Vorasidenib found to improve progression-free survival in IDH–mutant grade 2 gliomas

15th June 2023

Vorasidenib improves progression-free survival in patients with residual or recurrent grade 2 glioma, according to a recent double-blind, placebo-controlled trial.

Diffuse gliomas represent 75% of all primary malignant brain tumours in adults and are both locally aggressive and currently incurable. Moreover, mutations in the isocitrate dehydrogenases (IDHs) encoded by IDH1 and IDH2 are present in the majority of malignant gliomas. Vorasidenib is a novel dual inhibitor of mutant IDH1 and IDH2 enzymes with the potential to treat low grade glioma.

With a Phase 1 trial showing that vorasidenib was effective, the current Phase 3 trial, published in the New England Journal of Medicine, examined the value of the drug in patients with residual or recurrent grade 2 IDH-mutant glioma.

Eligible participants had residual or recurrent histologically established grade 2 oligodendroglioma or astrocytoma and confirmed IDH1 and IDH2 mutation status. Individuals were randomised to receive vorasidenib 40 mg daily or matching placebo in continuous 28-day cycles. The primary endpoint was imaging-based progression-free survival (PFS). An important secondary outcome was the time to the next anticancer intervention.

Vorasidenib and progression-free survival

The study included 331 patients who were assigned to receive either vorasidenib (168 patients) or a placebo. The median follow-up was 14.0 months in the vorasidenib group and 14.3 months in the placebo group.

The median imaging-based PFS was significantly longer in the drug group compared to placebo (27.7 months vs 11.1 months), representing a 61% lower risk of progression or death with the drug (hazard ratio, HR = 0.39, 95% CI, 0.27 – 0.56, p <0.001).

The time to the next intervention was also significantly improved with vorasidenib compared to placebo (HR = 0.26, 95% CI 0.15 – 0.43, p < 0.001). Both the PFS and delay in the time to next treatment advantages of the drug were seen across most of the subgroups studied.

Adverse events of grade 3 or above were higher with vorasidenib compared to the placebo (22.8% vs 13.5%). An increased alanine aminotransferase level of grade 3 or above was seen in 9.6% of vorasidenib and in none of the placebo patients.

MRI-guided thermoseed promising technique for brain tumour ablation

4th February 2022

An MRI-guided thermoseed navigated to a brain tumour and then ablated offers a minimally invasive alternative for brain cancer treatment

The use of a MRI-guided thermoseed that enables more precision targeting of tumours prior to ablation has been developed by a team from the Centre for Advanced Biomedical Imaging, Division of Medicine, University College, London, UK.

Advancements in surgery over the years have involved the development of less invasive procedures and more focused therapy with a view to targeting the tumour while sparing healthy tissue thereby improving the risk-benefit of cancer treatment.

With the aim of reducing the potential toxicity of treatments which negatively impact on patient’s quality of life, in the present study, the UK team developed a novel technique which they termed Minimally INvasive IMage-guided Ablation (MINIMA) which uses magnetic resonance navigation to direct a thermoseed through a particular tissue towards tumour cells prior to thermoablation of only those tumour cells.

The principle of this MRI-guided thermoseed technique is based on use of magnetic field gradients created by the MRI scanner itself and to use these fields to direct magnetic iron oxide nanoparticles towards the site of a tumour. Using MRI to direct magnetic particles to a site within the body is not new and in fact, the available evidence suggests that this approach enables scanners to track magnetically labelled particles and steer them into one or more target tissues.

MRI-guided thermoseed in the brain

Using a mouse tumour model, the researchers inserted the spherical, 2mm magnetic thermoseeds and transferred the animals into the MRI scanner. Once the thermoseed had been navigated to the tumour, thermoablation was delivered to the cells. The results demonstrated how an MRI-guided thermoseed could be accurately guided by the scanner to the site of the tumour and after heating, using a bespoke hyper thermic device, induce death of the tumour cells.

Speculating on the potential future value of the technology, the authors discussed how the MRI would enable location and subsequent monitoring of the position of the thermoseed along its planned route and that in the future, this process could easily become fully automated. For example, initially, a patient would undergo a pre-scan to determine the most direct route to the particular tumour and which avoided any important or delicate functioning structure.

They foresaw that if implemented, patients would be positioned within the MRI scanner and the thermoseed inserted either via a biopsy needle or through a catheter. Once it reached the tumour and ablated the cells, the thermoseed could then be easily directed back to its site of entry using the MRI scanner and removed.

They concluded that MINIMA offered a new paradigm in cancer therapy allowing for the diagnosis and delivery of treatment via a single platform.

Citation
Baker RR et al. Image‐Guided Magnetic Thermoseed Navigation and Tumor Ablation Using a Magnetic Resonance Imaging System. Adv Sci 2022

Survival benefit from carboplatin in children with high risk medulloblastoma

3rd August 2021

The use of carboplatin but not isotretinoin in children with high-risk medulloblastoma led to an increase in event-free survival at 5 years.

