Non small cell lung cancer intracranial metastases treatment

Non small cell lung cancer intracranial metastases treatment

Brain metastases are common in patients with non small cell lung cancer (NSCLC). Because of associated poor prognosis and limited specific treatment options, there is a real need for the development of medical therapies and strategies for affected patients. Novel compounds for epidermal growth factor receptor-dependent and anaplastic lymphoma kinase-dependent lung cancer have demonstrated blood-brain barrier permeability and have led to important improvements in central nervous system outcomes. Studies of targeted therapies for oncogene-driven tumors and of immunotherapies in patients with brain metastases have shown promise and, allied with novel radiation techniques, are driving a rapid evolution in treatment and prognosis for NSCLC brain metastases 1).


KPS score ≥ 70, RPA class I/II, and postoperative chemotherapy could benefit post-metastasectomy patients with brain metastases (BM) from Non small cell lung cancer (NSCLC). Conversely, the initial onset of intracranial lesions is an unfavorable factor that increases the risk of death. These findings support the use of personalized therapy for patients with BM from NSCLC 2).


EGFR and ALK tyrosine kinase inhibitors (TKIs) provide significantly superior systemic response rates and progression free survival compared to standard chemotherapy in the molecularly defined Non small cell lung cancer (NSCLC) subpopulations. An apparent intracranial activity of new generation TKIs triggered the discussion on their role in brain metastases in lieu of local therapies 3).


A article of Preusser et al., is the result of a round table discussion held at the European Lung Cancer Conference (ELCC) in Geneva in May 2017. Its purpose was to explore and discuss the advances in the knowledge about the biology and treatment of brain metastases originating from non-small cell lung cancer. The authors propose a series of recommendations for research and treatment within the discussed context 4).


PUBMEDEMBASE, the Cochrane LibraryWeb of Knowledge, Current Controlled Trials, Clinical Trials, and 2 conference websites were searched to select NSCLC patients with only single brain metastasis (SBM) who received brain surgery or SRS. SPSS 18.0 software was used to analyze the mean median survival time (MST) and Stata 11.0 software was used to calculate the overall survival (OS).

A total of 18 trials including 713 patients were systematically reviewed. The MST of the patients was 12.7 months in surgery group and 14.85 months in SRS group, respectively. The 1, 2, and 5 years OS of the patients were 59%, 33%, and 19% in surgery group, and 62%, 33%, and 14% in SRS group, respectively. Furthermore, in the surgery group, the 1 and 3 years OS were 68% and 15% in patients with controlled primary tumors, and 50% and 13% in the other patients with uncontrolled primary tumors, respectively. Interestingly, the 5-year OS was up to 21% in patients with controlled primary tumors.

There was no significant difference in MST or OS between patients treated with neurosurgery and SRS. Patients with resectable lung tumors and SBM may benefit from the resection of both primary lesions and metastasis 5).

Patients with NSCLC and synchronous brain metastases, presenting neurological symptoms showed no survival benefit from neurosurgical resection, although quality of life was improved due to early control of neurological symptoms 6).


Response rates after platinum based antineoplastics, range from 23% to 45%. Development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs): gefitinib or erlotinib, was an improvement in treatment of advanced NSCLC patients. EGFR mutations are present in 10-25% of NSCLC (mostly adenocarcinoma), and up to 55% in never-smoking women of East Asian descent. In the non-selected group of patients with BMF-NSCLC, the overall response rates after gefitinib or erlotinib treatment range from 10% to 38%, and the duration of response ranges from 9 to 13.5 months. In the case of present activating EGFR mutation, the response rate after EGRF-TKIs is greater than 50%, and in selected groups (adenocarcinoma, patients of Asian descent, never-smokers, asymptomatic BMF-NSCLC) even 70%. Gefitinib or erlotinib treatment improves survival of BMF-NSCLC patients with EGFR mutation in comparison to cases without the presence of this mutation. There is no data on the activity of the anti-EML4-ALK agent crizotinib. Bevacizumab, recombinant humanised monoclonal antibody anti-VEGF, in the treatment of advanced non-squamous NSCLC patients is a subject of intense research. Data from a clinical trial enrolling patients with pretreated or occult BMF-NSCLC proved that the addition of bevacizumab to various chemotherapy agents or erlotinib is a safe and efficient treatment, associated with a low incidence of CSN haemorrhages. However, the efficacy and safety of bevacizumab used for therapeutic intent, regarding active brain metastases is unknown 7).

