The evolving role of neurosurgery for central nervous system metastases in the era of personalized cancer therapy

Karschnia, Philipp; Rhun, Émilie Le; Vogelbaum, Michael A.; Bent, Martin J. van den; Grau, Stefan; Preusser, Matthias; Soffietti, Riccardo; Baumgarten, Louisa von; Westphal, Manfred; Weller, Michael; Tonn, Joerg‐Christian

doi:10.1016/j.ejca.2021.07.032

Cited by 18 publications

(12 citation statements)

References 121 publications

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“…Singular lesions amenable to safe surgical resection should be operated upon, space-occupying lesions may even require urgent decompression ( 4 , 5 ). Microsurgical tumor resection serves both therapeutic and diagnostic purposes, but at the risk of potential surgical complications particularly in frail patients ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

The value of stereotactic biopsy of primary and recurrent brain metastases in the era of precision medicine

Katzendobler

Weller

et al. 2022

Front. Oncol.

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BackgroundBrain metastases (BM) represent the most frequent intracranial tumors with increasing incidence. Many primary tumors are currently treated in protocols that incorporate targeted therapies either upfront or for progressive metastatic disease. Hence, molecular markers are gaining increasing importance in the diagnostic framework of BM. In cases with diagnostic uncertainty, both in newly diagnosed or recurrent BM, stereotactic biopsy serves as an alternative to microsurgical resection particularly whenever resection is not deemed to be safe or feasible. This retrospective study aimed to analyze both diagnostic yield and safety of an image-guided frame based stereotactic biopsy technique (STX).Material and methodsOur institutional neurosurgical data base was searched for any surgical procedure for suspected brain metastases between January 2016 and March 2021. Of these, only patients with STX were included. Clinical parameters, procedural complications, and tissue histology and concomitant molecular signature were assessed.ResultsOverall, 467 patients were identified including 234 (50%) with STX. Median age at biopsy was 64 years (range 29 – 87 years). MRI was used for frame-based trajectory planning in every case with additional PET-guidance in 38 cases (16%). In total, serial tumor probes provided a definite diagnosis in 230 procedures (98%). In 4 cases (1.7%), the pathological tissue did not allow a definitive neuropathological diagnosis. 24 cases had to be excluded due to non-metastatic histology, leaving 206 cases for further analyses. 114 patients (49%) exhibited newly diagnosed BM, while 46 patients (20%) displayed progressive BM. Pseudoprogression was seen in 46 patients, a median of 12 months after prior therapy. Pseudoprogression was always confirmed by clinical course. Metastatic tissue was found most frequently from lung cancer (40%), followed by breast cancer (9%), and malignant melanoma (7%). Other entities included gastrointestinal cancer, squamous cell cancer, renal cell carcinoma, and thyroid cancer, respectively. In 9 cases (4%), the tumor origin could not be identified (cancer of unknown primary). Molecular genetic analyses were successful in 137 out of 144 analyzed cases (95%). Additional next-generation sequencing revealed conclusive results in 12/18 (67%) cases. Relevant peri-procedural complications were observed in 5 cases (2.4%), which were all transient. No permanent morbidity or mortality was noted.ConclusionIn patients with BM, frame-based stereotactic biopsy constitutes a safe procedure with a high diagnostic yield. Importantly, this extended to discerning pseudoprogression from tumor relapse after prior therapy. Thus, comprehensive molecular characterization based on minimal-invasive stereotactic biopsies lays the foundation for precision medicine approaches in the treatment of primary and recurrent BM.

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Section: Introductionmentioning

confidence: 99%

The value of stereotactic biopsy of primary and recurrent brain metastases in the era of precision medicine

Katzendobler

Weller

et al. 2022

Front. Oncol.

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“…Scale bars: A, F: 1400 µm; B-E, G-J: 180 µm. K-M: Tumor volume (K; mm 3 ), intratumoral (CAR) T-cell density (L; cells/mm 3 ), and distribution of intratumoral (CAR) T-cells (M; percentage) on day 10 after injection of EpCAM/GFP CAR T-cells (green; n = 9) or GFP T-cells (gray; n = 8) determined by immunofluorescence. Mean ± SEM.…”

Section: Resultsmentioning

confidence: 99%

“… 1 , 2 This number might even increase in the next decades given that therapeutic advances for lung cancer involving immunotherapeutic or targeted agents have resulted in prolonged disease courses. 3 Although control of extracranial disease can often be achieved using such agents, a considerable number of patients succumb to their intracranial tumor. 4 Novel therapeutic strategies for the treatment of lung cancer brain metastases are therefore urgently warranted.…”

Section: Introductionmentioning

confidence: 99%

In vivo dynamics and anti-tumor effects of EpCAM-directed CAR T-cells against brain metastases from lung cancer

