Sir Peter MacCallum Department of Oncology - Research Publications
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ItemNo Preview AvailableRisk-Directed Ambulatory Thromboprophylaxis in Lung and Gastrointestinal Cancers The TARGET-TP Randomized Clinical Trial(American Medical Association, 2023-11)IMPORTANCE: Thromboprophylaxis for individuals receiving systemic anticancer therapies has proven to be effective. Potential to maximize benefits relies on improved risk-directed strategies, but existing risk models underperform in cohorts with lung and gastrointestinal cancers. OBJECTIVE: To assess clinical benefits and safety of biomarker-driven thromboprophylaxis and to externally validate a biomarker thrombosis risk assessment model for individuals with lung and gastrointestinal cancers. DESIGN, SETTING, AND PARTICIPANTS: This open-label, phase 3 randomized clinical trial (Targeted Thromboprophylaxis in Ambulatory Patients Receiving Anticancer Therapies [TARGET-TP]) conducted from June 2018 to July 2021 (with 6-month primary follow-up) included adults aged 18 years or older commencing systemic anticancer therapies for lung or gastrointestinal cancers at 1 metropolitan and 4 regional hospitals in Australia. Thromboembolism risk assessment based on fibrinogen and d-dimer levels stratified individuals into low-risk (observation) and high-risk (randomized) cohorts. INTERVENTIONS: High-risk patients were randomized 1:1 to receive enoxaparin, 40 mg, subcutaneously daily for 90 days (extending up to 180 days according to ongoing risk) or no thromboprophylaxis (control). MAIN OUTCOMES AND MEASURES: The primary outcome was objectively confirmed thromboembolism at 180 days. Key secondary outcomes included bleeding, survival, and risk model validation. RESULTS: Of 782 eligible adults, 328 (42%) were enrolled in the trial (median age, 65 years [range, 30-88 years]; 176 male [54%]). Of these participants, 201 (61%) had gastrointestinal cancer, 127 (39%) had lung cancer, and 132 (40%) had metastatic disease; 200 (61%) were high risk (100 in each group), and 128 (39%) were low risk. In the high-risk cohort, thromboembolism occurred in 8 individuals randomized to enoxaparin (8%) and 23 control individuals (23%) (hazard ratio [HR], 0.31; 95% CI, 0.15-0.70; P = .005; number needed to treat, 6.7). Thromboembolism occurred in 10 low-risk individuals (8%) (high-risk control vs low risk: HR, 3.33; 95% CI, 1.58-6.99; P = .002). Risk model sensitivity was 70%, and specificity was 61%. The rate of major bleeding was low, occurring in 1 participant randomized to enoxaparin (1%), 2 in the high-risk control group (2%), and 3 in the low-risk group (2%) (P = .88). Six-month mortality was 13% in the enoxaparin group vs 26% in the high-risk control group (HR, 0.48; 95% CI, 0.24-0.93; P = .03) and 7% in the low-risk group (vs high-risk control: HR, 4.71; 95% CI, 2.13-10.42; P < .001). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of individuals with lung and gastrointestinal cancers who were stratified by risk score according to thrombosis risk, risk-directed thromboprophylaxis reduced thromboembolism with a desirable number needed to treat, without safety concerns, and with reduced mortality. Individuals at low risk avoided unnecessary intervention. The findings suggest that biomarker-driven, risk-directed primary thromboprophylaxis is an appropriate approach in this population. TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12618000811202.
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ItemDihydropyrimidine Dehydrogenase Deficiency and Implementation of Upfront DPYD Genotyping(WILEY, 2022-10)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, 2022-06)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.
