This website is intended for healthcare professionals only.
Take a look at a selection of our recent media coverage:
25th January 2023
RRx-001 is a novel agent affecting the development of oral mucositis and reduced the duration of severe symptoms in a Phase II trial.
Oral mucositis (OM) represents a common and highly symptomatic complication of cancer therapy, which negatively impacts upon patient’s quality of life. OM affects virtually all patients undergoing radiation treatment for head and neck cancers and, given the inadequacy of pain relief offered by opiates, preventative rather than palliative measures are needed.
OM represents a significant unmet need for patients undergoing chemoradiation (CRT) for head and neck cancers, affecting individual’s ability to eat, drink and swallow, yet there are currently there are no approved treatments for the condition. While the underlying cause of OM remains to be determined, it is thought to arise largely as the consequence of cumulative CRT-induced biological changes overwhelming physiologic self-protective mechanisms.
RRx-001 is a white, crystalline, nitrogen containing small molecule with demonstrated anti-cancer activity affecting a number of pathways including nitric oxide. Moreover, data suggests that the compound is able to selectively protect normal cells, while inducing apoptosis within tumour cells.
In the current study, researchers randomised patients with squamous cell carcinoma and who received either definitive or postoperative cisplatin-based CRT, to three different dosing schedules of RRx-001 (arms 1 to 3) and a placebo arm. The severity of OM was assessed using the WHO grading scale and the incidence of severe OM was bases on WHO scores > 3.
Although 53 patients were enrolled, only 46 contributed to the efficacy data.
Overall, there were no severe adverse reactions attributed to the drug. Patients in arm 1 had the lowest median duration of severe OM which was 8.5 days compared to 17 days and 10 days in arms 2 and 3 respectively. Among those in the placebo arm, the median duration of severe OM was 24 days.
The authors concluded that these data supported both the safety and efficacy of RRx-001 while also highlighting the need for further studies to confirm these findings.
Citation
Bonomi R et al. PREVLAR: Phase 2a randomized trial to assess the safety and efficacy of RRx-001 in the attenuation of oral mucositis in patients receiving head and neck chemoradiotherapy Int J Radiat Oncol Biol Phys 2023;116(3):551-559.
Xofluza (baloxavir) has been approved in the EU for uncomplicated influenza and post-exposure prophylaxis for children aged one and older.
Roche’s Xofluza (baloxavir) is now approved for use for the treatment of both uncomplicated influenza and post-exposure prophylaxis of influenza in children from one year of age, the company has announced.
The human influenza viruses are known to cause regular epidemics creating a huge public health burden. Although influenza vaccines are available, there are also three classes of anti-viral agents that have also been used. The M2 proton channel blockers such as amantadine, neuraminidase inhibitors (e.g. oseltamivir) and finally, polymerase inhibitors like favipiravir, for example.
The influenza virus polymerase complex has become seen as a possible target for anti-viral agents and comprises three subunits: polymerase basic protein 1, polymerase basic protein 2 (PB2) and finally polymerase acidic protein (PA). These three subunits are highly conserved and PB2 is known to bind with the cap of the host cellular pre-messenger RNA and is subsequently cleaved by a cap-dependent endonuclease in the PA subunit. Xofluza contains the pro-drug baloxavir marboxil and inhibits the endonuclease activity of the polymerase acid protein.
Studies to date have shown that in adults, xofluza reduces the median time to the resolution of influenza symptoms by as much as 28 hours compared to placebo and the drug was originally indicated for use in patients from 12 years of age. The updated indication was based on the findings from two studies.
The first study, MiniSTONE-2 enrolled children between the ages of one and 12 years with a clinical diagnosis of influenza. Participants were randomised 2:1 to either a single dose of oral baloxavir or oseltamivir twice a day for five days. The results showed that Xofluza reduced the median time to symptom resolution to 138.1 hours compared to 150 hours with oseltamivir.
The second trial examined the post-exposure prophylactic efficacy of xofluza and found that the risk of influzena was lower with baloxavir compared to placebo (adjusted risk ratio = 0.43, 95% CI 0.32 – 0.58).
Another clinical trial has been designed to assess the safety and efficacy of baloxavir in healthy patients from birth to less than one year of age with influenza-like symptoms.
The updated information from the EMA can be found here.
