scholarly journals Advances in the diagnosis, evaluation, and management of leptomeningeal disease

2021 ◽  
Vol 3 (Supplement_5) ◽  
pp. v86-v95
Author(s):  
Ugur Sener ◽  
Priya Kumthekar ◽  
Adrienne Boire
Keyword(s):  
Dna Analysis ◽  
Symptomatic Relief ◽  
Treatment Options ◽  
Leptomeningeal Metastasis ◽  
Circulating Tumor Cell ◽  
Leptomeningeal Disease ◽  
Leptomeningeal Involvement ◽  
Whole Brain Radiation ◽  
Ventriculoperitoneal Shunting ◽  
Tumor Dna

Abstract Leptomeningeal metastasis (LM) is a devastating complication of cancer with variable clinical presentation and limited benefit from existing treatment options. In this review, we discuss advances in LM diagnostics and therapeutics with the potential to reverse this grim course. Emerging cerebrospinal fluid circulating tumor cell and cell-free tumor DNA analysis technologies will improve diagnosis of LM, while providing crucial genetic information, capturing tumor heterogeneity, and quantifying disease burden. Circulating tumor cells and cell-free tumor DNA have utility as biomarkers to track disease progression and treatment response. Treatment options for LM include ventriculoperitoneal shunting for symptomatic relief, radiation therapy including whole-brain radiation and focal radiation for bulky leptomeningeal involvement, and systemic and intrathecal medical therapies, including targeted and immunotherapies based on tumor mutational profiling. While existing treatments for LM have limited efficacy, recent advances in liquid biopsy together with increasing availability of targeted treatments will lead to rational multimodal individualized treatments and improved patient outcomes.

Trial in progress: Phase I/II study of radiation therapy followed by intrathecal trastuzumab/pertuzumab in the management of HER2+ breast leptomeningeal disease.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1099-TPS1099
Author(s):  
Kamran A. Ahmed ◽  
Youngchul Kim ◽  
Michelle DeJesus ◽  
Priya Kumthekar ◽  
Nicole Olivia Williams ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Radiation Therapy ◽  
Phase I ◽  
Systemic Disease ◽  
Symptomatic Relief ◽  
Treatment Options ◽  
Leptomeningeal Disease ◽  
Breast Cancer Patients ◽  
Open Label

TPS1099 Background: HER2+ breast cancer patients with leptomeningeal disease (LMD) represent a poor prognosis population with a high unmet clinical need. Although a multitude of treatment options are available for the management of systemic disease, once metastases travel to the leptomeninges, patients have a lack of treatment options aside from traditional local approaches. Data from a phase I/II study reveals intrathecal (IT) trastuzumab to be well tolerated with improved overall survival (OS) compared to historical controls in HER2+ breast LMD. Radiotherapy can improve the flow of IT therapy through the cerebrospinal fluid (CSF) and provide symptomatic relief. The monoclonal antibody pertuzumab is used in conjunction with trastuzumab in the management of metastatic and localized HER2+ breast cancer. Given the role of radiotherapy in the management of LMD along with the role of pertuzumab in the management of HER2+ breast cancer, there is a strong clinical rationale to combine radiotherapy with IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. Methods: The study is designed as a prospective, single-arm, nonrandomized, open-label, phase I/II trial of radiation therapy followed by IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. HER2+ LMD patients identified by magnetic resonance imaging (MRI) and/or CSF cytology, ≥ 18, with a life expectancy > 8 weeks are eligible. Treatment is initiated with radiotherapy, whole brain radiotherapy and/or focal brain/spine radiation followed by IT trastuzumab/pertuzumab. Safety and feasibility will be monitored by a modified toxicity probability interval-2 (mTPI-2) design. Dose reductions of IT trastuzumab will not be allowed. Once the maximum tolerated dose of IT pertuzumab is determined, the phase II portion of the study will commence to determine OS. Secondary objectives involve defining the CSF pharmacokinetics of IT trastuzumab/pertuzumab, evaluating the response rate (leptomeningeal and parenchymal), and progression free survival (leptomeningeal and parenchymal) following IT trastuzumab/pertuzumab. In the phase 2 portion, a single-arm two-stage trial is designed using the Restricted-Kwak-and-Jung’s Method. The primary endpoint is one-year OS. An interim analysis will be performed after 20 patients are enrolled. This study is open with 1 patient enrolled at the time of submission. Clinical trial information: NCT04588545 .