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ItemA PHASE II STUDY OF CONTINUOUS LOW DOSE PANOBINOSTAT IN PAEDIATRIC PATIENTS WITH MALIGNANT RHABDOID TUMOURS AND ATYPICAL TERATOID RHABDOID TUMOURS(OXFORD UNIV PRESS INC, 2022-06)Abstract BACKGROUND: Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumours (MRT) and atypical teratoid rhabdoid tumours (ATRT) in pre-clinical models. We report results of the open label, phase II study of oral panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumour activity of low dose, continuous oral panobinostat as well as its associated toxicities. To assess the biological activity of low dose panobinostat by measuring histone H4 acetylation status in peripheral mononuclear cells (PMNC), and differentiation markers. METHODS: Following primary institutional standard of care induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2/day, with a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat at different dosing levels. Patients were monitored for toxicity; dose reductions were in decrements of 2mg/m2/day. RESULTS: A total of 13 patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled. The average age at enrollment was 3.6 years (range 0.8-6.8 years). The mean treatment duration was 206 days (13-344 days). Currently, six patients (42.9%) remain on study with a mean study duration of 531 days (range 13-895 days). 6/14 patients (42.9%) were removed due to disease progression at a mean study duration of 245 days (44-560 days). 2/14 patients (14.3%) withdrew due to toxicity. 12/14 patients (85.7%) required dose reductions. The main toxicities were thrombocytopaenia and leukopaenia (Grade III-IV). Real-time pharmacodynamic assessment of panobinostat, at a dose as low as 6mg/m2/day resulted in significant acetylation of histone H4 in PMNC. CONCLUSIONS: Treatment with low dose panobinostat is well tolerated in infants and children with MRT/ATRT, with significant acetylation of histone H4 in PMNC.
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ItemReal-world staging computed tomography scanning technique and important reporting discrepancies in pancreatic ductal adenocarcinoma(WILEY, 2022-07)BACKGROUND: Computed tomography (CT) is the first-line staging imaging modality for pancreatic ductal adenocarcinoma (PDAC) which determines resectability and treatment pathways. METHODS: Between January 2016 and December 2019, prospectively collated data from two Australian cancer centres was extracted from the PURPLE Pancreatic Cancer registry. Real-world staging CTs and corresponding reports were blindly reviewed by a sub-specialist radiologist and compared to initial reports. RESULTS: Of 131 patients assessed, 117 (89.3%) presented with symptoms, 74 (56.5%) CTs included slices ≤3 mm thickness and CT pancreas protocol was applied in 69 (52.7%) patients. Initial reports lacked synoptic reporting in 131 (100%), tumour identification in 2 (1.6%) and tumour measurement in 13 (9.9%) cases. Tumour-vascular relationship reporting was missing in 69-109 (52.7-83.2%) for regarding the key arterial and venous structures that is required to assess resectability. Initial reports had no comment on venous thrombus or venous collaterals in 80 (61.1%) and 109 (83.2%) and lacked locoregional lymphadenopathy interpretation in 13 (9.9%) cases. Complete initial staging report was present in 72 (55.0%) patients. Sub-specialist radiological review resulted in down-staging in 16 (22.2%) and up-staging in 1 (1.4%) patient. Staging discrepancies were mainly regarding metastatic disease (12, 70.6%) and tumour-vascular relationship (5, 29.4%). CONCLUSION: Real-world staging imaging in PDAC patients show low proportion of dedicated CT pancreas protocol, high proportion of incomplete staging reports and no synoptic reporting. The most common discrepancy between initial and sub-specialist reporting was regarding metastases and tumour-vascular relationship assessment resulting in sub-specialist down-staging in almost every fifth case.
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ItemThe Impact of Neoadjuvant Chemotherapy on the Surgical Management of Colorectal Peritoneal Metastases: A Systematic Review and Meta-Analysis(SPRINGER, 2022-10)BACKGROUND: Cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) is a well-recognised treatment option for the management of colorectal peritoneal metastases (CRPM). However, incorporating the routine use of neoadjuvant chemotherapy (NAC) into this management plan is controversial. METHODS: A systematic review and meta-analysis were conducted to evaluate the impact of neoadjuvant chemotherapy on perioperative morbidity and mortality, and long-term survival of patients with CRPM undergoing CRS and HIPEC. RESULTS: Twelve studies met the inclusion criteria (n = 2,463 patients). Ten were retrospective cohort, one was prospective cohort, and one was a prospective randomised by design. Patients who received NAC followed by CRS and HIPEC experienced no difference in major perioperative morbidity and mortality compared with patients who underwent surgery first (SF). There was no difference in overall survival at 3 years, but at 5 years NAC patients had superior survival (relative risk [RR] 1.31; 95% confidence interval [CI] 1.11-1.54, P < 0.001). There were no differences in 1- and 3-year, disease-free survival (DFS) between groups. Study heterogeneity was generally high across all outcome measures. CONCLUSIONS: Patients who received neoadjuvant chemotherapy did not experience any increase in perioperative morbidity or mortality. The potential improvement in 5-year overall survival in patients receiving NAC is based on limited confidence due to several limitations in the data, but not sufficiently enough to curtail its use. The practice of NAC in this setting will remain heterogeneous and guided by retrospective evidence until prospective, randomised data are reported.
