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• W3003972052 abstract "The development of leptomeningeal meningeal disease (LMD) in the central nervous system has traditionally been considered a harbinger of rapidly fatal outcome, portending death in a few months.1Buszek S.M. Chung C. Radiotherapy in leptomeningeal disease: A systematic review of randomized and nonrandomized trials.Front Oncol. 2019; 9: 1224Crossref PubMed Scopus (7) Google Scholar Many radiologists and oncologists equate the finding of “leptomeningeal disease” or “meningeal involvement” on a brain or spine magnetic resonance imaging (MRI) report with “leptomeningeal carcinomatosis” or “carcinomatous meningitis,” in which tumor cells cover and infiltrate a broad expanse of the meninges, giving the appearance of “sugar coating” these surfaces. However, as Turner et al2Turner B.E. Prabhu R.S. Burri S.H. et al.Nodular leptomeningeal disease - a distinct pattern of recurrence after post-resection stereotactic radiosurgery for brain metastases: A multi-institutional study of inter-observer reliability.Int J Radiat Oncol Biol Phys. 2019; Google Scholar discuss in their paper on classifying leptomeningeal disease published in this issue, more discrete forms of LMD are frequently observed, and appropriate classification of LMD has potentially significant clinical implications for preventing and managing this entity. The recognition of discrete or nodular leptomeningeal disease as a distinct entity has been driven, in part, by the increased frequency of “nodular” LMD (nLMD) reported with postoperative stereotactic radiosurgery (SRS), in which the resection cavity is irradiated in 1 to 5 fractions. Although the original approach was to use whole-brain radiation therapy (WBRT) postoperatively to reduce the high rates of recurrence observed with surgical resection alone of a brain metastasis,3Patchell R.A. Tibbs P.A. Regine W.F. et al.Postoperative radiotherapy in the treatment of single metastases to the brain: A randomized trial.JAMA. 1998; 280: 1485-1489Crossref PubMed Scopus (1386) Google Scholar concerns for neurocognitive decline drove many practitioners to use SRS alone. Indeed, a randomized trial of postoperative SRS versus WBRT demonstrated significantly reduced neurocognitive decline with SRS.4Brown P.D. Ballman K.V. Cerhan J.H. et al.Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC.3): A multicentre, randomised, controlled, phase 3 trial.Lancet Oncol. 2017; 18: 1049-1060Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar However, although SRS substantially reduced the rate of local recurrence compared with observation alone,5Mahajan A. Ahmed S. McAleer M.F. et al.Postoperative stereotactic radiosurgery versus observation for completely resected brain metastases: A single-centre, randomised, controlled, phase 3 trial.Lancet Oncol. 2017; 18: 1040-1048Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar the omission of WBRT resulted in much higher rates of appearance of new metastases elsewhere in the brain. Moreover, unexpectedly high rates of LMD appeared to be associated with postoperative SRS, with a crude incidence as high as 30%. In a multi-institutional study of patients who had undergone surgical resection of a brain metastasis followed by SRS to the resection cavity, Prabhu et al6Prabhu R.S. Turner B.E. Asher A.L. et al.A multi-institutional analysis of presentation and outcomes for leptomeningeal disease recurrence after surgical resection and radiosurgery for brain metastases.Neuro Oncol. 2019; Crossref Scopus (25) Google Scholar astutely observed 2 categories of LMD: nLMD, in which discrete, limited disease is present in/on the leptomeninges, versus classical LMD, in which disease diffusely coats meningeal surfaces (which we will call here dLMD). A total of 147 patients with LMD were identified, primarily on the basis of MRI alone, with 63 patients (43%) classified as having dLMD and 84 (57%) presenting with nLMD. At presentation, a total of 60% of patients were symptomatic, with patients with dLMD more frequently symptomatic than those with nLMD (71 vs 51%, P = .1). The median overall survival was far longer in the patients with nLMD (8.2 vs 3.3 months, P < .001). Treatment of intact versus resected brain metastases also appears to influence the development of nLMD, as reported by Cagney et al.7Cagney D.N. Lamba N. Sinha S. et al.Association of neurosurgical resection with development of pachymeningeal seeding in patients with brain metastases.JAMA Oncol. 2019; 5: 703-709Crossref PubMed Scopus (24) Google Scholar In this study of 1188 patients with brain metastases treated with SRS, 316 initially underwent surgical resection. Although the rate of diffuse leptomeningeal disease was no different between the surgical and nonsurgical groups (∼20%), 36 of 318 patients in the surgical cohort developed nLMD versus 0 of 870 in the nonsurgical group (21 vs 0%, P < .001). The authors observed that salvage radiation therapy was somewhat effective in nLMD, with 49% of patients alive 1 year after salvage radiation therapy. Nonetheless, 72% of patients undergoing salvage treatment exhibited neurologic death. A study by Nguyen et al8Nguyen T.K. Sahgal A. Detsky J. et al.Predictors of leptomeningeal disease following hypofractionated stereotactic radiotherapy for intact and resected brain metastases.Neuro Oncol. 2020; 22: 84-93Crossref PubMed Scopus (13) Google Scholar of hypofractionated SRS (typically 30 Gy in 5 fractions) to the resection cavity or intact brain metastases also identified surgical resection as an adverse predictor for the development of LMD (odds ratio, 2.30; P = .008). Conversely, the use of targeted or immunotherapeutic agents conferred protection from LMD. LMD was classified as 1 of 4 patterns based on the extent (diffuse vs focal) and morphology (nodular vs classic) and, in contrast to the study by Prabhu et al,6Prabhu R.S. Turner B.E. Asher A.L. et al.A multi-institutional analysis of presentation and outcomes for leptomeningeal disease recurrence after surgical resection and radiosurgery for brain metastases.Neuro Oncol. 