24th January 2023
Treatment with the loop diuretic torsemide (TM) leads to a similar level of all-cause mortality and all-cause hospitalisations as furosemide (FM) following hospital discharge in patients with heart failure according to the findings of a randomised trial by US researchers.
Heart failure is growing public health concern with an estimated global prevalence exceeding 37.7 million people. Both fluid retention and congestion are key features of the condition which are treated with loop diuretics and this approach is recommended in therapy guidelines. Although furosemide is an established loop diuretic, another agent, torsemide, has both a longer half-life and greater oral bioavailability than furosemide. Moreover, some evidence points to a lower mortality in patients with congestive heart failure treated with torsemide compared to furosemide. However, studies have not been sufficiently powered to address mortality differences between the two agents.
In the present study, researchers undertook an open-label, randomised trial to examine the comparative effectiveness of TM and FM in patients discharged from hospital following an admission for heart failure, irrespective of their ejection fraction. The researchers hypothesised that torsemide would lower all-cause mortality by 20% compared to furosemide. Patients were eligible if they were hospitalised for either de novo heart failure or a worsening of chronic heart failure and randomised 1:1 to either furosemide or torsemide. The researchers set the primary effectiveness outcome as all cause mortality whereas one of the main secondary outcomes was all-cause hospitalisations.
Torsemide and all-cause mortality
A total of 2,859 patients with a mean age of 64.5 years (36.9% female) were randomised to either diuretic and followed for a median of 17.4 months.
During follow-up, death occurred in 26.1% of the TM group and 26.2% of the FM group and this difference was not significant (hazard ratio, HR = 1.02, 95% CI 0.89 – 1.18, p = 0.76). In addition, all-cause mortality or all-cause hospitalisations occurred in 47.3% of those assigned to TM and 49.3% of patients in the FM group (HR = 0.92, 95% CI 0.83 – 1.02). There were also no significant differences in any of the subgroups analysed, including patients with differing levels of ejection fractions.
Although there were no significant differences between the two loop diuretics, the researchers did acknowledge at least two potentially important study limitations including treatment discontinuation (9.5% of any agent at 6 months) and cross-over (7% for TM to FM) between the two agents could have had an effect.
They concluded that while torsemide did not lower all-cause mortality compared to furosemide, these findings should be interpreted with caution given the rates of discontinuation and cross-over.
Citation
Mentz RJ et al. Effect of torsemide vs furosemide after discharge on all-cause mortality in patients hospitalized with heart failure: The TRANSFORM-HF randomized clinical trial. JAMA 2023
23rd January 2023
A gradient boosting (XGBoost) model, which made use of both clinical and demographic factors, was able predict the most important factors associated with metformin failure in type 2 diabetics according to work by a team of US researchers.
It has been estimated that globally, some 415 million people are currently living with diabetes and the World Health Organization suggests that more than 95% of those with diabetes have type 2 disease. One of the most widely used anti-diabetic agents is metformin and the drug is suggested as a first-line treatment either alone or in combination for those with type 2 disease. Nevertheless, some evidence highlights that monotherapy with metformin is associated with treatment failure. In one study, for instance it was found that, the proportion of patients able to a achieve an HbA1c of below 7% in the first year, ranged from 19 to 86% of those started on metformin. Understanding the factors linked to a respond to metformin can therefore help to personalise medicine and allow for an early adjustment of therapy. However, determining which specific factors are relevant to metformin treatment failure from an examination of a patient’s electronic health record (EHR) is challenging. In an attempt to identify relevant predictors held within the patient’s EHR, in the current study, the US researchers made use of a machine learning model and turned to a patient cohort with at least one abnormal diabetic result (e.g., elevated fasting glucose or HbA1c) that lead to the initiation of metformin treatment. For the purposes of they study, the team defined treatment failure as either an inability to achieve a target HbA1c or < 7% within 18 months of initiation or the addition of other pharmacological agents during the same time frame. Many of the EHR factors were assimilated into the model and included demographics (age, gender, ethnicity), lifestyle factors (smoking status), body mass index as well as laboratory findings such as lipid profiles, blood pressure and liver function tests. The predictive value of the model was assessed using the C-index and individual predictors using Shapley Additive Explanations (SHAP), for which higher values indicated a more important contribution to the model.
