Surgery (RMH) - Research Publications
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ItemReal-world adjuvant chemotherapy treatment patterns and outcomes over time for resected stage II and III colorectal cancer(Wiley, 2023-06)BACKGROUND: The administration of adjuvant chemotherapy (AC) to colorectal cancer (CRC) patients in Australia and impact of recent trial data has not been well reported. We aim to evaluate temporal trends in AC treatment and outcomes in real-world Australian patients. METHODS: CRC patients were analyzed from 13 hospitals, stratified by stage (II or III) and three 5-year time periods (A: 2005-2009, B: 2010-2014, C: 2015-2019). Stage III was further stratified as pre- and post publication of the International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration (March 2018). AC prescription, time-to-recurrence (TTR), and overall survival (OS) was compared across the time periods. RESULTS: Of 3977 identified patients, 1148 (stage II: 640, stage III: 508), 1525 (856 vs. 669), and 1304 (669 vs. 635) were diagnosed in Period A, B, and C, respectively. Fewer patients in Period C received AC compared to Period B in stage II (10% vs. 15%, p <.01) and III (70% vs. 79%, p <.01). Post-IDEA, the proportion of patients receiving ≤3 months of oxaliplatin-based AC increased (45% vs. 13%, p <.01). The proportion of patients who remained recurrence free at 3 years was similar between time periods in stage II (A: 89% vs. B: 88% vs. C: 90%, p = .53) and stage III (72% vs. 76% vs. 72%, p = .08). OS significantly improved for stage II (80%-85%, p = .04) and stage III (69%-77%, <.01) from period A to B. CONCLUSION: AC use has moderately decreased over time with no impact on recurrence rates. Improved survival in more recent years despite similar recurrence rates may be related to improved baseline staging, better postrecurrence treatment, and reduced noncancer-related mortality.
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ItemUse and outcomes from neoadjuvant chemotherapy in borderline resectable pancreatic ductal adenocarcinoma in an Australasian population(WILEY, 2023-02-01)Background: Use of neoadjuvant (NA) chemotherapy is recommended when pancreatic ductal adenocarcinoma (PDAC) is borderline resectable. Method: A retrospective analysis of consecutive patients with localized PDAC between January 2016 and March 2019 within the Australasian Pancreatic Cancer Registry (PURPLE, Pancreatic cancer: Understanding Routine Practice and Lifting End results) was performed. Clinicopathological characteristics, treatment, and outcome were analyzed. Overall survival (OS) comparison was performed using log-rank model and Kaplan–Meier analysis. Results: The PURPLE database included 754 cases with localised PDAC, including 148 (20%) cases with borderline resectable pancreatic cancer (BRPC). Of the 148 BRPC patients, 44 (30%) underwent immediate surgery, 80 (54%) received NA chemotherapy, and 24 (16%) were inoperable. The median age of NA therapy patients was 63 years and FOLFIRINOX (53%) was more often used as NA therapy than gemcitabine/nab-paclitaxel (31%). Patients who received FOLFIRINOX were younger than those who received gemcitabine/nab-paclitaxel (60 years vs. 67 years, p =.01). Surgery was performed in 54% (43 of 80) of BRPC patients receiving NA chemotherapy, with 53% (16 of 30) achieving R0 resections. BRPC patients undergoing surgery had a median OS of 30 months, and 38% (9 of 24) achieved R0 resection. NA chemotherapy patients had a median OS of 20 months, improving to 24 months versus 10 months for patients receiving FOLFIRINOX compared to gemcitabine/nab-paclitaxel (Hazard Ratio (HR).3, p <.0001). Conclusions: NA chemotherapy use in BRPC is increasing in Australia. One half of patients receiving NA chemotherapy proceed to curative resection, with 53% achieving R0 resections. Patients receiving Infusional 5-flurouracil, Irinotecan and Oxaliplatin (FOLIRINOX) had increased survival than gemcitabine/nab-paclitaxel. Treatment strategies are being explored in the MASTERPLAN and DYNAMIC-Pancreas trials.
