Stephen. P. Ackland

Background: Implementing pharmacogenomic‐guided management in cancer patients equitably and effectively in a large population presents challenges. DPYD genotyping determines clinically significant variants of patients at increased risk of developing grade3–5 fluoropyrimidine (FP) toxicity. FP chemotherapies are prescribed for ~16,000 Australians with a 10%–40% grade3–4 toxicity incidence and 1% mortality. Variant carriers can have FP dosing adjusted to improve treatment tolerance without compromising anticancer effect. This strategy has not been formally adopted within Australia, despite widespread international standardisation.Aim: This pilot study determined genotyping turnaround‐times (TAT) for 4 DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/Haplotype B3) in Australian patients. Secondary objectives were identification of FP toxicities of DPYD variant carriers, and analysis of healthcare stakeholder perspectives, including enablers/barriers to implementation.Methods: Genotyping was determined by Real‐Time Polymerase Chain Reaction. Qualitative data were determined through semi‐structured questionnaire.Results: 104 patients recruited over 24 months had a mean TAT of 7.2 days, 5.2 business days (range 1–30). Grade3–4 toxicity occurred in 9/16 DPYD variant carriers, including 2 ICU admissions and 1 death. Themes from 30 questionnaire respondents suggest that clinical environment and resources were fundamental barriers, and motivation to improve patient care was the predominant enabler of change.Conclusion: DPYD genotyping is feasible for improving precision‐oncology for patients requiring FP chemotherapies. A TAT of 7 days is acceptable by both stakeholder respondents and national oncology clinician groups. This pilot study, although small, informs a large national project evaluating prospective DPYD genotyping and its impact on FP tolerability, patient safety and cost‐effectiveness in Australia.

Background: Despite common global usage, fluoropyrimidine (FP; 5‐flurouracil and capecitabine)‐related chemotherapy toxicity is poorly reported in the literature, with serious toxicity ranging from 10% to 40% and early toxicity (within 60 days of exposure) quoted at 14%. Data reflecting the incidence of Grades 3–5 FP‐related toxicity in Australian cancer patients is scant, despite the significant impact of toxicity on patients (hospitalisations, intensive care unit (ICU) admissions and even death).Aims: This retrospective audit evaluated Grades 3–5 toxicities in a contemporaneous cohort of 500 patients receiving FP chemotherapies within the Hunter‐New England Local Health District from June 2020 to June 2022. Data were extracted from public hospital records and oncology‐specific e‐records to determine rates of toxicity and associated hospitalisations, intensive care admissions and deaths that occurred within 60 days of first exposure to FP chemotherapy‐containing regimens.Results: One hundred and fifty incidents of Grades 3–4 toxicity in the first 60 days led to 87 patients presenting to hospital (87/500, 17.4%). The most common serious toxicities were diarrhoea (39.3%), nausea and vomiting (22.7%) and febrile neutropaenia (10%). Four patients were admitted to the ICU, and four patients died of toxicity. Within the first 60 days, 22.2% of patients required treatment delays, 21.4% required dose reductions, and 7.8% of patients ceased treatment because of toxicities.Discussion and Conclusion: Our experience reflects international reports and is likely generalisable to the Australian population. These data are a basis to understand the potential benefits of precision medicine strategies such as pharmacogenomic screening to improve patient tolerability and the cost‐effectiveness of FP chemotherapy prescribing.

Early‐onset colorectal cancer (EOCRC) incidence has increased in most Western countries over the last decade, with Australia at the forefront. Recent literature has thus focused on characterizing EOCRC from later‐onset colorectal cancer (LOCRC). Earlier exposure to modifiable risk factors resulting in gut dysbiosis has been linked with EOCRC development. EOCRCs have more aggressive histopathological features with somatic mutations resulting in pro‐inflammatory tumor microenvironments. There is a tendency to treat EOCRCs with multimodal chemotherapeutic regimens and more extensive surgery than LOCRCs with conflicting postoperative outcomes and survival data. Current research is limited by a lack of Australasian studies, retrospective study designs, and heterogeneous definitions of EOCRC. Future research should address these and focus on investigating the role of immunotherapies, establishing minimally invasive diagnostic biomarkers and nomograms, and evaluating the survival and functional outcomes of EOCRC.