Karschnia

Cadilha

et al. 2023

OncoImmunology

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Lung cancer patients are at risk for brain metastases and often succumb to their intracranial disease. Chimeric Antigen Receptor (CAR) T-cells emerged as a powerful cell-based immunotherapy for hematological malignancies; however, it remains unclear whether CAR T-cells represent a viable therapy for brain metastases. Here, we established a syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning-microscopy. This approach enabled in vivo -characterization of fluorescent CAR T-cells and tumor cells on a single-cell level over weeks. Intraparenchymal injection of Lewis lung carcinoma cells (expressing the tumor cell-antigen EpCAM) was performed, and EpCAM-directed CAR T-cells were injected either intravenously or into the adjacent brain parenchyma. In mice receiving EpCAM-directed CAR T-cells intravenously, we neither observed substantial CAR T-cell accumulation within the tumor nor relevant anti-tumor effects. Local CAR T-cell injection, however, resulted in intratumoral CAR T-cell accumulation compared to controls treated with T-cells lacking a CAR. This finding was accompanied by reduced tumorous growth as determined per in vivo -microscopy and immunofluorescence of excised brains and also translated into prolonged survival. However, the intratumoral number of EpCAM-directed CAR T-cells decreased during the observation period, pointing toward insufficient persistence. No CNS-specific or systemic toxicities of EpCAM-directed CAR T-cells were observed in our fully immunocompetent model. Collectively, our findings indicate that locally (but not intravenously) injected CAR T-cells may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Strategies improving the intratumoral CAR T-cell persistence may further boost the therapeutic success.

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“…Removing symptomatic masses through surgical resection may improve the neurological and systemic status of patients. Meanwhile, tumor markers and gene mutations elucidated from surgical pathological specimens can often guide the selection of targeted therapeutic agents for the postoperative systemic treatment of BM patients [ 2 ]. Consequently, patients with no more than four BM were included in this study.…”

Section: Discussionmentioning

confidence: 99%

“…BM are terminal manifestations of malignant tumors with poor prognosis, and the main purpose of treatment is to alleviate neurological symptoms and improve the quality of life. Currently, treatment methods for BM mainly include surgery, SRS, whole brain radiotherapy (WBRT), chemotherapy, and targeted therapy [ 2 , 3 ]. Owing to better healing efficacy, relatively faster treatment time, and lower neurotoxicity, SRS has been increasingly applied for patients with a limited number of BM [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Key Clinical Variables and Radiological Manifestations Associated with the Treatment Response of Patients with Brain Metastases to Stereotactic Radiosurgery

Chen

Shen³

et al. 2022

JCM

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Background: Stereotactic radiosurgery (SRS) is considered a promising treatment for brain metastases (BM) with better healing efficacy, relatively faster treatment time, and lower neurotoxicity, which can achieve local control rates above 70%. Although SRS improves the local control of BM, this may not translate into improvements in survival time. Thus, screening out the key factors influencing the treatment response to SRS, instead of the survival time following SRS, might be of more significance. This may assist doctors when making adjustments to treatment strategies for patients with BM. Methods: This is a retrospective review of 696 patients with BM who were treated with SRS at Huashan Hospital, Fudan University between June 2015 and February 2020. According to the patients’ treatment response to SRS, the patients were divided into an improved group (IG) and a progressive group (PG). The clinical data and magnetic resonance imaging (MRI) performed pre- and post-treatment were collected for the two groups. Five clinical variables (gender, age, Karnofsky performance status (KPS), primary tumor type, and extracranial lesion control) and seven radiological manifestations (location, number, volume, maximum diameter, edema index (EI), diffusion weighted imaging (DWI) sequence signal, and enhanced pattern) were selected and compared. A stepwise regression analysis was performed in order to obtain the best prediction effect of a group of variables and their regression coefficients, and finally to build an SRS treatment response scoring model based on the coefficients. The performance of the model was evaluated by calculating the AUC and performing the Hosmer–Lemeshow test. Results: A total of 323 patients were enrolled in the study based on the inclusion and exclusion criteria, including 209 patients in the IG and 114 patients in the PG. In the Chi-square test and t-test analysis, the significant p values of KPS, extracranial lesion control, volume, and EI were less than 0.05. Moreover, the cut-off values for volume and EI were 1801.145 mm3 and 3.835, respectively. The scoring model that was based on multivariate logistic regression coefficients performed better, achieving AUCs of 0.755 ± 0.062 and 0.780 ± 0.061 for the internal validation and validation cohorts, with p values of 0.168 and 0.073 for the Hosmer–Lemeshow test. Conclusions: KPS, extracranial lesion control, tumor volume, and EI had a certain correlation with the treatment response to SRS. Scoring models that are based on these variables can accurately predict the treatment response of patients with BM to SRS, thereby assisting doctors to make an appropriate first treatment strategy for patients with BM to a certain degree.

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The evolving role of neurosurgery for central nervous system metastases in the era of personalized cancer therapy

Cited by 18 publications

References 121 publications

The value of stereotactic biopsy of primary and recurrent brain metastases in the era of precision medicine

The value of stereotactic biopsy of primary and recurrent brain metastases in the era of precision medicine

In vivo dynamics and anti-tumor effects of EpCAM-directed CAR T-cells against brain metastases from lung cancer

Analysis of Key Clinical Variables and Radiological Manifestations Associated with the Treatment Response of Patients with Brain Metastases to Stereotactic Radiosurgery

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