scholarly journals Challenges and Advances in Diagnosis and Treatment of Leptomeningeal Disease (LMD)

2022 ◽  
Vol 11 ◽  
Author(s):  
Sherise D. Ferguson ◽  
Elena I. Fomchenko ◽  
Renato A. Guerrieri ◽  
Isabella C. Glitza Oliva
Keyword(s):  
Poor Prognosis ◽  
Treatment Options ◽  
Circulating Tumor Dna ◽  
Diagnosis And Treatment ◽  
Leptomeningeal Disease ◽  
Survival Times ◽  
Aggressive Therapy ◽  
Treatment Prognosis ◽  
Tumor Dna

Leptomeningeal disease (LMD) is a devastating category of CNS metastasis with a very poor prognosis and limited treatment options. With maximal aggressive therapy, survival times remain short and, without treatment, prognosis is measured in weeks. Both LMD diagnosis and treatment are challenging topics within neuro-oncology. In this review, we discuss the advances in LMD diagnosis with a focus on the role of circulating tumor DNA (ctDNA) and discuss the role of targeted and immunotherapy in LMD treatment.

scholarly journals SURG-25. EFFECT OF VENTRICULAR ENTRY DURING GLIOBLASTOMA RESECTION ON PATIENT OUTCOMES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii209-ii209
Author(s):  
Jacob Young ◽  
Andrew Gogos ◽  
Matheus Pereira ◽  
Ramin Morshed ◽  
Jing Li ◽  
...  
Keyword(s):  
Extent Of Resection ◽  
Tumor Location ◽  
Senior Author ◽  
Recurrent Glioblastoma ◽  
Leptomeningeal Disease ◽  
Newly Diagnosed ◽  
Ventriculoperitoneal Shunting ◽  
Two Factors ◽  
Postoperative Hydrocephalus

Abstract BACKGROUND Tumor proximity to the ventricle and ventricular entry (VE) during surgery have both been associated with poorer prognoses; however, the interaction between these two factors is poorly understood. METHODS The UCSF tumor registry was searched for patients with newly diagnosed and recurrent supratentorial glioblastoma who underwent surgical resection with the senior author between 2013 – 2018. Tumor location with respect to the subventricular zone (SVZ), size, VE, and extent of resection were assessed using pre and postoperative imaging. RESULTS In the 200-patient cohort of newly diagnosed and recurrent glioblastoma, 26.5% had VE. Comparing patients with VE to those without VE, there was no difference in postoperative hydrocephalus (1.9% vs. 4.8%, p = 0.36), ventriculoperitoneal shunting (0% vs. 3.4%, p = 0.17), pseudomeningoceles (7.5% vs. 5.4%, p = 0.58), or subdural hematomas (11.3% vs. 3.4%, p = 0.07). Importantly, rates of leptomeningeal disease (7.5% in VE vs. 10.2% w/o VE, p = 0.57) and distant parenchymal recurrence (17.9% in VE vs. 23.1% w/o VE, p = 0.35) were not different between the groups. There was no effect of VE on EOR when controlling for SVZ type. Newly diagnosed patients with tumors contacting the SVZ (Type 1 or 2) had worse survival than patients with tumors that did not contact the SVZ (Type 3 or 4) (1.27 vs 1.84 years, p = 0.014, HR 1.8, CI 1.08 – 3.03), but VE was not associated with worse survival in these patients with high risk SVZ Type 1 and 2 tumors (1.15 vs 1.68 years, p = 0.151, HR 0.59, CI 0.26 – 1.34). DISCUSSION VE was well tolerated with complications being rare events. There was no increase in leptomeningeal spread or distant parenchymal recurrence in patients with VE. Finally, VE did not change survival for patients with tumors contacting the ventricle.