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ItemT-stage downstaging of locally advanced rectal cancer after neoadjuvant chemoradiotherapy is not associated with reduced recurrence after adjusting for tumour characteristics(WILEY, 2022-09)BACKGROUND AND OBJECTIVES: Prior studies examining prognostic outcomes of locally advanced rectal adenocarcinomas achieving a complete pathological response following neoadjuvant chemoradiotherapy (nCRT) did not adjust for adverse prognostic factors in multivariate analyses and account for magnetic resonance imaging tumour staging inaccuracy pre-nCRT. We aimed to clarify prognostic outcomes in mT3 rectal adenocarcinomas with ypT-downstaging post-nCRT in robust adjusted analyses. METHODS: Retrospective analysis of prospectively-collected clinical data from 528 mT3 rectal adenocarcinomas ≤12 cm from the anal verge, any N-stage, no metastases, post-nCRT following total mesorectal excision (TME). Recurrence outcomes (local and distant combined) of tumours with complete ypT-downstaging (ypT0) post-nCRT before TME compared with no ypT-downstaging (≥ypT3) were examined using multivariate Cox regression, adjusting for confounders and accounting for pre-nCRT mT3-staging inaccuracy using bootstrapping. RESULTS: Complete ypT-downstaging was achieved in of 17.6% tumours and correlated strongly with complete pathological response. Complete ypT-downstaging was not associated with reduced recurrence hazards compared with no ypT-downstaging (hazard ratio = 0.60; 95% confidence interval [CI]: 0.23-1.56; p = 0.30). Lymphovascular invasion (LVI) and ypN+ve increased recurrence hazards by 1.8-fold (95% CI: 1.10-2.79; p = 0.02) and 2.3-fold (95% CI: 1.48-3.54; p = 0.0002), respectively. CONCLUSION: Complete ypT-downstaging was not associated with reduced recurrence after adjusting for confounders and accounting for mT3-staging inaccuracy, even in the absence of adverse prognostic factors (ypN+, LVI).
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ItemIs increasing nodal count associated with improved recurrence-free and overall survival following standard right hemicolectomy for colon cancer?(WILEY, 2022-09)BACKGROUND AND OBJECTIVES: Increasing lymph node harvest for right-sided colon cancer is associated with improved overall survival (OS), but most relevant studies failed to report the extent of resection. We examined the association between increasing lymph node count with standard right hemicolectomy according to nodal status and prognostic outcomes in right-sided tumors. METHODS: Retrospective analysis of prospectively collected clinical data from patients with proximal colonic adenocarcinomas (n = 1390) following right hemicolectomy. Associations between lymph node counts (0-12 vs. 13-15, 16-20, and >20) and recurrence-free survival (RFS) and OS were examined using multivariate Cox modeling adjusted for confounders. RESULTS: We found no association between increasing nodal count and RFS, regardless of nodal status. In the absence of nodal metastases, increasing nodal count (16-20 and >20 vs. 0-12 nodes) was associated with 57% (95% confidence interval [CI]: 0.21-0.89) and 52% (95% CI: 0.24-0.95) improved OS, respectively. In the presence of nodal metastases, increasing nodal count was not associated with OS. Adjuvant chemotherapy did not modify this effect. CONCLUSION: Increasing nodal count (>15 nodes) with right hemicolectomy was not associated with improved RFS. Improved OS was only found for node-negative tumors, casting some doubt on the benefits of resecting more lymph nodes in the presence of nodal metastases.
