97.5%) patients; the median was 1.0 mm (range, 0.09‐85). It was reported as whole numbers (15.6%), to 1 decimal (78.2%) and 2 decimal places (6.2%)—thin tumors with more precision than thick tumors. Terminal digit clustering was found with marked peaks in the observed frequency distribution for terminal digits 0 and 5, and with drops around these peaks. Terminal digit clustering increased proportions of patients classified with T1 and T4 tumors and decreased proportions classified with T2 and T3. Limitations: Breslow thickness was not reported in 2.5% of cases. Conclusions: The Norwegian recommendation of measurement to the nearest 0.1 mm was not followed. Terminal digit clustering was marked, with consequences for T category. Pathologists, clinicians, and epidemiologists should know that clustering of thickness data around T category cut points can impact melanoma staging with consequent effect on patient management and prognosis.

Abstract 1471: Immunotherapy revised: Ipilimumab potentiates the vascular response to stereotactic radiosurgery in patients with brain metastases

Introduction: While immunotherapy is a promising treatment option for advanced metastatic disease, the survival benefit of adding ipilimumab to stereotactic radiosurgery (SRS) in unselected patients with metastases to the brain seems limited [1, 2]. Moreover, because conventional diagnostic methods for assessing treatment response were not designed for these therapies, the mechanisms of action in vivo are poorly understood. To reveal potential synergistic effects of adding ipilimumab to SRS, we here present preliminary data on the vascular response to SRS and ipilimumab in patients with brain metastases from malignant melanomas and non-small cell lung cancer. Methods: Voxel-wise estimations of blood volume and vessel calibers were acquired by perfusion MRI and Vessel Architectural Imaging [3], respectively, in 13 patients with brain metastases from lung cancer receiving SRS only (N = 6; 7 lesions) and malignant melanomas receiving SRS only (N = 4; 5 lesions) or SRS and ipilimumab (N = 3; 5 lesions). Regions of enhancing tumor were identified on contrast-enhanced MRIs, whereas peri-tumoral tissue regions included a region containing a 2mm wide dilation of the enhancing tumor and outside the SRS target area. MRIs were performed at baseline (pre SRS) and repeated every three months. Ipilimumab (3mg/kg) were administered intravenously over 90 min every third week for four cycles. SRS was delivered to the tumor (visual metastasis + 2 mm margin) with a peripheral dose of 18 Gy or 25 Gy, depending on tumor size. Results: For patients treated with SRS only, the vessel calibers decreased with a median value of 15% in the peri-tumoral area at 3 months following SRS (P Conclusion: The enlarged average vessel calibers and the subsequent lack of an increase in blood volume suggest ipilimumab helps clean up the vascular bed by removing small caliber vessels and effectively reducing the capillary vessel density. Our advanced MRI data provide valuable and novel insights into the biological mechanisms of response to ipilimumab and at study end may help identify patients with metastatic disease that benefit from this therapy by prolonged survival. References: 1. Mathew et al, Melanoma Res 2013. 23(3):191-5 2. Patel et al, Am J Clin Oncol 2015. May 16:[Epub] 3. Emblem et al, Nat Med 2013. 19(9):1178-83 Citation Format: Ingrid Digernes, Cathrine Saxhaug, Oliver Geier, Edmund Reitan, Einar Waldeland, Kunt Hakon Hole, Kari Dolven Jacobsen, Aslaug Helland, Kyrre Eeg Emblem. Immunotherapy revised: Ipilimumab potentiates the vascular response to stereotactic radiosurgery in patients with brain metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1471.