Abstract Background glioblastomas are highly vascularized tumors and various antiangiogenic drugs have been investigated in clinical trials showing unclear results. We performed a systematic review ...and a meta-analysis to clarify and evaluate their effectiveness in glioblastoma patients. Patients and methods we searched relevant published and unpublished randomized clinical trials analyzing antiangiogenic drugs versus chemotherapy in glioblastoma patients from January 2006 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases. Results fourteen randomized clinical trials were identified (7 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) were identified including 4330 patients. Antiangiogenic drugs showed no improvement in overall survival with a pooled HR of 1.00, a trend for an inferior outcome, in terms of overall survival, was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone (HR = 1.24, p = 0.056). Bevacizumab did not improve overall survival. Twelve trials (4113 patients) were analyzed for progression-free survival. Among antiangiogenic drugs, only bevacizumab demonstrated an improvement of progression-free survival (HR = 0.63, p < 0.001), both alone (HR = 0.60, p = 0.003) or in combination to chemotherapy (HR = 0.63; p<0.001), both as first-line treatment (HR = 0.70, p < 0.001) or in recurrent disease (HR = 0.52, p < 0.001). Conclusions antiangiogenic drugs did not improve overall survival in glioblastoma patients, either as first or second-line treatment, and either as single agent or in combination with chemotherapy. Among antiangiogenic drugs, only bevacizumab improved progression-free survival regardless of treatment line, both as single agent or in combination with chemotherapy
Background: Treatment of elderly glioblastoma patients (EGP) is a challenge in neuro-oncology. The comprehensive geriatric assessment (CGA) is currently used to assess geriatric oncological patients ...with other types of tumors. We performed a large retrospective study to analyze its predictive role in EGP. Methods: Patients aged ≥65 years with histologically confirmed diagnosis of glioblastoma were enrolled. CGA included the following tests: the Cumulative Illness Rating Scale-Comorbidity and Severity Index, Activities of Daily Living, Instrumental Activities of Daily Living, the Mini Mental State Examination, and the Geriatric Depression Scale. Based on CGA results, each patient was categorized as fit, vulnerable, or frail. Results: We enrolled 113 patients. According to the CGA scores, 35% of patients were categorized as “fit”, 30% as “vulnerable”, and 35% as “frail” patients. Median overall survival was 16.5, 12.1, and 10.3 months in fit, vulnerable, and frail patients (p = 0.1), respectively. On multivariate analysis, the CGA score resulted an independent predictor of survival; indeed, vulnerable and frail patients had a hazard ratio of 1.5 and 2.2, respectively, compared to fit patients (p = 0.04). No association between CGA and progression-free survival (PFS) was demonstrated. Conclusions: The CGA score proved to be a significant predictor of mortality in EGP, and it could be a useful treatment decision tool.
Abstract
Background
We quantified the spontaneous imaging growth rate of oligodendrogliomas. We assessed whether (i) it discriminates between World Health Organization (WHO) grade II and grade III ...oligodendrogliomas, and (ii) grade III oligodendrogliomas with neo-angiogenesis are associated with more fast growth rates (≥8 mm/y).
Methods
This work employed a retrospective bicentric cohort study (2010–2016) of adult patients harboring a newly diagnosed supratentorial oligodendroglioma, isocitrate dehydrogenase (IDH) mutant and 1p/19q codeleted (WHO 2016 classification), with a minimum of 2 available MRIs before any treatment (minimum 6-week interval) to measure the spontaneous tumor growth rate.