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ItemMolecular classification of hormone-sensitive and castration-resistant prostate cancer, using nonnegative matrix factorization molecular subtyping of primary and metastatic specimens(WILEY, 2022-06)BACKGROUND: Despite the rapidly evolving therapeutic landscape, immunotherapy has demonstrated limited activity in prostate cancer. A greater understanding of the molecular landscape, particularly the expression of immune-related pathways, will inform future immunotherapeutic strategies. Consensus nonnegative matrix factorization (cNMF) is a novel model of molecular classification analyzing gene expression data, focusing on biological interpretation of metagenes and selecting meaningful clusters. OBJECTIVE: We aimed to identify molecular subtypes of prostate cancer using cNMF and correlate these with existing biomarkers to inform future immunotherapeutic strategies. METHODS: A cohort of archival tumor specimens from hormone-sensitive and castration-resistant disease was studied. Whole transcriptomic profiles were generated using TruSeq RNA Access technology and subjected to cNMF. Comprehensive genomic profiling was performed with the FoundationOne assay. NMF subtypes were characterized by gene expression pathways, genomic alterations and correlated with clinical data, then applied to The Cancer Genome Atlas data set. RESULTS: We studied 164 specimens, including 52 castration-resistant and 13 paired primary/metastatic specimens. cNMF identified four distinct subtypes. NMF1 (19%) is enriched for immune-related and stromal-related pathways with transforming growth factor β (TGFβ) signature. NMF2 (36%) is associated with FOXO-mediated transcription signature and AKT signaling, NMF3 (26%) is enriched for ribosomal RNA processing, while NMF4 (19%) is enriched for cell cycle and DNA-repair pathways. The most common gene alterations included TMPRSS22 (42%), TP53 (23%), and DNA-repair genes (19%), occurring across all subtypes. NMF4 is significantly enriched for MYC and Wnt-signaling gene alterations. TMB, CD8 density, and PD-L1 expression were low overall. NMF1 and NMF4 were NMF2 was associated with superior overall survival. CONCLUSIONS: Using cNMF, we identified four molecularly distinct subtypes which may inform treatment selection. NMF1 demonstrates the most inflammatory signature with asuppressive TGFβ signature, suggesting potential benefit with immunotherapy combination strategies targeting TGFβ and PD-(L)1. Prospective studies are required to evaluate the use of this novel model to molecularly stratify patients for optimal treatment selection.
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ItemUptake of bone-modifying agents in patients with HER2+metastatic breast cancer with bone metastases - prospective data from a multi-site Australian registry(WILEY, 2022-10)BACKGROUND: International practice guidelines recommend administration of bone-modifying agents (BMA) in metastatic breast cancer (MBC) patients with bone metastases to reduce skeletal-related events (SRE). Optimal delivery of BMA in routine clinical practice, including agent selection and prescribing intervals, remains unclear. AIM: To describe real-world practice of Australian breast oncologists. METHODS: Prospective data from February 2015 to July 2020 on BMA delivery to MBC patients with bone metastases was analysed from Treatment of Advanced Breast Cancer in the Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Australian Patient (TABITHA), a multi-site Australian HER2+ MBC registry. RESULTS: Of 333 HER2+ MBC patients, 171 (51%) had bone metastases at diagnosis, with a mean age of 58.1 years (range, 32-87). One hundred and thirty (76%) patients received a BMA, with 90 (69%) receiving denosumab and 40 (31%) receiving a bisphosphonate. Patients who received a BMA were more likely to have received concurrent first-line systemic anti-HER2 therapy (95% vs 83%; P = 0.04), to present with bone-only metastases at diagnosis (24% vs 7%; P = 0.02) and less likely to have visceral metastases (51% vs 71%; P = 0.03). Ten of 40 (25%) bisphosphonate patients and 45 of 90 (50%) denosumab patients received their BMA at the recommended 4-weekly interval. Prescribing intervals varied over time. Adverse events reported were consistent with clinical trial data. CONCLUSION: Three-quarters of Australian HER2+ MBC patients with bone metastases receive a BMA, often at different schedules than guidelines recommend. Further studies, including all MBC subtypes, are warranted to better understand clinicians' prescribing rationale and potential consequences of current prescribing practice on SRE incidence.