2019; Crossref Scopus (25) Google Scholar no relationship between the category of LMD and the risk of developing LMD was observed. It has been said in a quotation widely attributed to Socrates, although this is a topic of debate, that “the beginning of wisdom is the definition of terms,” and accurately and consistently defining and classifying leptomeningeal disease is essential to identifying, understanding, and appropriately treating both discrete and diffuse LMD. In a study by Turner et al,2Turner B.E. Prabhu R.S. Burri S.H. et al.Nodular leptomeningeal disease - a distinct pattern of recurrence after post-resection stereotactic radiosurgery for brain metastases: A multi-institutional study of inter-observer reliability.Int J Radiat Oncol Biol Phys. 2019; Google Scholar 22 physicians, 15 with expertise in central nervous system disease, were asked to examine contrast-enhanced brain MRI scans from 30 cases of recurrent disease post-SRS and to classify metastatic disease as local recurrence at the site of treatment, distant parenchymal recurrence, nLMD, or classical LMD (which includes enhancement of cranial nerves and extensive of foliar, sulcal, and cisternal surfaces, in addition to diffuse “sugar coating”). In the pretraining phase of the study, a high degree of discordance was observed, particularly in the cases involving nLMD, with an interrater reliability of K = 0.33. A training module was developed to guide practitioners on the appropriate classification of intracranial metastatic disease, and the participants in the survey were asked to classify these 30 cases after training. Discordance in classification was reduced significantly posttraining, with the greatest gains in interrater reliability noted for cases involving LMD. For example, 27% to 29% of cases initially diagnosed as local or distant brain recurrence were reclassified as nLMD after training. Further validation of the clinical significance and outcome for discrete versus diffuse LMD would benefit from the definition and teaching proposed by Turner et al.2Turner B.E. Prabhu R.S. Burri S.H. et al.Nodular leptomeningeal disease - a distinct pattern of recurrence after post-resection stereotactic radiosurgery for brain metastases: A multi-institutional study of inter-observer reliability.Int J Radiat Oncol Biol Phys. 2019; Google Scholar Treatment for diffuse leptomeningeal disease (ie, carcinomatous meningitis) may involve invasive or morbid approaches, including WBRT, craniospinal irradiation, or intrathecal chemotherapy.1Buszek S.M. Chung C. Radiotherapy in leptomeningeal disease: A systematic review of randomized and nonrandomized trials.Front Oncol. 2019; 9: 1224Crossref PubMed Scopus (7) Google Scholar Patients with poor performance status and diffuse LMD might be better served by supportive care alone rather than an intervention, and providing these patients with a reasonable estimate of their prognosis—which depends on accurate characterization of the nature of their LMD—would be essential for them to make an informed decision on care. Conversely, identification of nLMD would suggest consideration of focal SRS to these lesions,6Prabhu R.S. Turner B.E. Asher A.L. et al.A multi-institutional analysis of presentation and outcomes for leptomeningeal disease recurrence after surgical resection and radiosurgery for brain metastases.Neuro Oncol. 2019; Crossref Scopus (25) Google Scholar,7Cagney D.N. Lamba N. Sinha S. et al.Association of neurosurgical resection with development of pachymeningeal seeding in patients with brain metastases.JAMA Oncol. 2019; 5: 703-709Crossref PubMed Scopus (24) Google Scholar perhaps along with novel systemic treatments,9Exman P. Mallery R.M. Lin N.U. Parsons H.A. Response to olaparib in a patient with germline BRCA2 mutation and breast cancer leptomeningeal carcinomatosis.NPJ Breast Cancer. 2019; 5: 46Crossref PubMed Scopus (4) Google Scholar, 10Gill C.M. Brastianos P.K. Management of leptomeningeal carcinomatosis and challenges of trial design.Curr Opin Oncol. 2019; 31: 508-513Crossref PubMed Scopus (4) Google Scholar, 11Yang J.C.H. Kim S.W. Kim D.W. et al.Osimertinib in patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer and leptomeningeal metastases: The BLOOM Study.J Clin Oncol. 2019; (JCO1900457)Google Scholar though the optimal treatment is far from established. Developing and implementing more efficacious and less morbid approaches to the treatment of both diffuse and discrete LMD will require well-designed and thoughtfully analyzed clinical trials. The application of the classification system and training materials described by Turner et al2Turner B.E. Prabhu R.S. Burri S.H. et al.Nodular leptomeningeal disease - a distinct pattern of recurrence after post-resection stereotactic radiosurgery for brain metastases: A multi-institutional study of inter-observer reliability.Int J Radiat Oncol Biol Phys. 2019; Google Scholar would appear to be a key element in trial design and stratification, as well as clinical practice. Finally, we should ask our radiology colleagues about how they will approach classification of LMD, particularly regarding reporting of MRI results." @default.
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• W3003972052 title "Classifying Leptomeningeal Disease: An Essential Element in Managing Advanced Metastatic Disease in the Central Nervous System" @default.
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