Sir Peter MacCallum Department of Oncology - Research Publications
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ItemmRNA vaccine against malaria tailored for liver-resident memory T cells(NATURE PORTFOLIO, 2023-09)Malaria is caused by Plasmodium species transmitted by Anopheles mosquitoes. Following a mosquito bite, Plasmodium sporozoites migrate from skin to liver, where extensive replication occurs, emerging later as merozoites that can infect red blood cells and cause symptoms of disease. As liver tissue-resident memory T cells (Trm cells) have recently been shown to control liver-stage infections, we embarked on a messenger RNA (mRNA)-based vaccine strategy to induce liver Trm cells to prevent malaria. Although a standard mRNA vaccine was unable to generate liver Trm or protect against challenge with Plasmodium berghei sporozoites in mice, addition of an agonist that recruits T cell help from type I natural killer T cells under mRNA-vaccination conditions resulted in significant generation of liver Trm cells and effective protection. Moreover, whereas previous exposure of mice to blood-stage infection impaired traditional vaccines based on attenuated sporozoites, mRNA vaccination was unaffected, underlining the potential for such a rational mRNA-based strategy in malaria-endemic regions.
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ItemExecutive summary of consensus clinical practice guidelines for the prevention of infection in patients with multiple myeloma(WILEY, 2023-08)Infection remains a significant contributor to morbidity and mortality in patients with myeloma. This guideline was developed by a multidisciplinary group of clinicians who specialise in the management of patients with myeloma and infection from the medical and scientific advisory group from Myeloma Australia and the National Centre for Infections in Cancer. In addition to summarising the current epidemiology and risk factors for infection in patients with myeloma, this guideline provides recommendations that address three key areas in the prevention of infection: screening for latent infection, use of antimicrobial prophylaxis and immunoglobulin replacement and vaccination against leading respiratory infections (severe acute respiratory syndrome coronavirus 2, influenza and Streptococcus pneumoniae) and other preventable infections. This guideline provides a practical approach to the prevention of infection in patients with myeloma and harmonises the clinical approach to screening for infection, use of prophylaxis and vaccination to prevent infectious complications.
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ItemThe importance of frailty assessment in multiple myeloma: a position statement from the Myeloma Scientific Advisory Group to Myeloma Australia(WILEY, 2023-05)Multiple myeloma (MM) is a disease of older people, yet factors relating to comorbidity and frailty may threaten treatment tolerability for many of this heterogenous group. There has been increasing interest in defining specific and clinically relevant frailty assessment tools within the MM population, with the goal of using these frailty scores, not just as a prognostic instrument, but also as a predictive tool to allow for a frailty-adapted treatment approach. This paper reviews the various frailty assessment frameworks used in the evaluation of patients with MM, including the International Myeloma Working Group Frailty Index (IMWG-FI), the Mayo Frailty Index and the simplified frailty scale. While the IMWG-FI remains the most widely accepted tool, the simplified frailty scale is the most user-friendly in busy day-to-day clinics based on its ease of use. This paper summarises the recommendations from the Myeloma Scientific Advisory Group (MSAG) of Myeloma Australia, on the use of frailty assessment tools in clinical practice and proposes a frailty-stratified treatment algorithm to aid clinicians in tailoring therapy for this highly heterogeneous patient population.
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ItemComprehensive review of the use of hydrogel spacers prior to radiation therapy for prostate cancer(WILEY, 2023-03)OBJECTIVES: To provide a comprehensive narrative review of the published data on the impact of hydrogel spacers on rectal dosimetry and toxicity and to outline the practicalities of inserting hydrogel spacers. RESULTS: A growing body of evidence suggests that the administration of hydrogel spacers is safe and is associated with limited peri-operative morbidity. The impact on rectal dosimetry has been clearly established and use of hydrogel spacers is associated with reduced rectal morbidity. These results have been corroborated by several Phase II and III clinical trials and subsequent meta-analysis. There are several areas for future research, including the role of hydrogel spacers in prostate stereotactic beam radiotherapy and post-radiotherapy local recurrence. CONCLUSIONS: Hydrogel spacers provide a low-morbidity method to potential reduce rectal toxicity after radiation therapy in men with prostate cancer. Data outlining sexual function and oncological outcomes are limited to date. Future studies, currently being conducted, may provide further clarification of the role of hydrogel spacers in prostate cancer management.