Model predictors and metformin failure
The study included 22,047 patients with a mean age of 57 years (48% female) who were started on metformin, Using the target of an HbA1c of below 7%, the overall metformin failure rate was 33% and the median time to failure was 3.9 months.
When the XGBoost model included baseline values of HBA1c, age, gender and ethnicity, it had a high discrimination performance for the risk of metformin failure (C-index = 0.73, 95% CI 0.72 – 0.74). There were a total of 15 different influential factors identified that impacted on metformin failure, the most important of which, was the baseline HBA1c value (SHAP value = 0.76). In contrast, factors such as age (SHAP = 0.016) or body mass index (SHAP = 0.041) were less important. Nonetheless, incorporation of each of these 15 factors did improve the model’s performance (C-index = 0.745, 95% CI 0.73 – 0.75, p < 0.0001).
The authors concluded that although baseline HBA1c was the most important factor in metformin failure, adding other important and readily available variables to the model, improved its performance. They suggested that is was therefore possible to easily identify patients most at risk of metformin failure and who would benefit from closer monitoring and earlier treatment modification.
Citation
Bielinski SJ et al. Predictors of Metformin Failure: Repurposing Electronic Health Record Data to Identify High-Risk Patients. J Clin Endrocrinol Met 2023
22nd January 2023
In a press release from the manufacturer, AstraZeneca, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has now approved a pre-filled pen containing tezepelumab, for self-administration to patients aged 12 years and older with severe asthma. The release adds that the CHMP opinion can actually be implemented without the need for a European Committee decision due to the nature of the type II label variation.
Tezepelumab is a first-in-class monoclonal antibody that specifically binds to thymic stromal lymphopoietin thereby stopping its interaction with the heterodimeric receptor. Thymic stromal lymphopoietin is an epithelial-derived cytokine with an important role in both the initiation and persistence of airway inflammation in asthma. When used as an add-on treatment for patients with severe, uncontrolled asthma, tezepelumab has been shown to be both safe and effective. Data for the drug in patients with severe asthma has shown that it leads to fewer disease exacerbations, improved lung function, asthma control and health-related quality of life compared with placebo.
Tezepelumab (brand name Tezspire) will be available as a fixed-dose 210mg subcutaneous injection via a pre-filled, single use auto-injector but also as single-use syringe with both forms designed to be given every four weeks. The pre-filled pen enables both patients and carers to self-administer the treatment at home.
Tezepelumab pre-filled pen efficacy
Data on the use of the pre-filled pen comes from a study which showed that in 315 adults, the pre-filled syringe provided similar pharmacokinetic parameters when compared to a single subcutaneous dose. In addition, a second study showed that use of the pre-filled syringe and an auto-injector gave rise to similar and clinically meaningful improvements in the asthma control questionnaire-6 score after 24 weeks.
In the press release, Professor Ian Pavord, Professor of Respiratory Medicine at the University of Oxford and Honorary Consultant Physician at the Oxford University Hospitals, said: ‘Severe asthma continues to have a debilitating impact for people living with the disease. I believe the approval of the Tezspire pre-filled pen will be welcome news for physicians and patients in Europe as it offers increased choice and greater flexibility when administering this important medicine.’
AstraZeneca has also submitted data to the US Food and Drug Administration for approval of the pre-filled pen.
21st January 2023
Metomidate used as a PET radiotracer and in combination with high resolution computed tomography (CT) has been shown to be non-inferior to adrenal vein sampling (AVS), as a non-invasive means of detecting primary aldosteronism according to a study by a team of UK researchers.
Primary aldosteronism (PA) has been shown to be responsible for 5.9% of cases of hypertension and this figure increased to 11.8% in patients with stage 3 hypertension. PA can be surgically corrected when caused by unilateral aldosterone hyper-secretion for which the usual cause is an aldosterone-producing adenoma. Moreover, hypertension due to PA has a worse prognosis compared with blood pressure-matched essential hypertension. The use of AVS is recognised as the most reliable means of identifying whether aldosterone production is uni- or bilateral. Nevertheless, an alternative is the use of imaging modality, such as metomidate positron emission tomography computed tomography (MTO) and which, in one small study has been shown to both a sensitive and specific alternative to adrenal vein sampling. Nevertheless, with a limited evidence base to demonstrate the value of this imaging modality, in the present study, researchers set out to compare the accuracy of MTO and AVS at predicting the outcome following adrenalectomy in patients with PA and ultimately resolution of hypertension in these patients. Individuals with confirmed PA underwent both MTO and AVS and were commenced on spironolactone 50mg but which was increased to 100mg after two weeks. Both techniques were used to assess the probability of unilateral PA and where this was high, unilateral adrenalectomy was recommended, or medical management where it was not detected.