Non small cell lung cancer intracranial metastases whole brain radiotherapy

Non small cell lung cancer intracranial metastases radiosurgery

Non small cell lung cancer intracranial metastases surgery

References

1)

Bulbul A, Forde PM, Murtuza A, Woodward B, Yang H, Bastian I, Ferguson PK, Lopez-Diaz F, Ettinger DS, Husain H. Systemic Treatment Options for Brain Metastases from Non-Small-Cell Lung Cancer. Oncology (Williston Park). 2018 Apr 15;32(4):156-63. Review. PubMed PMID: 29684234.
2)

She C, Wang R, Lu C, Sun Z, Li P, Yin Q, Liu Q, Wang P, Li W. Prognostic factors and outcome of surgically treated patients with brain metastases of non-small cell lung cancer. Thorac Cancer. 2018 Nov 28. doi: 10.1111/1759-7714.12913. [Epub ahead of print] PubMed PMID: 30485664.
3)

Wrona A, Dziadziuszko R, Jassem J. Management of brain metastases in non-small cell lung cancer in the era of tyrosine kinase inhibitors. Cancer Treat Rev. 2018 Dec;71:59-67. doi: 10.1016/j.ctrv.2018.10.011. Epub 2018 Oct 21. Review. PubMed PMID: 30366200.
4)

Preusser M, Winkler F, Valiente M, Manegold C, Moyal E, Widhalm G, Tonn JC, Zielinski C. Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: summary of a multidisciplinary roundtable discussion. ESMO Open. 2018 Jan 26;3(1):e000262. doi: 10.1136/esmoopen-2017-000262. eCollection 2018. Review. PubMed PMID: 29387475; PubMed Central PMCID: PMC5786916.
5)

Qin H, Wang C, Jiang Y, Zhang X, Zhang Y, Ruan Z. Patients with single brain metastasis from non-small cell lung cancer equally benefit from stereotactic radiosurgery and surgery: a systematic review. Med Sci Monit. 2015 Jan 12;21:144-52. doi: 10.12659/MSM.892405. PubMed PMID: 25579245.
6)

Kim SY, Hong CK, Kim TH, Hong JB, Park CH, Chang YS, Kim HJ, Ahn CM, Byun MK. Efficacy of surgical treatment for brain metastasis in patients with non-small cell lung cancer. Yonsei Med J. 2015 Jan 1;56(1):103-11. doi: 10.3349/ymj.2015.56.1.103. PubMed PMID: 25510753; PubMed Central PMCID: PMC4276743.
7)

Cedrych I, Kruczała MA, Walasek T, Jakubowicz J, Blecharz P, Reinfuss M. Systemic treatment of non-small cell lung cancer brain metastases. Contemp Oncol (Pozn). 2016;20(5):352-357. doi: 10.5114/wo.2016.64593. Epub 2016 Dec 20. Review. PubMed PMID: 28373815; PubMed Central PMCID: PMC5371701.

VIM targeting

VIM targeting

The ventral intermediate nucleus of the thalamus is not readily visible on structural magnetic resonance imaging. Therefore, a method for its visualization for stereotactictargeting is desirable.

The objective of a study of Sammartino et al., from the Toronto Western Hospital was to define a tractography-based methodology for the stereotactic targeting of the ventral intermediate nucleus.

