Stellenwert und Komplikationsraten stereotaktischer Probenentnahmen in der Gliomdiagnostik und -therapie

Histopathological and molecular characterization of gliomas is necessary to determine subtype and therapy of the tumor. Tissue sampling through open resection or biopsy is possible. Different biopsy techniques are used when resection is deemed not safely feasible. Postoperative strategies for treatment of isocitrate dehydrogenase (IDH)-mutant astrocytomas are controversial. We first aimed at determining the safety and efficacy of stereotactic biopsies in patients with suspected gliomas overall and secondly investigated outcome of patients with IDH-mutant astrocytomas according to different treatment strategies after diagnosis through stereotactic biopsy or tumor resection: wait-and-scan, radiotherapy or temozolomide. Temozolomide has been reported to be associated with poor outcome in some patients with IDH-mutant astrocytomas. We retrospectively screened our databases for patients that had undergone stereotactic biopsies for suspected glioma between January 2016 and March 2021. Patient characteristics and procedural data were assessed. Complication rates were determined according to the Common Terminology Criteria for Adverse Events Version 5 (CTCAE). Additionally, patients diagnosed with IDH-mutant astrocytomas WHO grade 2 or 3 (n=183), either diagnosed by biopsy or resection, were further investigated for progression-free and overall survival. The cohort was stratified according to the postoperative strategy: wait-and-scan (n=98), radiotherapy (n=37) or temozolomide alone (n=48). Subgroup and matched-pair analyses were conducted. Within the biopsy cohort of 1’214 individual patients, 617 patients (50.8%) received a biopsy for a newly diagnosed lesion and 597 patients (49.2%) for a suspected recurrence. An integrated diagnosis was possible in 96.3% of all patients. IDH wildtype glioblastoma was the most frequent diagnosis with 596 patients (49.2%) affected, followed by oligodendroglioma WHO grade 2 (n = 109; 9%), astrocytoma WHO grade 3 (n = 108; 8.9%), oligodendroglioma WHO grade 3 (n = 76; 6.3%), and astrocytoma WHO grade 2 (n = 66; 5.4%). Peri-procedural complications CTCAE grade 3 or higher occurred in 1.2% of patients overall with no fatal outcome. In the treatment of IDH-mutant astrocytomas, radiotherapy alone was associated with better overall survival than temozolomide alone (14.4 vs 10.7 years, p=0.02). Patients from the wait-and-scan cohort also lived significantly longer than patients treated with temozolomide (not reached vs 10.7 years, p<0.01). This association was confirmed in subgroup and matched-pair analyses. Image-guided, stereotactic biopsies yield diagnoses with high accuracy and low peri-procedural complication rates initially and during clinical course. The implication of temozolomide chemotherapy alone in IDH-mutant astrocytomas remains uncertain and potential detrimental effects on outcome need to be further evaluated

PCV chemotherapy alone for WHO grade 2 oligodendroglioma: prolonged disease control with low risk of malignant progression

INTRODUCTION The role of chemotherapy alone in newly diagnosed WHO grade 2 oligodendroglioma after biopsy, incomplete or gross total resection remains controversial. We here analyze the clinical outcome of four patient cohorts being treated with either procarbazine, CCNU and vincristine (PCV) or temozolomide (TMZ) after biopsy, resection only, or wait-and-scan after biopsy. METHODS Patients (n = 142) with molecularly defined oligodendroglioma (WHO 2016) were assigned to four cohorts: W&S, wait-and-scan after stereotactic biopsy (n = 59); RES, surgical resection only (n = 27); TMZ, temozolomide after biopsy (n = 26) or PCV (n = 30) after biopsy. Presurgical MRI T2 tumor volumes were obtained by manual segmentation. Progression-free survival (PFS), post-recurrence PFS (PR-PFS) and rate of histological progression to grade 3 were analyzed. RESULTS PFS was longest after PCV (9.1 years), compared to 5.1 years after W&S, 4.4 years after RES and 3.6 years after TMZ. The rate of histological progression from grade 2 to 3 within 10 years was 9% for the PCV, 29% for the W&S, 67% for the RES and 75% for the TMZ group (p = 0.01). In the W&S group, patients treated with PCV at first relapse had a longer PFS from intervention than those treated with TMZ (7.2 vs 4.0 years, p = 0.04). Multivariate analysis identified smaller tumor volume prior to any intervention (p = 0.02) to be prognostic for PFS. CONCLUSIONS PCV chemotherapy alone is an effective treatment for WHO grade 2 oligodendroglioma, with long PFS and low rate of histological progression

Diagnostic Yield and Complication Rate of Stereotactic Biopsies in Precision Medicine of Gliomas