Results
We included 108 patients (age 44.7 ± 14.1 y, 60 males). The tumor growth rate was higher in grade III oligodendrogliomas with neo-angiogenesis (n = 37, median 10.4 mm/y, mean 10.0 ± 6.9) than in grade III oligodendrogliomas with increased mitosis count only (cutoff ≥6 mitoses, n = 18, median 3.9 mm/y, mean 4.5 ± 3.2; P = 0.004), and higher than in grade II oligodendrogliomas (n = 53, median 2.3 mm/y, mean 2.8 ± 2.2; P < 0.001). There was increased prevalence of fast tumor growth rates in grade III oligodendrogliomas with neo-angiogenesis (54.1%) compared with grade III oligodendrogliomas with increased mitosis count only (11.1%; P < 0.001), and in grade II oligodendrogliomas (0.0%; P < 0.001). The tumor growth rate trends did not differ between centers (P = 0.121). Neo-angiogenesis (P < 0.001) and mitosis count at ≥9 (P = 0.013) were independently associated with tumor growth rates ≥8 mm/year. A tumor growth rate ≥8 mm/year was the only predictor independently associated with shorter progression-free survival (P = 0.041).
Conclusions
The spontaneous tumor growth rate recapitulates oligodendroglioma aggressiveness, permits identification of grade III oligodendrogliomas preoperatively when ≥8 mm/year, and questions the grading by mitosis count.
Comparative prospective data regarding different radiosurgery (SRS) modalities for treating brain metastases (BMs) from solid tumors are not available. To investigate with a single institute phase ...III randomized trial whether SRS executed with linac (Arm-B) is superior to a dedicated multi-source gamma-ray stereotactic platform (Arm-A).
Adults patients with 1-4 BMs from solid tumors up to 30 mm in maximum diameter were randomly assigned to arms A and B. The primary endpoint was cumulative incidence of symptomatic (grade 2-3) radionecrosis (CIRN). Secondary endpoints were local progression cumulative incidence (CILP), distant brain failure, disease-free survival (DFS), and overall survival (OS).
A total of 251 patients were randomly assigned to Arm-A (121) or Arm-B (130). The 1-year RN cumulative incidence was 6.7% in whole cohort, 3.8% (95% CI 1.9-7.4%) in Arm-B, and 9.3% (95% CI 6.2-13.8%) in the Arm-A (p = 0.43). CIRN was influenced by target volume irradiated only for the Arm-A (p << 0.001; HR 1.36 95% CI 1.25-1.48). Symptomatic RN occurred in 56 cases at a median time of 10.3 months (range 1.15-54.8 months), 27 in the Arm-B at a median time of 15.9 months (range 4.9-54.8 months), and 29 in the Arm-A at a median time of 6.9 months (1.2-32.3 months), without statistically significant differences between the two arms. No statistically significant differences were recorded between the two arms in CILP, BDF, DFS or OS. The mean beam-on time to deliver SRS was 49.0 ± 36.2 min in Arm-A, and 3.1 ± 1.6 min in Arm-B.
Given the technical differences between the treatment platforms investigated in this single-institution study, linac-based SRS (Arm-B) did not lead to significantly lower grade 2-3 RN rates versus the multi-source gamma-ray system (Arm-A) in a population of patients with limited brain metastases of small volume. No significant difference in local control was observed between both arms. For Arm-B, the treatment delivery time was significantly lower than for Arm-A.
ClinicalTrials.gov Identifier NCT02355613.
Purpose
To improve the workflow of total marrow and lymphoid irradiation (TMLI) by enhancing the delineation of organs at risk (OARs) and clinical target volume (CTV) using deep learning (DL) and ...atlas-based (AB) segmentation models.
Materials and methods
Ninety-five TMLI plans optimized in our institute were analyzed. Two commercial DL software were tested for segmenting 18 OARs. An AB model for lymph node CTV (CTV_LN) delineation was built using 20 TMLI patients. The AB model was evaluated on 20 independent patients, and a semiautomatic approach was tested by correcting the automatic contours. The generated OARs and CTV_LN contours were compared to manual contours in terms of topological agreement, dose statistics, and time workload. A clinical decision tree was developed to define a specific contouring strategy for each OAR.