scholarly journals Outcome comparison of patients who develop leptomeningeal disease or distant brain recurrence after brain metastases resection cavity radiosurgery

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Achiraya Teyateeti ◽  
Paul D Brown ◽  
Anita Mahajan ◽  
Nadia N Laack ◽  
Bruce E Pollock
Keyword(s):  
Overall Survival ◽  
Brain Metastases ◽  
Median Overall Survival ◽  
Recursive Partitioning ◽  
Leptomeningeal Disease ◽  
Resection Cavity ◽  
Whole Brain Radiation ◽  
Class 1 ◽  
Outcome Comparison ◽  
Brain Radiation

Abstract Background To compare the outcomes between patients with leptomeningeal disease (LMD) and distant brain recurrence (DBR) after stereotactic radiosurgery (SRS) brain metastases (BM) resection cavity. Methods Twenty-nine patients having single-fraction SRS after BM resection who developed either LMD (n = 11) or DBR (n = 18) as their initial and only site of intracranial progression were retrospectively reviewed. Results Patients developing LMD more commonly had a metachronous presentation (91% vs 50%, P = .04) and recursive partitioning class 1 status (45% vs 6%, P = .02). There was no difference in the median time from SRS to the development of LMD or DBR (5.0 vs 3.8 months, P = .68). The majority of patients with LMD (10/11, 91%) developed the nodular variant (nLMD). Treatment for LMD was repeat SRS (n = 4), whole-brain radiation therapy (WBRT; n = 5), resection + WBRT (n = 1), and no treatment (n = 1). Treatment for DBR was repeat SRS (n = 9), WBRT (n = 3), resection + resection cavity SRS (n = 1), and no treatment (n = 5). Median overall survival (OS) from time of resection cavity SRS was 15.7 months in the LMD group and 12.7 months in the DBR group (P = .60), respectively. Median OS in salvage SRS and salvage WBRT were 25.4 and 5.0 months in the nLMD group (P = .004) while 18.7 and 16.2 months in the DBR group (P = .30), respectively. Conclusions Following BM resection cavity SRS, nLMD recurrence is much more frequent than classical LMD. Salvage SRS may be considered for selected patients with nLMD, reserving salvage WBRT for patients with extensive intracranial disease without compromising survival. Further study with larger numbers of patients is needed.

scholarly journals Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Gillian Vandekerkhove ◽  
Jean-Michel Lavoie ◽  
Matti Annala ◽  
Andrew J. Murtha ◽  
Nora Sundahl ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Treatment Options ◽  
Circulating Tumor Dna ◽  
Molecular Stratification ◽  
Clinical Biomarkers ◽  
Surgery Patient ◽  
Metastatic Urothelial Carcinoma ◽  
Ctdna Analysis ◽  
Clinical Genomic ◽  
Tumor Dna

AbstractMolecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.

scholarly journals Circulating Tumor DNA Analysis during Radiation Therapy for Localized Lung Cancer Predicts Treatment Outcome

2017 ◽  
Vol 99 (2) ◽  
pp. S1-S2 ◽  
Author(s):  
A.A. Chaudhuri ◽  
A.F. Lovejoy ◽  
J.J. Chabon ◽  
A. Newman ◽  
H. Stehr ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Radiation Therapy ◽  
Treatment Outcome ◽  
Dna Analysis ◽  
Circulating Tumor Dna ◽  
Tumor Dna

Incidence, timing, and treatment of new brain metastases after Gamma Knife surgery for limited brain disease: the case for reducing the use of whole-brain radiation therapy

2011 ◽  
Vol 115 (1) ◽  
pp. 37-48 ◽  
Author(s):  
Stephen Rush ◽  
Robert E. Elliott ◽  
Amr Morsi ◽  
Nisha Mehta ◽  
Jeri Spriet ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Brain Metastases ◽  
Gamma Knife ◽  
Gamma Knife Surgery ◽  
Whole Brain Radiation Therapy ◽  
Leptomeningeal Disease ◽  
Whole Brain ◽  
Whole Brain Radiation ◽  
Brain Radiation