The lateral and posterior borders of the ventral intermediate nucleus were defined by tracking the pyramidal tract and medial lemniscus, respectively. A thalamic seed was then created 3 mm medial and anterior to these borders, and its structural connections were analyzed. The application of this method was assessed in an imaging cohort of 14 tremorpatients and 15 healthy controls, in which they compared the tractography-based targeting to conventional targeting. In a separate surgical cohort (3 tremor and 3 tremor-dominant Parkinson’s disease patients), they analyzed the accuracy of this method by correlating it with intraoperativeneurophysiology.

Tractography of the thalamic seed revealed the tracts corresponding to cerebellar input and motor cortical output fibers. The tractography-based target was more lateral (12.5 [1.2] mm vs 11.5 mm for conventional targeting) and anterior (8.5 [1.1] mm vs 6.7 [0.3] mm, anterior to the posterior commissure). In the surgical cohort, the Euclidean distance between the ventral intermediate nucleus identified by tractography and the surgical target was 1.6 [1.1] mm. The locations of the sensory thalamus, lemniscus, and pyramidal tracts were concordant within <1 mm between tractography and neurophysiology.

The tractography-based methodology for identification of the ventral intermediate nucleus is accurate and useful. This method may be used to improve stereotactic targeting in functional neurosurgery procedures 1).


Krishna et al., from the Center for Neuromodulation, The Ohio State University Wexner Medical Center,prospectively assessed the outcomes of Focused ultrasound thalamotomy (FUS-T) in 10 essential tremor (ET) patients using tractography-based targeting of the ventral intermediate nucleus (VIM).

VIM was identified at the intercommissural plane based on its neighboring tracts: the pyramidal tract and medial lemniscus. FUS-T was performed at the center of tractography-defined VIM. Tremor outcomes, at baseline and 3 months, were assessed independently by the Tremor Research Group. They analyzed targeting coordinates, clinical outcomes, and adverse events. The FUS-T lesion location was analyzed in relation to unbiased thalamic parcellation using probabilistic tractography. Quantitative diffusion weighted imaging changes were also studied in fiber tracts of interest.

The tractography coordinates were more anterior than the standard. Intraoperatively, therapeutic sonications at the tractography target improved tremor (>50% improvement) without motor or sensory side effects. Sustained improvement in tremor was observed at 3 mo (tremor score: 18.3 ± 6.9 vs 8.1 ± 4.4, P = .001). No motor weakness and sensory deficits after FUS-T were observed during 6-mo follow-up. Ataxia was observed in 3 patients. FUS-T lesions overlapped with the VIM parcellated with probablisitic tractography. Significant microstructural changes were observed in the white matter connecting VIM with cerebellum and motor cortex.

This is the first report of prospective VIM targeting with tractography for FUS-T. These results suggest that tractography-guided targeting is safe and has satisfactory short-term clinical outcomes 2).

Clinical trials

Optimization of VIM Targeting in Essential Tremor Surgery (Opti-VIM) https://clinicaltrials.gov/ct2/show/NCT03760406

References

1)

Sammartino F, Krishna V, King NK, Lozano AM, Schwartz ML, Huang Y, Hodaie M. Tractography-Based Ventral Intermediate Nucleus Targeting: Novel Methodology and Intraoperative Validation. Mov Disord. 2016 Aug;31(8):1217-25. doi: 10.1002/mds.26633. Epub 2016 May 23. PubMed PMID: 27214406; PubMed Central PMCID: PMC5089633.
2)

Krishna V, Sammartino F, Agrawal P, Changizi BK, Bourekas E, Knopp MV, Rezai A. Prospective Tractography-Based Targeting for Improved Safety of Focused Ultrasound Thalamotomy. Neurosurgery. 2019 Jan 1;84(1):160-168. doi: 10.1093/neuros/nyy020. PubMed PMID: 29579287.

Fluorescence-Guided Neurosurgery

Fluorescence-Guided Neurosurgery

see 5 aminolevulinic acid fluorescence guided resection.

see Fluorescein sodium guided resection.

see Fluorescence guided surgery of glioma.

The first use of fluorescence for brain tumour surgery was in 1948 by G.E. Moore 1) using fluorescein sodium.