Metomidate scanning and the outcome following adrenalectomy
A total of 128 patients with a median age of 52 years (68% male) were included in the study.
The use of MTO graded 52% of patients with a high probability of unilateral PA compared with 45% following AVS, although overall, 67% of the entire cohort were scored as having a high probability of unilateral PA.
Following surgery, the accuracy of MTO at predicting clinical success was 65.4% compared to 61.5% for AVS. These differences did not reach the predefined inferiority statistical margin; in other words, MTO was not inferior to AVS. Only 23 of 78 patients undergoing surgery achieved blood pressure readings of below 135/85mmHg, although 12 individuals were able to stop antihypertensive treatment.
There were a total of 24 serious adverse events although none of these were considered to be related to the procedures, and 22 fully resolved.
The authors concluded that MTO was an effective non-invasive means to diagnose unilateral PA and could be used as an alternative to AVS.
Citation
Wu X et al. [11C]metomidate PET-CT versus adrenal vein sampling for diagnosing surgically curable primary aldosteronism: a prospective, within-patient trial. Nat Med 2023
20th January 2023
Intermittent oral corticosteroid (OCS) use in asthmatics, even as a one-off course, is associated with a higher risk of OCS-related adverse outcomes according to the findings from an observational study by an international research group.
Significant adverse effects have been associated with continuous exposure to oral corticosteroids and a 2021 Delphi study has offered expert consensus on OCS use, tapering, adverse-effect screening, recommending a dose of 0.5 mg/kg/day for a short course of OCS. Nevertheless, intermittent oral corticosteroid use is widespread across European countries, with one study revealing how the annual prevalence of high OCS use across all countries was approximately 3% and that of 702 685 patients with asthma, 14-44% were OCS users and 6-9% were high OCS users at some point. Even short-term use of OCS is linked to the development of adverse outcomes, with one US study showing that one in five American adults were given prescriptions for short-term use of oral corticosteroids during a three year period, with an associated increased risk of adverse events.
Despite the above findings, no previous studies have focused exclusively on intermittent oral corticosteroid use. In the present study, researchers used data derived from two anonymised, real-life databases and included asthmatic patients aged ≥ 4 years with at least 12 months’ clinical data prior to OCS use. The subsequent use of OCS was then categorised into three patterns: one-off (single), less frequent (≥ 90 day gap) and frequent (< 90 day gap) and individuals were matched with a non-oral corticosteroid control group, based on age and gender. The subsequent risk of developing an adverse outcome (AO) was then examined using survival analysis.
Intermittent oral corticosteroid use and adverse outcomes
A total of 476,167 OCS individuals with a mean age of 38.1 years (55.7% female) were matched and followed for a median of 8.3 years. Among the cohort, 41.7% had a one-off prescription whereas 26.8% and 31.6% had less frequent and frequent intermittent OCS prescribing patterns, respectively.
When compared to non-OCS patients, the risk of experiencing any adverse outcomes was elevated, even for one-off OCS individuals and was higher with increasing frequent pattern of intermittent OCS prescribing. For example, the hazard ratio (HR) of experiencing any adverse outcomes versus non-OCS patients was 1.19 (95% CI 1.18 – 1.20) for one-off OCS users, 1.35 (95% CI 1.34 – 1.36) for less frequent OCS users and 1.42 (95% CI 1.42 – 1.43) for frequent pattern of OCS prescriptions. Moreover, this risk was consistently elevated across all subgroups, based on age and other used treatments. Interestingly, the risk of each of the individual OCS-related adverse outcomes, with the exception of behavioural disorders, renal impairment and peptic ulcer was apparent even in one-off OCS users.
The authors concluded that a considerable proportion of patients with asthma who are prescribed OCS intermittently have a frequent pattern of use at some point, and which was associated with a higher risk of individual OCS-related adverse outcomes.