Medulloblastoma is the second most common, malignant brain tumour in children. It develops in between 250 and 400 children each year and more than 70% of cases occur in those younger than 10 years of age. It is a highly invasive cancer that arises in the cerebellum and disseminates throughout the central nervous system. Survival depends to a large extent on whether or not the disease has spread. For example, among children without disseminated disease, the event-free survival at 5 years has been shown to be around 80%. However, the cancer can return and the 3-year survival rate for relapsed cancer is low at around 18%. Medulloblastomas are categorised into different groups, with group 3 being more aggressive and therefore high-risk, with a 5-year survival of approximately 20%–30%. The use of carboplatin as a radiosensitiser has been found to be a promising strategy in patients with high-risk medulloblastoma and isotretinoin has been shown to induce apoptosis of medulloblastoma cells. There is also data showing that the addition of isotretinoin to carboplatin, enhances tumour sensitivity in squamous cell carcinoma xenografts.

With some evidence suggesting that the combination of isotretinoin and carboplatin may be of greater value in the treatment of medulloblastoma, a team from the Cancer and Blood Disorders Centre, Seattle, US, decided to undertake a randomised trial to examine the impact on survival of combination therapy in children with high-risk (group 3) medulloblastoma. Included patients were randomised to chemotherapy with 36-GY craniospinal radiation therapy and weekly vincristine with or without daily carboplatin, followed by 6 cycles of maintenance chemotherapy with or without 12 cycles of isotretinoin. The primary outcome of the trial was event-free survival.

Findings
There were 261 children with a mean age of 8.6 years (70% male), 72% of whom at metastatic disease included in the analysis and the median follow-up time was 6.7 years. For all participants, the 5-year overall survival was 73.4% (95% CI 66.7–80.1%). The overall 5-year event-free survival with carboplatin was 66.4% (95% CI 56.4%–76.4%) vs 59.2% (95% CI 48.8%–69.6%) without carboplatin. However, in the subgroup of patients with group 3 medulloblastoma, the 5-year event-free survival for patients given carboplatin was even higher, 73.2% vs 53.7% without carboplatin. In addition, the overall survival with carboplatin was 82.8% vs 63.7% without the drug. The isotretinoin arm was closed early due to an interim analysis finding that addition of the drug was unlikely to have a positive effect on event-free survival, i.e., 68.6% with isotretinoin vs 67.8% without.
The authors concluded that the use of carboplatin and radiotherapy should be recommended for paediatric patients with high risk medulloblastoma although use of isotretinoin added little value.

Citation
Leary SES et al. Efficacy of Carboplatin and Isotretinoin in Children with High-risk Medulloblastoma. A Randomised Clinical Trial from the Children’s Oncology Group. JAMA Oncol 2021

Urine microRNA profile a biomarker for brain tumours

22nd June 2021

Mass screening of urine for a unique microRNA biomarker profile could represent means of early detection for brain tumours.

Few people undergo routine brain scans to help identify potential early signs of a tumour. While imaging modalities such as MRI and CT are a very sensitive and effective means of testing, these are expensive and thus unsuitable for mass screening.

Nevertheless, the detection of shed tumour components such as DNA or cellular fragments into the general circulation could be used for the early detection of a tumour.

The use of microRNAs, i.e. small and non-coding fragments of RNA, in blood samples has already been utilised of early detection of breast, ovarian and bladder cancers.

However, urine-based detection of microRNAs offers some advantages over blood samples in so far as these can be self-performed and repeated with minimal effort.

The use of urine-based methods has yet to be explored in detail and this was the subject of a study by a team from the Department of Neurosurgery, Graduate School of Medicine, Nagoya, Japan.

The researchers developed a device that contained 100 million zinc oxide nanowires, that could be sterilised and equally importantly, mass produced.

The device required only 1 ml of urine but was able to extract a much larger number of microRNAs compared to ultracentrifugation, which is the most commonly used extraction device.

The researchers examined urine samples from patients with and without brain tumours and used microarray analysis to determine whether there was a specific and diagnostic microRNA profile that could be used as a biomarker.

Findings

The researcher used urine samples from 109 patients with a brain tumour and compared the microRNA profile with 100 non-cancer patients.

Initially, the team used organoids (i.e. a collection of cells) from glioblastoma, an aggressive form of brain tumour, to determine the profile of urinary microRNAs likely to be produced by patients with the tumour.

The analysis revealed how the glioblastoma organoid-derived sample differentially expressed microRNAs, included 73.4% of the microRNAs found in the urine samples of patients with glioblastoma. In comparison, this microRNA profile was produced in only 3.9% of the non-cancer patient samples.

Having established that this profile, which contained 23 separate microRNAs, was characteristically produced in patients with glioblastoma, the researchers sought to determine if the profile could serve as a biomarker.

Using the area under the receiver operator curves, the profile produced a sensitivity of 100% and a specificity of 97%.

Based on these findings, the authors concluded that this specific microRNA profile, could potentially be used for mass screening purposes for the early detection of potentially aggressive brain tumours.

Citation
Kitano Y et al. Urinary MicroRNA-Based Diagnostic Model for Central Nervous System Tumours Using Nanowire Scaffolds. ACS Appl Mater interfaces 2021;13:17316 – 17329.