Background: An integrated diagnosis consisting of histology and molecular markers is the basis of the current WHO classification system of gliomas. In patients with suspected newly diagnosed or recurrent glioma, stereotactic biopsy is an alternative in cases in which microsurgical resection is deemed to not be safely feasible or indicated. In this retrospective study, we aimed to analyze both the diagnostic yield and the safety of a standardized biopsy technique. Material and Methods: The institutional database was screened for frame-based biopsy procedures (January 2016 until March 2021). Only patients with a suspected diagnosis of glioma based on imaging were included. All tumors were classified according to the current WHO grading system. The clinical parameters, procedural complications, histology, and molecular signature of the tissues obtained were assessed. Results: Between January 2016 and March 2021, 1,214 patients underwent a stereotactic biopsy: 617 (50.8%) for a newly diagnosed lesion and 597 (49.2%) for a suspected recurrence. The median age was 56.9 years (range 5 months−94.4 years). Magnetic resonance imaging (MRI)-guidance was used in 99.3% of cases and additional positron emission tomography (PET)-guidance in 34.3% of cases. In total, stereotactic serial biopsy provided an integrated diagnosis in 96.3% of all procedures. The most frequent diagnoses were isocitrate dehydrogenase (IDH) wildtype glioblastoma (n = 596; 49.2%), oligodendroglioma grade 2 (n = 109; 9%), astrocytoma grade 3 (n = 108; 8.9%), oligodendroglioma grade 3 (n = 76; 6.3%), and astrocytoma grade 2 (n = 66; 5.4%). A detailed determination was successful for IDH 1/2 mutation in 99.4% of cases, for 1p/19q codeletion in 97.4% of cases, for TERT mutation in 98.9% of cases, and for MGMT promoter methylation in 99.1% of cases. Next-generation sequencing was evaluable in 64/67 (95.5%) of cases and DNA methylome analysis in 41/44 (93.2%) of cases. Thirteen (1.1%) cases showed glial tumors that could not be further specified. Seventy-three tumors were different non-glioma entities, e.g., of infectious or inflammatory nature. Seventy-five out of 597 suspected recurrences turned out to be post-therapeutic changes only. The rate of post-procedural complications with clinical symptoms of the Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher was 1.2% in overall patients and 2.6% in the subgroup of brainstem biopsies. There was no fatal outcome in the entire series. Conclusion: Image-guided stereotactic serial biopsy enables obtaining reliable histopathological and molecular diagnoses with a very low complication rate even in tumors with critical localization. Thus, in patients not undergoing microsurgical resection, this is a valuable tool for precision medicine of patients with glioma

Limited efficacy of temozolomide alone for astrocytoma, IDH-mutant, CNS WHO grades 2 or 3

PURPOSE The role of temozolomide chemotherapy alone in isocitrate dehydrogenase (IDH)-mutant astrocytomas has not been conclusively determined. Radiotherapy might be superior to temozolomide. Recent studies have linked temozolomide with induction of hypermutation and poor clinical course in some IDH-mutant gliomas. METHODS In this retrospective study, 183 patients with astrocytoma, IDH-mutant, CNS WHO grade 2 or 3 and diagnosed between 2001 and 2019 were included. Patients initially monitored by wait-and-scan strategies or treated with radiotherapy or temozolomide alone were studied. Patient data were correlated with outcome. Matched pair and subgroup analyses were conducted. RESULTS Radiotherapy was associated with longer progression-free survival than temozolomide (6.2 vs 3.4 years, p = 0.02) and wait-and-scan strategies (6.2 vs 4 years, p = 0.03). Patients treated with radiotherapy lived longer than patients treated with temozolomide (14.4 vs 10.7 years, p = 0.02). Survival was longer in the wait-and-scan cohort than in the temozolomide cohort (not reached vs 10.7 years, p < 0.01). Patients from the wait-and-scan cohort receiving temozolomide at first progression had significantly shorter survival times than patients treated with any other therapy at first progression (p < 0.01). Post-surgical T2 tumor volume, contrast enhancement on MRI and WHO grade were associated with overall survival in univariate analyses (p < 0.01). CONCLUSION The results suggest superiority of radiotherapy over temozolomide and wait-and-scan strategies regarding progression-free survival and superiority of radiotherapy over temozolomide regarding overall survival. Our results are consistent with the notion that early temozolomide might compromise outcome in some patients

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

Background: Brain 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 methods: Our 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. Results: Overall, 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. Conclusion: In 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

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

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

PCV chemotherapy alone for WHO grade 2 oligodendroglioma: prolonged disease control with low risk of malignant progression