Achieving a maximal safe extent of resection during brain tumor surgery is the goal for improved patient prognosisFluorescence-guided neurosurgery using 5-aminolevulinic acid (5-ALA) induced Protoporphyrin IX has thereby become a valuable tool enabling a high frequency of complete resections and a prolonged progression free survival in glioblastoma patients.

Erkkilä et al., from the Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Advanced Development Microsurgery, Carl Zeiss Meditec AG, Christian Doppler Laboratory for Innovative Optical Imaging and Its Translation to Medicine, Medical University of Vienna, Institute of Neurology, Department of Neurosurgery, General Hospital and Medical University of Vienna, presented a widefield fluorescence lifetime imaging device with 250 mm working distance working under similar conditions like surgical microscopes based on a time-of-flight based dual tap CMOS camera. In contrast to intensity-based fluorescence imaging this method is invariant to light scattering and absorption while being sensitive to the molecular composition of the tissue. They evaluated the feasibility of lifetime imaging of Protoporphyrin IX using the system to analyze brain tumor phantoms and fresh 5-ALA labeled human tissue samples. The results demonstrate the potential of this lifetime sensing device to go beyond the limitation of current intensity-based fluorescence-guided neurosurgery 2).

Books

Fluorescence-Guided Neurosurgery: Neuro-oncology and Cerebrovascular Applications September 10, 2018 The definitive textbook on state-of-the-art fluorescence-guided neurosurgery

Advances in fluorescence-guided surgery (FGS) have resulted in a paradigm shift in neurosurgical approaches to neuro-oncological and cerebrovascular pathologies. Edited by two of the foremost authorities on the topic, Fluorescence-Guided Neurosurgery: Neuro-oncology and Cerebrovascular Applications encompasses the depth and breadth of this groundbreaking, still nascent technology. The book reflects significant contributions made by world renowned neurosurgeons Constantinos Hadjipanayis, Walter Stummer, and esteemed contributors on the growing uses of 5-aminolevulinic acid (5-ALA) and other FGS agents.

The European Medicine Agency approved 5-ALA in 2007, heralding the birth of FGS globally. In 2017, the U.S. Food and Drug Administration approved 5-ALA (Gleolan) as an imaging agent to facilitate realtime detection and visualization of malignant tissue during glioma surgery. In the two decades since Dr. Stummer’s initial description of 5-ALA FGS in a human patient, major strides have been made in its practical applications, leading to improved resection outcomes. As FGS is increasingly incorporated into neurosurgical practice, it holds promise for future innovations. Generously-illustrated and enhanced with online videos, this textbook is the definitive resource on the subject.

Key Features

The improved efficacy of 5-ALA for resecting high- and low-grade gliomas, recurrences, meningiomas, brain metastases, spinal cord tumors, pediatric brain tumors, and other adult tumors The future of fluorescence, including potentially powerful new fluorophores molecularly targeted specifically to tumors The use of the fluorescent agent indocyanine green (ICG) for brain tumors, cerebral aneurysms, AVMs, and cerebral vascularization Special topics such as fluorescein, illuminating tumor paint, confocal microscopy, Raman spectroscopy, and integrating FGS with intraoperative imaging and brain mapping This single accessible reference presents the current state-of-the-art on this emerging, exciting surgical technology. As such, it is a must-have for neurosurgical residents, fellows, and practicing neurosurgeons.

1)

Moore GE, Peyton WT, French LA, Walker WW (1948) The clinical use of fluorescein in neurosurgery; the localization of brain tumors. J Neurosurg 5:392–398
2)

Erkkilä MT, Bauer B, Hecker-Denschlag N, Madera Medina MJ, Leitgeb RA, Unterhuber A, Gesperger J, Roetzer T, Hauger C, Drexler W, Widhalm G, Andreana M. Widefield fluorescence lifetime imaging of protoporphyrin IX for fluorescence-guided neurosurgery: an ex vivo feasibility study. J Biophotonics. 2019 Jan 12. doi: 10.1002/jbio.201800378. [Epub ahead of print] PubMed PMID: 30636030.
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