Citation
Heatley H et al. Observational UK cohort study to describe intermittent oral corticosteroid prescribing patterns and their association with adverse outcomes in asthma. Thorax 2022
Contrast-enhanced computed tomography (CT) assessment of liver enhancing tumour burden in those with multifocal neuroendocrine liver metastases, enables predictions of patient outcomes, according to a retrospective study by a team of European researchers.
Neuroendocrine tumours are a heterogenous group of cancers most often in the gastrointestinal or respiratory tract. Although neuroendocrine metastases are rare, hepatic metastases can occur in as many as 75% of patients, which significantly worsens their prognosis.
There are several intra-arterial therapeutic options available to treat metastatic disease and while the evidence base was deemed of moderate quality, these approaches have been endorsed in consensus guidelines.
Volumetric assessment of metastatic disease in the whole of the liver, is known as the liver enhancing tumour burden and provides a means of evaluating a patient’s response to treatment following intra-arterial therapy.
However, in most cases, these assessment have been undertaken using MRI. In the resent study, researchers investigated the value of contrast-enhanced CT to assess liver enhancing tumour burden and to explore whether changes in this burden might serve as an early response marker to help predict survival outcomes for patients with multifocal neuroendocrine liver metastases after intra-arterial therapy.
The researchers retrospectively identified individuals with neuroendocrine liver metastases who had undergone intra-arterial treatment with either transarterial embolism or chemoembolism and who had contrast-enhanced CT scans. The liver enhancing tumour burden was quantified before treatment and then at the first post-treatment CT scan. The researchers calculated overall survival (OS) and progression-free survival (PFS) using Cox proportional hazard analysis.
A total of 119 patients with a mean age of 60 years (51.2% male) and who underwent 161 treatments were included in the analysis. Contrast-enhanced CT revealed a median pre-treatment liver enhancing tumour burden of 17%.
Following intra-arterial treatment, the liver enhancing tumour burden reduced by a median of 25.8%. This change was the best discriminator for overall survival (83 months among responders compared to 51 months in non-responders, p = 0.02) and for whole-body progression-free survival (18 months vs eight months, p < 0.001). The change in liver enhancing tumour burden was found to be independently associated with improved OS (hazard ratio, HR = 0.56, 95% CI 0.33 – 0.95, p = 0.03).
In addition, a 10% reduction in liver enhancing tumour burden best predicted the time to when intra-arterial treatment would be unfeasible (HR = 0.44, 95% CI 0.28 – 0.70, p = 0.01).
The authors concluded that the use of contrast-enhanced CT assessment of liver enhancing tumour burden, could help to predict survival outcomes in patients with neuroendocrine metastases following intra-arterial treatment.
They also proposed that future studies should focus on whether their approach might be generalisable to enable an assessment of other treatment modalities and systemic treatments.
Citation
Assouline J et al. Volumetric Enhancing Tumor Burden at CT to Predict Survival Outcomes in Patients with Neuroendocrine Liver Metastases after Intra-arterial Treatment. Radiol Imaging Cancer 2023.
MRI guided stereotactic radiotherapy is superior than that provided via CT guidance with respect to adverse effects for men with prostate cancer.
A randomised trial by Californian researchers has shown that magnetic resonance imaging (MRI)-guided stereotactic body radiation, significantly reduced grade 2 or higher acute physician-scored genitourinary and gastrointestinal toxic effects as well as patient self-reported prostate cancer symptom scores, compared to computed tomography (CT)-guided radiotherapy.
Stereotactic radiotherapy delivers treatment with high precision from a number of different angles around the body and is designed to reduce adverse effects on the tissue surrounding a tumour. Furthermore, results from several trials, indicate that this approach does not increase gastrointestinal or genitourinary acute toxicity.
While stereotactic radiotherapy has traditionally been delivered using linear accelerators and guided by computed tomography (CT) imaging, MRI-guided adaptive radiotherapy is seen as an emerging and alternative approach.
Moreover, it may also be possible using MRI to reduce the radiotherapy planning target volume (PTV) which encompasses the clinical target volume to account for possible uncertainties in beam alignment, patient positioning, organ motion, and organ deformation.