Results
The two DL models achieved a median interquartile range dice similarity coefficient (DSC) of 0.84 0.71;0.93 and 0.85 0.70;0.93 across the OARs. The absolute median Dmean difference between manual and the two DL models was 2.0 0.7;6.6% and 2.4 0.9;7.1%. The AB model achieved a median DSC of 0.70 0.66;0.74 for CTV_LN delineation, increasing to 0.94 0.94;0.95 after manual revision, with minimal Dmean differences. Since September 2022, our institution has implemented DL and AB models for all TMLI patients, reducing from 5 to 2 h the time required to complete the entire segmentation process.
Conclusion
DL models can streamline the TMLI contouring process of OARs. Manual revision is still necessary for lymph node delineation using AB models.
The total marrow and lymph node irradiation (TMLI) target includes the bones, spleen, and lymph node chains, with the latter being the most challenging structures to contour. We evaluated the impact ...of introducing internal contour guidelines to reduce the inter- and intraobserver lymph node delineation variability in TMLI treatments.
A total of 10 patients were randomly selected from our database of 104 TMLI patients so as to evaluate the guidelines' efficacy. The lymph node clinical target volume (CTV_LN) was recontoured according to the guidelines (CTV_LN_GL_RO1) and compared to the historical guidelines (CTV_LN_Old). Both topological (i.e., Dice similarity coefficient (DSC)) and dosimetric (i.e., V95 (the volume receiving 95% of the prescription dose) metrics were calculated for all paired contours.
The mean DSCs were 0.82 ± 0.09, 0.97 ± 0.01, and 0.98 ± 0.02, respectively, for CTV_LN_Old vs. CTV_LN_GL_RO1, and between the inter- and intraobserver contours following the guidelines. Correspondingly, the mean CTV_LN-V95 dose differences were 4.8 ± 4.7%, 0.03 ± 0.5%, and 0.1 ± 0.1%.
The guidelines reduced the CTV_LN contour variability. The high target coverage agreement revealed that historical CTV-to-planning-target-volume margins were safe, even if a relatively low DSC was observed.
Background. O6-methylguanine (O6-MeG)-DNA methyltransferase (MGMT) methylation status is a predictive factor for alkylating treatment efficacy in glioblastoma patients, but its prognostic role is ...still unclear. We performed a large, multicenter study to evaluate the association between MGMT methylation value and survival. Methods. We evaluated glioblastoma patients with an assessment of MGMT methylation status by pyrosequencing from nine Italian centers. The inclusion criteria were histological diagnosis of IDH wild-type glioblastoma, Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤2, and radio-chemotherapy treatment with temozolomide. The relationship between OS and MGMT was investigated with a time-dependent Receiver Operating Characteristics (ROC) curve and Cox regression models. Results. In total, 591 newly diagnosed glioblastoma patients were analyzed. The median OS was 16.2 months. The ROC analysis suggested a cut-off of 15% for MGMT methylation. The 2-year Overall Survival (OS) was 18.3% and 51.8% for MGMT methylation <15% and ≥15% (p < 0.0001). In the multivariable analysis, MGMT methylation <15% was associated with impaired survival (p < 0.00001). However, we also found a non-linear association between MGMT methylation and OS (p = 0.002): median OS was 14.8 months for MGMT in 0−4%, 18.9 months for MGMT in 4−40%, and 29.9 months for MGMT in 40−100%. Conclusions. Our findings suggested a non-linear relationship between OS and MGMT promoter methylation, which implies a varying magnitude of prognostic effect across values of MGMT promoter methylation by pyrosequencing in newly diagnosed IDH wild-type glioblastoma patients treated with chemoradiotherapy.