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ItemOutcomes from cytoreduction and hyperthermic intraperitoneal chemotherapy for appendiceal epithelial neoplasms(WILEY, 2019-09-01)Background Appendiceal epithelial neoplasms are rare cancers. Management of peritoneal disease from appendiceal neoplasms has historically been with debulking surgery. In recent decades, the advent of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has become the standard of care. Here, we report our single institution 10‐year experience with CRS and HIPEC for appendiceal neoplasms. Methods This is a retrospective review from 1 January 2008 to 1 June 2017 of all patients undergoing CRS and HIPEC for appendiceal neoplasms. Institutional ethics approval was granted for this project. Results One hundred and seventy‐two patients underwent 208 CRSs during this time. Overall, 83.72% of patients had one CRS and HIPEC procedure. Pseudomyxoma peritonei from a perforated appendiceal mucinous neoplasm accounted for 67.9% of cases. The median peritoneal carcinomatosis index (PCI) was 14, with complete cytoreduction achieved in 74.2% of patients. Fifty‐four percent of patients had at least one complication, with one (0.5%) peri‐operative mortality in our cohort. For the entire cohort, the median overall survival was 104 months and a 5‐year survival of 75%. In those having a complete cytoreduction, 5‐year survival was 90%, with a median disease free interval of 63 months. PCI and completeness of cytoreduction were independent predictors of overall survival. Conclusion Our results demonstrate that CRS and HIPEC for appendiceal neoplasms are safe and effective. Despite carrying some morbidity, it offers patients an excellent disease free and overall survival.
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ItemPrognostic value of tumour regression grade in locally advanced rectal cancer: a systematic review and meta-analysis(WILEY, 2018-07)AIM: The current standard of care for locally advanced rectal cancer involves neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision. There is a spectrum of response to neoadjuvant therapy; however, the prognostic value of tumour regression grade (TRG) in predicting disease-free survival (DFS) or overall survival (OS) is inconsistent in the literature. METHOD: This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was undertaken using Ovid MEDLINE, Embase and Google Scholar. Inclusion criteria were Stage II and III locally advanced rectal cancer treated with long-course CRT followed by radical surgery. The aim of the meta-analysis was to assess the prognostic implication of each TRG for rectal cancer following neoadjuvant CRT. Long-term prognosis was assessed. The main outcome measures were DFS and OS. A random effects model was performed to pool the hazard ratio (HR) from all included studies. RESULTS: There were 4875 patients from 17 studies, with 775 (15.9%) attaining a pathological complete response (pCR) and 719 (29.9%) with no response. A significant association with OS was identified from a pooled-estimated HR for pCR (HR = 0.47, P = 0.002) and nonresponding tumours (HR = 2.97; P < 0.001). Previously known tumour characteristics, such as ypN, lymphovascular invasion and perineural invasion, were also significantly associated with DFS and OS, with estimated pooled HRs of 2.2, 1.4 and 2.3, respectively. CONCLUSION: In conclusion, the degree of TRG was of prognostic value in predicting long-term outcomes. The current challenge is the development of a high-validity tests to predict pCR.
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ItemA PHASE II STUDY OF CONTINUOUS LOW DOSE PANOBINOSTAT IN PAEDIATRIC PATIENTS WITH MALIGNANT RHABDOID TUMORS/ATYPICAL TERATOID RHABDOID TUMORS(OXFORD UNIV PRESS INC, 2020-12)Abstract
BACKGROUND
Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumor (MRT)/atypical teratoid rhabdoid tumors (ATRT) in pre-clinical models. This is an open label, phase II study of panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumor activity of low dose, continuous panobinostat, its associated toxicities, the biological activity of low dose panobinostat by measuring histone acetylation status in peripheral mononuclear cells (PMNC), and markers of differentiation in fresh tumor tissue specimens.METHODS
Following cycles of induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2 following a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat. Patients were monitored for drug toxicities with the possibility of dose reductions in decrements of 2mg/m2.RESULTS
Six patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled to date. The average age at enrollment was 2.5 years. Currently, six patients (85.7%) remain on study with a mean treatment duration of 170 days (range 44–327 days). One patient was removed from study at day 44 due to disease progression. The main dose-limiting toxicity observed to date has been myelosuppression. Panobinostat, at a dose of 10mg/m2, caused significant acetylation of H4 in PMNC.CONCLUSIONS
Treatment with panobinostat appears to be well tolerated in infants with MRT/ATRT, with successful real-time pharmacodynamic assessment of H4 acetylation.