INTRODUCTION The role of chemotherapy alone in newly diagnosed WHO grade 2 oligodendroglioma after biopsy, incomplete or gross total resection remains controversial. We here analyze the clinical outcome of four patient cohorts being treated with either procarbazine, CCNU and vincristine (PCV) or temozolomide (TMZ) after biopsy, resection only, or wait-and-scan after biopsy. METHODS Patients (n = 142) with molecularly defined oligodendroglioma (WHO 2016) were assigned to four cohorts: W&S, wait-and-scan after stereotactic biopsy (n = 59); RES, surgical resection only (n = 27); TMZ, temozolomide after biopsy (n = 26) or PCV (n = 30) after biopsy. Presurgical MRI T2 tumor volumes were obtained by manual segmentation. Progression-free survival (PFS), post-recurrence PFS (PR-PFS) and rate of histological progression to grade 3 were analyzed. RESULTS PFS was longest after PCV (9.1 years), compared to 5.1 years after W&S, 4.4 years after RES and 3.6 years after TMZ. The rate of histological progression from grade 2 to 3 within 10 years was 9% for the PCV, 29% for the W&S, 67% for the RES and 75% for the TMZ group (p = 0.01). In the W&S group, patients treated with PCV at first relapse had a longer PFS from intervention than those treated with TMZ (7.2 vs 4.0 years, p = 0.04). Multivariate analysis identified smaller tumor volume prior to any intervention (p = 0.02) to be prognostic for PFS. CONCLUSIONS PCV chemotherapy alone is an effective treatment for WHO grade 2 oligodendroglioma, with long PFS and low rate of histological progression

Bilateral and Optimistic Warning Paradigms Improve the Predictive Power of Intraoperative Facial Motor Evoked Potentials during Vestibular Schwannoma Surgery

Facial muscle corticobulbar motor evoked potentials (FMcoMEPs) are used to monitor facial nerve integrity during vestibular schwannoma resections to increase maximal safe tumor resection. Established warning criteria, based on ipsilateral amplitude reduction, have the limitation that the rate of false positive alarms is high, in part because FMcoMEP changes occur on both sides, e.g., due to brain shift or pneumocephalus. We retrospectively compared the predictive value of ipsilateral-only warning criteria and actual intraoperative warnings with a novel candidate warning criterion, based on “ipsilateral versus contralateral difference in relative stimulation threshold increase, from baseline to end of resection” (BilatMT ≥ 20%), combined with an optimistic approach in which a warning would be triggered only if all facial muscles on the affected side deteriorated. We included 60 patients who underwent resection of vestibular schwannoma. The outcome variable was postoperative facial muscle function. Retrospectively applying BilatMT, with the optimistic approach, was found to have a significantly better false positive rate, which was much lower (9% at day 90) than the traditionally used ipsilateral warning criteria (>20%) and was also lower than actual intraoperative warnings. This is the first report combining the threshold method with an optimistic approach in a bilateral multi-facial muscle setup. This method could substantially reduce the rate of false positive alarms in FMcoMEP monitoring

Limited efficacy of temozolomide alone for astrocytoma, IDH-mutant, CNS WHO grades 2 or 3

Purpose The role of temozolomide chemotherapy alone in isocitrate dehydrogenase (IDH)-mutant astrocytomas has not been conclusively determined. Radiotherapy might be superior to temozolomide. Recent studies have linked temozolomide with induction of hypermutation and poor clinical course in some IDH-mutant gliomas. Methods In this retrospective study, 183 patients with astrocytoma, IDH-mutant, CNS WHO grade 2 or 3 and diagnosed between 2001 and 2019 were included. Patients initially monitored by wait-and-scan strategies or treated with radiotherapy or temozolomide alone were studied. Patient data were correlated with outcome. Matched pair and subgroup analyses were conducted. Results Radiotherapy was associated with longer progression-free survival than temozolomide (6.2 vs 3.4 years, p = 0.02) and wait-and-scan strategies (6.2 vs 4 years, p = 0.03). Patients treated with radiotherapy lived longer than patients treated with temozolomide (14.4 vs 10.7 years, p = 0.02). Survival was longer in the wait-and-scan cohort than in the temozolomide cohort (not reached vs 10.7 years, p < 0.01). Patients from the wait-and-scan cohort receiving temozolomide at first progression had significantly shorter survival times than patients treated with any other therapy at first progression (p < 0.01). Post-surgical T2 tumor volume, contrast enhancement on MRI and WHO grade were associated with overall survival in univariate analyses (p < 0.01). Conclusion The results suggest superiority of radiotherapy over temozolomide and wait-and-scan strategies regarding progression-free survival and superiority of radiotherapy over temozolomide regarding overall survival. Our results are consistent with the notion that early temozolomide might compromise outcome in some patients