Total marrow (lymph node) irradiation (TMI/TMLI) delivery requires more time than standard radiotherapy treatments. The patient's extremities, through the joints, can experience large movements. The ...reproducibility of TMI/TMLI patients' extremities was evaluated to find the best positioning and reduce unwanted movements. Eighty TMI/TMLI patients were selected (2013-2022). During treatment, a cone-beam computed tomography (CBCT) was performed for each isocenter to reposition the patient. CBCT-CT pairs were evaluated considering: (i) online vector shift (OVS) that matched the two series; (ii) residual vector shift (RVS) to reposition the patient's extremities; (iii) qualitative agreement (range 1-5). Patients were subdivided into (i) arms either leaning on the frame or above the body; (ii) with or without a personal cushion for foot positioning. The Mann-Whitney test was considered (
< 0.05 significant). Six-hundred-twenty-nine CBCTs were analyzed. The median OVS was 4.0 mm, with only 1.6% of cases ranked < 3, and 24% of RVS > 10 mm. Arms leaning on the frame had significantly smaller RVS than above the body (median: 8.0 mm/6.0 mm,
< 0.05). Using a personal cushion for the feet significantly improved the RVS than without cushions (median: 8.5 mm/1.8 mm,
< 0.01). The role and experience of the radiotherapy team are fundamental to optimizing the TMI/TMLI patient setup.
(1) Background: We investigated the role of 11C-methionine PET in a cohort of newly diagnosed glioblastoma multiforme (GBM) patients to evaluate whether it could modify the extent of surgical ...resection and improve radiation therapy volume delineation. (2) Methods: Newly diagnosed GBM patients, ages 18–70, with a Karnofsky performance scale (KPS) ≥ 70 with available MRI and 11C-methionine PET were included. Patients were treated with different amounts of surgical resection followed by radio-chemotherapy. The role of 11C-methionine PET in surgical and RT planning was analyzed. A threshold of SUVmax was searched. (3) Results: From August 2013 to April 2016, 93 patients were treated and included in this analysis. Residual tumor volume was detected in 63 cases on MRI and in 78 on 11C-methionine PET, including 15 receiving gross total resection. The location of uptake was mainly observed in FLAIR abnormalities. 11C-methionine uptake changed RT volume in 11% of patients. The presence of 11C-methionine uptake in patients receiving GTR proved to influence survival (p = 0.029). The threshold of the SUVmax conditioning outcome was five. (4) Conclusions: 11C-methionine PET allowed to detect areas at higher risk of recurrence located in FLAIR abnormalities in patients affected by GBM. A challenging issue is represented by integrating morphological and functional imaging to better define the extent of surgical resection to perform.
Glioblastoma is a highly vascularised tumour and there are few treatment options after disease recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor ...tyrosine kinases. We aimed to assess the efficacy and safety of regorafenib in the treatment of recurrent glioblastoma.
REGOMA is a randomised, multicentre, open-label phase 2 trial done in ten centres in Italy. Eligible patients (aged ≥18 years) with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after surgery followed by radiotherapy and temozolomide chemoradiotherapy were randomly assigned (1:1) by a web-based system, stratified by centre and surgery at recurrence (yes vs no), to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m2 once every 6 weeks until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02926222, and is currently in follow-up.
Between Nov 27, 2015, and Feb 23, 2017, 124 patients were screened and 119 eligible patients were randomly assigned to receive regorafenib (n=59) or lomustine (n=60). Median follow-up was 15·4 months (IQR 13·8–18·1). At the analysis cutoff date, 99 (83%) of 119 patients had died: 42 (71%) of 59 in the regorafenib group and 57 (95%) of 60 in the lomustine group. Overall survival was significantly improved in the regorafenib group compared with the lomustine group, with a median overall survival of 7·4 months (95% CI 5·8–12·0) in the regorafenib group and 5·6 months (4·7–7·3) in the lomustine group (hazard ratio 0·50, 95% CI 0·33–0·75; log-rank p=0·0009). Grade 3–4 treatment-related adverse events occurred in 33 (56%) of 59 patients treated with regorafenib and 24 (40%) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand–foot skin reaction, increased lipase, and blood bilirubin increased (in six 10% of 59 patients each). In the lomustine group, the most common grade 3 or 4 adverse events were decreased platelet count (eight 13% of 60 patients), decreased lymphocyte count (eight 13%), and neutropenia (seven 12%). No death was considered by the investigators to be drug related.
REGOMA showed an encouraging overall survival benefit of regorafenib in recurrent glioblastoma. This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study.
Veneto Institute of Oncology and Bayer Italy.
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