In the present study, the US researchers undertook a phase 3 study, with a view to demonstrating a reduced PTV with MRI compared to CT guidance, following stereotactic body radiotherapy for men with localised prostate cancer. Eligible men were randomised 1:1 to either MRI- or CT-guided stereotactic radiotherapy although neither the treating physician or patient were blinded to the treatment allocation.
The primary outcome was set as the incidence of acute (defined by occurring less than 90 days after stereotactic therapy) grade 2 or higher genitourinary (GU) toxic effects, whereas secondary outcomes included gastrointestinal toxic effects.
Other measures assessed included changes in the international prostate symptom score (IPSS) and for which increases of 15 points or more are considered to be clinically relevant.
A total of 156 men with a mean age of 71 years were randomised to the MRI arm (77) or the CT arm.
The proportion of GU toxic effects of grade 2 or higher was significantly lower among those receiving MRI-guided stereotactic therapy (24.4% vs 43.4%, p = 0.01). There were no reported gastrointestinal toxic effects at grade 2 or higher compared to 10.5% in the CT-guided group (p = 0.003).
The researchers also observed a significantly lower proportion of men with an IPSS score increase of 15 points or more after 4 weeks (6.8% vs 19.4%, p = 0.01).
The authors concluded that MRI-guided stereotactic radiotherapy reduced physician-reported toxic GU and gastrointestinal adverse effects than CT-guided stereotactic radiotherapy and called for future studies to examine the sustainability of these benefits.
Citation
Kishan AU et al. Magnetic Resonance Imaging-Guided vs Computed Tomography-Guided Stereotactic Body Radiotherapy for Prostate Cancer: The MIRAGE Randomized Clinical Trial. JAMA Oncol 2023
Using contrast-enhanced cone beam breast CT provides a more accurate assessment of residual tumour following neoadjuvant chemotherapy compared to magnetic resonance imaging (MRI) according to the findings of a comparative study by Chinese researchers.
Neoadjuvant chemotherapy is used prior to breast cancer surgery in patients with locally advanced breast cancer to reduce the size of the tumour. An assessment of the size of unresectable residual tumour is required since this is an important factor in the local recurrence of disease following breast conserving therapy. Radiological examination has an important role in the assessment of residual tumour and MRI has been shown to be more accurate that other imaging modalities for an evaluation of the response to treatment. Cone beam breast CT is a relatively novel technique that has shown promise for the early diagnosis of malignant breast cancer and can also differentiate between malignant and benign breast tissue.
However, to date, no studies have examined the accuracy of cone beam breast CT for the assessment of residual tumour following neoadjuvant chemotherapy. In the current study, the Chinese team compared cone beam breast CT and MRI for the assessment of tumour size following neoadjuvant chemotherapy and retrospectively compared the results of the two methods with those obtained with the findings from pathology. In addition, the researchers examined the predictive value of the two approaches for a pathological complete response. The level of agreement between the tumour size based on the two methods was compared to the findings on pathology and assessed using the intraclass correlation coefficient (ICC).
Cone beam breast CT and assessment of residual tumour
Data were available for 91 women with a median age of 45 years, the majority (73.6%) of whom were premenopausal.
When compared with pathology, there was good agreement for the cone beam breast CT (ICC = 0.64, 95% CI 0.35 – 0.78). In contrast, comparison with MRI was only moderate (ICC= 0.59, 95% CI 0.36 – 0.77). In subgroup analysis, the cone beam was also superior to MRI for residual ductal carcinoma in situ (p < 0.001).
For predictive purposes, the area under the receiver operating characteristics curve for predicting a pathological complete response were similar for both imaging modalities (AUC = 0.749 for cone beam and 0.733 for MRI, p > 0.05).
The authors concluded that cone beam breast CT was superior to MRI for an assessment of residual tumour following neoadjuvant chemotherapy and could therefore be seen as an alternative means of assessment.
Citation
Wang Y et al. Accuracy of Preoperative Contrast-enhanced Cone Beam Breast CT in Assessment of Residual Tumor after Neoadjuvant Chemotherapy: A Comparative Study with Breast MRI. Acad Radiol 2023
IMPORTANT LINKS
MORE FROM COGORA
© Cogora 2025
Cogora Limited. 1 Giltspur Street, London EC1A 9DD
Registered in the United Kingdom. Reg. No. 2147432