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 theDPYDgene, is the critical enzyme implicated in FP metabolism.DPYDvariant 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. UpfrontDPYDgenotyping 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. UpfrontDPYDgenotyping has been recently endorsed by several countries in Europe and the United Kingdom. This review summarizes current knowledge about DPD deficiency and upfrontDPYDgenotyping, including clinical and cost‐effectiveness outcomes, with the intent of supporting implementation of an upfrontDPYDgenotyping service with individualized dose‐personalization.

Advanced adrenocortical cancer (ACC) is a rare, highly aggressive malignancy, which typically has a poor prognosis. In advanced ACC, the overall trend is toward a short PFS interval following first-line systemic therapy, highlighting a clear need for improved second-/third-line treatment strategies. We conducted a review of the literature and relevant scientific guidelines related to systemic therapy for advanced ACC. Public indexes including PubMed/MEDLINE were searched. Treatment selection in the second-line setting is based on small phase 2 trials, case reports, and pre-clinical evidence. The best data available for initial second-line therapy selection supports the use of gemcitabine and capecitabine (G + C) or streptozotocin (S), both with or without mitotane. G + C is becoming increasingly recommended based on phase 2 clinical trial data in patients of good PS, due to the inferred superior PFS and OS from non-comparative trials. Alternatively, streptozotocin was better tolerated than EDP + M in the FIRM-ACT study and remains an option when warranted. Beyond this, further treatment approaches should be tailored to individual patient characteristics, utilizing a mixture of systemic therapies, local therapies, and enrolment in clinical trials where available. Additionally, the role of molecular stratification, predictive biomarkers, and immune checkpoint inhibitors in specific individuals, such as Lynch syndrome, is evolving and may become increasingly utilized in clinical practice. Advanced ACC necessitates a multidisciplinary approach and is best managed in a specialist center. Although there is no one definitive second-line treatment strategy, there are some favorable approaches, which require further validation in larger clinical trials.

Background: Retrospective studies show improved outcomes in colorectal cancer patients if taking statins, including overall survival, pathological response of rectal cancer to preoperative chemoradiotherapy (pCRT), and reduced acute and late toxicities of pelvic radiation. Major tumour regression following pCRT has strong prognostic significance and can be assessed in vivo using MRI-based tumour regression grading (mrTRG) or after surgery using pathological TRG (pathTRG). Methods: A double-blind phase 2 trial will randomise 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 18+ sites in New Zealand and Australia. Patients will receive simvastatin 40 mg or placebo daily for 90 days starting 1 week prior to standard pCRT. Pelvic MRI 6 weeks after pCRT will assess mrTRG grading prior to surgery. The primary objective is rates of favourable (grades 1–2) mrTRG following pCRT with simvastatin compared to placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4–5). Secondary objectives include comparison of: rates of favourable pathTRG in resected tumours; incidence of toxicity; compliance with intended pCRT and trial medication; proportion of patients undergoing surgical resection; cancer outcomes and pathological scores for radiation colitis. Tertiary objectives include: association between mrTRG and pathTRG grouping; inter-observer agreement on mrTRG scoring and pathTRG scoring; studies of T-cell infiltrates in diagnostic biopsies and irradiated resected normal and malignant tissue; and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Trial recruitment commenced April 2018. Discussion: When completed this study will be able to observe meaningful differences in measurable tumour outcome parameters and/or toxicity from simvastatin. A positive result will require a larger RCT to confirm and validate the merit of statins in the preoperative management of rectal cancer. Such a finding could also lead to studies of statins in conjunction with chemoradiation in a range of other malignancies, as well as further exploration of possible mechanisms of action and interaction of statins with both radiation and chemotherapy. The translational substudies undertaken with this trial will provisionally explore some of these possible mechanisms, and the tissue and data can be made available for further investigations. Trial registration: ANZ Clinical Trials Register ACTRN12617001087347. (www.anzctr.org.au, registered 26/7/2017) Protocol Version: 1.1 (June 2017).

The separate impacts of dose and dose intensity of chemotherapy for metastatic breast cancer remain uncertain. The primary objective of this trial was to compare a short, high-dose, intensive course of epirubicin and cyclophosphamide (EC) with a longer conventional dose regimen delivering the same total dose of chemotherapy.