Project description:BackgroundStereotactic radiosurgery (SRS) is a frequently chosen treatment for patients with brain metastases and the number of long-term survivors is increasing. Brain necrosis (e.g. radionecrosis) is the most important long-term side effect of the treatment. Retrospective studies show a lower risk of radionecrosis and local tumor recurrence after fractionated stereotactic radiosurgery (fSRS, e.g. five fractions) compared with stereotactic radiosurgery in one or three fractions. This is especially true for patients with large brain metastases. As such, the 2022 ASTRO guideline of radiotherapy for brain metastases recommends more research to fSRS to reduce the risk of radionecrosis. This multicenter prospective randomized study aims to determine whether the incidence of adverse local events (either local failure or radionecrosis) can be reduced using fSRS versus SRS in one or three fractions in patients with brain metastases.MethodsPatients are eligible with one or more brain metastases from a solid primary tumor, age of 18 years or older, and a Karnofsky Performance Status ≥ 70. Exclusion criteria include patients with small cell lung cancer, germinoma or lymphoma, leptomeningeal metastases, a contraindication for MRI, prior inclusion in this study, prior surgery for brain metastases, prior radiotherapy for the same brain metastases (in-field re-irradiation). Participants will be randomized between SRS with a dose of 15-24 Gy in 1 or 3 fractions (standard arm) or fSRS 35 Gy in five fractions (experimental arm). The primary endpoint is the incidence of a local adverse event (local tumor failure or radionecrosis identified on MRI scans) at two years after treatment. Secondary endpoints are salvage treatment and the use of corticosteroids, bevacizumab, or antiepileptic drugs, survival, distant brain recurrences, toxicity, and quality of life.DiscussionCurrently, limiting the risk of adverse events such as radionecrosis is a major challenge in the treatment of brain metastases. fSRS potentially reduces this risk of radionecrosis and local tumor failure.Trial registrationClincalTrials.gov, trial registration number: NCT05346367 , trial registration date: 26 April 2022.

Project description:BackgroundThe management of vestibular schwannoma has evolved over the past hundred years. In the last decades, surgery has been gradually replaced by radiation therapy as a primary treatment modality, particularly for small tumors, due to the less invasive nature and the compared reported outcomes in tumor control and hearing preservation. However, irradiation sometimes fails to stop tumor growth. In a long-term follow-up after primary fractionated stereotactic radiotherapy, the rate of treatment failure was reported as 3% and needed surgical salvage. For single-fraction modality, Hasegawa et al. reported salvage treatment after primary Gamma Knife radiosurgery in 8%, where 90% of these underwent surgery and 50% of those who were treated with a second gamma knife surgery required surgical intervention later. An increase in tumor volume by more than 10-20%, tumor growth after three years, and no return to pretreatment volume after transient swelling have been considered as tumor recurrence rather than pseudoprogression, a transient increase in tumor volume after radiotherapy that occurs up to 30% of cases. It has been reported that microsurgery after radiotherapy is more difficult, with most authors reporting a loss of defined arachnoid planes and worse cranial nerve outcomes, especially for hearing and facial nerve function.Case descriptionA 43-year-old female patient was incidentally (asymptomatic) diagnosed on a magnetic resonance imaging (MRI) scan harboring a left vestibular schwannoma, grade T2 (Hannover classification), in 2015. Neurologic examination was unremarkable, and audiometry testing was normal. She was initially treated with observation. Three years later, in 2018, the lesion had enlarged, becoming a grade T3a and reaching the cistern of the cerebellopontine angle. The tumor was then treated with fractionated stereotactic radiosurgery (5 sessions of 5 Gy). MRI scans in 2019 and 2020 showed slight tumor growth. This enlargement was attributed to a pseudoprogression after radiosurgery, and only observation was advocated. In 2022, 4 years later, after radiosurgery, the tumor was still growing, and the patient began to suffer from hearing loss. A failure treatment was considered, and microsurgery was indicated. The patient was counseled about the risk of functional nerve impairment, and surgical consent was obtained. A retro sigmoid approach was planned. A gross total resection was attempted due to the clear subperineural plane during tumor dissection and because it was the only option that would provide a cure for the patient. The adjacent neurovascular structures were firmly adhered to the tumor capsule, which represented a major challenge for microdissection. The tumor was soft, without significant bleeding. A total resection was achieved, and the facial nerve was anatomically preserved. The patient developed facial paresis (House-Brackmann III) in the immediate postoperative period, which improved at the 6-month follow-up. Hearing loss did not improve. Postoperative MRI showed total resection.ConclusionMicrosurgery after radiotherapy for vestibular schwannoma is challenging in terms of indication, when to indicate, resection target, difficulty in dissection due to local changes, and outcome. Gross total resection may be considered, as it is the only treatment that may provide a cure for the patient. However, the patient should be counseled about the risks.