Object In this paper, the authors' goal was to analyze the incidence, timing, and treatment of new metastases following initial treatment with 20-Gy Gamma Knife surgery (GKS) alone in patients with limited brain metastases without whole-brain radiation therapy (WBRT). Methods A retrospective analysis of 114 consecutive adults (75 women and 34 men; median age 61 years) with KPS scores of 60 or higher who received GKS for 1–3 brain metastases ≤ 2 cm was performed (median lesion volume 0.35 cm3). Five patients lacking follow-up data were excluded from analysis. After treatment, patients underwent MR imaging at 6 weeks and every 3 months thereafter. New metastases were preferentially treated with additional GKS. Indications for WBRT included development of numerous metastases, leptomeningeal disease, or diffuse surgical-site recurrence. Results The median overall survival from GKS was 13.8 months. Excluding the 3 patients who died before follow-up imaging, 12 patients (11.3%) experienced local failure at a median of 7.4 months. Fifty-three patients (50%) developed new metastases at a median of 5 months. Six (7%) of 86 instances of new lesions were symptomatic. Most patients (67%) with distant failures were successfully treated using salvage GKS alone. Whole-brain radiotherapy was indicated in 20 patients (18.3%). Thirteen patients (11.9%) died of neurological disease. Conclusions For patients with limited brain metastases and functional independence, 20-Gy GKS provides excellent disease control and high-functioning survival with minimal morbidity. New metastases developed in almost 50% of patients, but additional GKS was extremely effective in controlling disease. Using our algorithm, fewer than 20% of patients required WBRT, and only 12% died of progressive intracranial disease.

scholarly journals GENE-40. CIRCULATING TUMOR DNA ANALYSIS IN PATIENT-DERIVED XENOGRAFT MODELS OF GLIOBLASTOMA

2017 ◽  
Vol 19 (suppl_6) ◽  
pp. vi101-vi101
Author(s):  
Nieves Perdigones ◽  
Sydney Connor ◽  
Lauren Hartman ◽  
Tania Contente-Cuomo ◽  
George Reid ◽  
...  
Keyword(s):  
Dna Analysis ◽  
Circulating Tumor Dna ◽  
Patient Derived Xenograft ◽  
Xenograft Models ◽  
Tumor Dna

CTIM-02. PHASE II STUDY OF IPILIMUMAB AND NIVOLUMAB IN LEPTOMENINGEAL CARCINOMATOSIS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi49-vi49
Author(s):  
Matthew Strickland ◽  
Eudocia Quant Lee ◽  
Nancy Wang ◽  
Justine Cohen ◽  
Ugonma Chukwueke ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Solid Tumor ◽  
Primary Tumor ◽  
Phase Ii Study ◽  
Treatment Options ◽  
Leptomeningeal Carcinomatosis ◽  
Leptomeningeal Disease ◽  
Dosing Regimens ◽  
Unacceptable Toxicity

Abstract Leptomeningeal disease (LMD) is an increasingly common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We conducted a single arm Phase II study of combined ipilimumab and nivolumab in patients with LMD from solid tumor malignancies (NCT02939300). Patients received manufacturer-specific dosing regimens of combined ipilimumab and nivolumab based on primary-tumor histology until definitive progression or unacceptable toxicity. The primary end point was rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Eighteen patients with diverse primary tumor histologies were enrolled and all received at least one dose of combined ipilimumab and nivolumab. Median follow up based on patients still alive was 8.0 months (range: 0.5 to 15.9 months). The study met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients were alive at three months after enrollment. One third of patients experienced one (or more) grade-3 or higher adverse events possibly related to treatment. Two patients discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events overall included fatigue (N=7), nausea (N=6), fever (N=6), anorexia (N=6) and rash (N=6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients; this therapeutic approach should be studied in larger, multicenter clinical trials to validate these results as well as better identify patients who will benefit.

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