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ItemCompliance with Therapeutic Goods Association prescribing information: weekly or second weekly cetuximab for the treatment of metastatic colorectal cancer(WILEY, 2022-09-13)BACKGROUND: Treatment with cetuximab provides a survival benefit for patients with RAS wild-type metastatic colorectal cancer (mCRC). Practice-defining cetuximab studies utilised weekly (q1w) administration. More convenient second weekly (q2w) administration is supported by pharmacokinetic data and a recent meta-analysis, but large head-to-head studies have not been conducted. Therapeutic Goods Association (TGA) prescribing information states cetuximab be administered q1w for all indications. AIM: To assess the real-world use of q1w versus q2w cetuximab schedule and any difference in outcomes. METHODS: We analysed data from a prospective mCRC database at seven Melbourne hospitals from January 2010 to August 2019. Characteristics and outcomes for cetuximab-treated patients were examined, comparing q1w versus q2w schedules. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints. RESULTS: Of 214 eligible patients, 103 (48%) received q1w and 111 (52%) received q2w cetuximab. Q2w cetuximab has been used in >70% of patients from 2015. Q2w was more commonly used in public patients (70% vs 13% in private, P < 0.001), in left-sided primary tumours (83% vs 68%, P = 0.025) and in combination with chemotherapy (73% q2w vs 40% q1w, P < 0.001). Q2w treatment was less common in BRAFV600E mutated tumours (4% vs 13%, P = 0.001). PFS was similar across all lines of therapy, including when analyses were limited to a left-sided primary and there was no difference in OS in multivariate analysis. CONCLUSION: This real-world analysis shows q2w cetuximab has become the dominant method of administration, despite TGA guidance. Our outcome data adds to other data supporting the use of q2w cetuximab as the standard option. Consideration could be given to modifying current TGA advice.
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ItemDihydropyrimidine Dehydrogenase Deficiency and Implementation of Upfront DPYD Genotyping(WILEY, 2022-06-12)Fluoropyrimidines (FP; 5-fluorouracil, capecitabine, and tegafur) are a commonly prescribed class of antimetabolite chemotherapies, used for various solid organ malignancies in over 2 million patients globally per annum. Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the critical enzyme implicated in FP metabolism. DPYD variant genotypes can result in decreased DPD production, leading to the development of severe toxicities resulting in hospitalization, intensive care admission, and even death. Management of toxicity incurs financial burden on both patients and healthcare systems alike. Upfront DPYD genotyping to identify variant carriers allows an opportunity to identify patients who are at high risk to suffer from serious toxicities and allow prospective dose adjustment of FP treatment. This approach has been shown to reduce patient morbidity, as well as improve the cost-effectiveness of managing FP treatment. Upfront DPYD genotyping has been recently endorsed by several countries in Europe and the United Kingdom. This review summarizes current knowledge about DPD deficiency and upfront DPYD genotyping, including clinical and cost-effectiveness outcomes, with the intent of supporting implementation of an upfront DPYD genotyping service with individualized dose-personalization.
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ItemPrevalence of malnutrition and nutrition-related complications in patients with gastroenteropancreatic neuroendocrine tumours(WILEY, 2022-04-12)Cross-sectional studies report that up to 25% of people with gastroenteropancreatic neuroendocrine tumours (GEP NET) are malnourished. However, the changes in nutritional status and dietary intake over time are unknown. The present study aimed to comprehensively describe the impact of a GEP NET on nutritional status and quality of life (QOL). Patients diagnosed with a GEP NET were recruited to this prospective longitudinal study on initial attendance to the NET Unit at two tertiary hospitals in Melbourne (VIC, Australia). Patient self-reported QOL measures (European Organisation for Research and Treatment Cancer QLC-C30 and QLC-GINET21) and nutritional outcomes (nutritional status, weight change, fat-free mass [FFM], dietary change, dietitian contact) were collected bi-monthly for six months. Sixty-one patients were recruited (66% male) with a mean ± SD age of 62 ± 12 years, predominantly diagnosed with small intestinal NET and Grade 1/2 disease. Commonly reported symptoms were fatigue (79%), abdominal discomfort (75%) and pain (68%). More patients were malnourished at baseline than at 6 months (29% vs. 13%). Over this 6 months, 48% lost weight, 20% lost ≥ 5% of their body weight, and 62% lost FFM with an average FFM loss of 2.8 kg (95% confidence interval = 2.0, 3.6), consistent with altered body composition. Dietary change was reported by 56% at baseline and 53% at six months, but only 21% consulted a dietitian at baseline and 18% at 6 months. Clinically significant loss of weight and FFM affected many patients with a GEP NET; however, few patients were referred to/or received a consultation with a dietitian. Valid screening practices are needed to identify weight loss and nutrition issues in GEP NET patients, and to facilitate referral to dietitian services.