Project description:BackgroundSurgery is an important therapeutic option for brain metastases. Currently, postoperative stereotactic radiosurgery (SRT) leads to 6-month and 1-year local control estimated at 70 and 62% respectively. However, there is an increased risk of radio-necrosis and leptomeningeal relapse. Preoperative SRT might be an alternative, providing local control remains at least equivalent. It is an innovative concept that could enable the stereotactic benefits to be retained with advantages over post-operative SRT.MethodsSTEP has been designed as a national, multicentre, open-label, prospective, non-randomized, phase-II trial. Seventeen patients are expected to be recruited in the study from 7 sites and they will be followed for 12 months. Patients with more than 4 distinct brain metastases, including one with a surgical indication, and an indication for SRT and surgery, are eligible for enrolment. The primary objective of the trial is to assess 6-month local control after preoperative SRT. The secondary objectives include the assessment of local control, radio-necrosis, overall survival, toxicities, leptomeningeal relapse, distant control, cognitive function, and quality of life. The experimental design is based on a Flemming plan.DiscussionThere is very little data available in the literature on preoperative SRT: there have only been 3 American single or two-centre retrospective studies. STEP is the first prospective trial on preoperative SRT in Europe. Compared to postoperative stereotactic radiotherapy, preoperative stereotactic radiotherapy will enable reduction in the irradiated volume, leptomeningeal relapse and the total duration of the combined treatment (from 4 to 6 weeks to a few days).Trial registration numberClinicaltrials.gov: NCT04503772 , registered on August 07, 2020. Identifier with the French National Agency for the Safety of Medicines and Health Products (ANSM): N°ID RCB 2020-A00403-36, registered in February 2020.Protocolversion 4, 07 December 2020.

Project description:PurposeTo simulate and analyze the dosimetric differences of intraoperative radiotherapy (IORT) or pre-operative single-fraction stereotactic radiosurgery (SRS) in addition to post-operative external beam radiotherapy (EBRT) in Glioblastoma (GB).MethodsImaging series of previously treated patients with adjuvant radiochemotherapy were analyzed. For SRS target definition, pre-operative MRIs were co-registered to planning CT scans and a pre-operative T1-weighted gross target volume (GTV) plus a 2-mm planning target volume (PTV) were created. For IORT, a modified (m)GTV was expanded from the pre-operative volume, in order to mimic a round cavity as during IORT. Dose prescription was 20 Gy, homogeneously planned for SRS and calculated at the surface for IORT, to cover 99% and 90% of the volumes, respectively. For tumors > 2cm in maximum diameter, a 15 Gy dose was prescribed. Plan assessment was performed after calculating the 2-Gy equivalent doses (EQD2) for both boost modalities and including them into the EBRT plan. Main points of interest encompass differences in target coverage, brain volume receiving 12 Gy or more (V12), and doses to various organs-at-risk (OARs).ResultsSeventeen pre-delivered treatment plans were included in the study. The mean GTV was 21.72 cm3 (SD ± 19.36) and mGTV 29.64 cm3 (SD ± 25.64). The mean EBRT and SRS PTV were 254.09 (SD ± 80.0) and 36.20 cm3 (SD ± 31.48), respectively. Eight SRS plans were calculated to 15 Gy according to larger tumor sizes, while all IORT plans to 20 Gy. The mean EBRT D95 was 97.13% (SD ± 3.48) the SRS D99 99.91% (SD ± 0.35) and IORT D90 83.59% (SD ± 3.55). Accounting for only-boost approaches, the brain V12 was 49.68 cm3 (SD ± 26.70) and 16.94 cm3 (SD ± 13.33) (p<0.001) for SRS and IORT, respectively. After adding EBRT results respectively to SRS and IORT doses, significant lower doses were found in the latter for mean Dmax of chiasma (p=0.01), left optic nerve (p=0.023), right (p=0.008) and left retina (p<0.001). No significant differences were obtained for brainstem and cochleae.ConclusionDose escalation for Glioblastoma using IORT results in lower OAR exposure as conventional SRS.

Project description:Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary brain tumor with median overall survival of 15 months and 5-7 months for patients with newly diagnosed or recurrent disease (nGBM or rGBM), respectively. Selinexor is a first-in-class, oral, selective inhibitor of nuclear export which blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing cancer cell death. Increased XPO1 expression in gliomas is associated with higher pathological grade and poorer prognosis. Consistent with these data, selinexor inhibited tumor growth and prolonged survival in an animal model of GBM. Importantly, selinexor showed encouraging intra-tumoral penetration and single-agent efficacy in rGBM (KING study). The current trial tests the hypothesis that adding selinexor to standard therapy will improve clinical outcomes for patients with nGBM or rGBM. METHODS To facilitate the successful development of new therapies, consensus recommendations are to use biomarker enrichment and flexible design that allows expansion of promising cohorts. Accordingly, this phase 1a dose finding study is followed by a phase 1b dose expansion (and ultimately by a 1:1 randomized phase 2 efficacy exploration trial) to independently evaluate: radiation + selinexor in nGBM with unmethylated MGMT promoter (Arm A), radiation + temozolomide + selinexor for nGBM with methylated MGMT promoter (Arm B), and lomustine + selinexor in rGBM (Arm C). Bevacizumab or TTField + selinexor in rGBM (Arms D & E, respectively) are being considered. The Phase 1a primary endpoint is maximum tolerated dose/recommended phase 2 dose. The phase 1b primary endpoint is PFS at 3 months against historic controls. The phase 1b dose expansion is included to evaluate preliminary efficacy before launching into a randomized phase 2 trial. Patient quality of life during the trial will be objectively measured using digital devices (e.g. smartwatch/customized smartphone app). We are currently enrolling patients nationwide. Clinical Trial Registration number: NCT04421378.

Dataset Information

CTNI-40. PHASE I TRIAL OF SULFASALAZINE COMBINED WITH STEREOTACTIC RADIOSURGERY FOR RECURRENT GLIOBLASTOMA: STUDY PROTOCOL FOR NCT04205357

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