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ItemNo Preview AvailableDetection of low-frequency DNA variants by targeted sequencing of the Watson and Crick strands(NATURE PORTFOLIO, 2021-10)Identification and quantification of low-frequency mutations remain challenging despite improvements in the baseline error rate of next-generation sequencing technologies. Here, we describe a method, termed SaferSeqS, that addresses these challenges by (1) efficiently introducing identical molecular barcodes in the Watson and Crick strands of template molecules and (2) enriching target sequences with strand-specific PCR. The method achieves high sensitivity and specificity and detects variants at frequencies below 1 in 100,000 DNA template molecules with a background mutation rate of <5 × 10-7 mutants per base pair (bp). We demonstrate that it can evaluate mutations in a single amplicon or simultaneously in multiple amplicons, assess limited quantities of cell-free DNA with high recovery of both strands and reduce the error rate of existing PCR-based molecular barcoding approaches by >100-fold.
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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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ItemDisparities in quality of life, social distress and employment outcomes in Australian cancer survivors(SPRINGER, 2022-06)PURPOSE: To examine how socio-demographic, comorbidities and information needs influence quality of life (QoL) outcomes of survivors of breast, colorectal, or prostate cancer, non-Hodgkin lymphoma or melanoma. METHODS: Cross-sectional postal survey with eligible participants identified through a population-based cancer registry. QoL outcomes were assessed by EQ-5D-5L, social difficulties index (SDI) and, for those employed at diagnosis, current employment. Regression analyses explored associations between outcome variables and cancer type, age, time since diagnosis, residential location, socio-economic disadvantage, comorbidities and unmet information needs. Mediation analyses examined whether comorbidities and information needs explained relationships between outcome variables and socio-economic disadvantage. RESULTS: 2115 survivors participated. Mean EQ-5D-5L scores (mean = 0.84) were similar to population averages and SDI scores were low for the entire sample (mean = 3.80). In multivariate analyses, being aged over 80, greater socio-economic disadvantage, comorbidities and unmet information needs decreased EQ-5D-5L scores. Higher SDI scores were associated with socio-economic disadvantage, comorbidities and unmet information needs. Not being employed was associated with being aged over 50, more comorbidities and socio-economic disadvantage. Comorbidities but not information needs partially mediated the impact of socio-economic disadvantage on EQ-5D-5L and SDI accounting for 17% and 14% of the total effect of socio-economic disadvantage respectively. Neither comorbidities nor information needs mediated the association between socio-economic disadvantage and employment outcomes. CONCLUSIONS: To improve quality of life, survivorship care should be better tailored to address the needs of individuals given their overall health and impact of comorbidities, their age and type of cancer and not simply time since diagnosis.
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ItemReal-world first-line systemic therapy patterns in metastatic castration-resistant prostate cancer(WILEY, 2022-05)INTRODUCTION: Several systemic therapies have demonstrated a survival advantage in metastatic castration resistant prostate cancer (mCRPC). Access to these medications varies significantly worldwide. In Australia until recently, patients must have received docetaxel first, unless unsuitable for chemotherapy, despite no evidence suggesting superiority over androgen receptor signalling inhibitors (ARSIs). Our study investigated real-world systemic treatment patterns in Australian patients with mCRPC. METHODS: The electronic CRPC Australian Database (ePAD) was interrogated to identify mCRPC patients. Clinicopathological features, treatment and outcome data, stratified by first-line systemic therapies, were extracted. Comparisons between groups utilised Kruskal-Wallis tests and Chi-Square analyses. Time-to-event data were calculated using Kaplan-Meier methods and groups compared using log-rank tests. Factors influencing overall survival (OS) and time to treatment failure (TTF) were analysed through Cox proportional hazards regression models. RESULTS: We identified 578 patients who received first-line systemic therapy for mCRPC. Enzalutamide (ENZ) was most commonly prescribed (n = 240, 41%), followed by docetaxel (DOC, n = 164, 28%) and abiraterone (AA, n = 100, 17%). Patients receiving ENZ or AA were older (79, 78.5 years respectively) compared with DOC (71 years, p = 0.001) and less likely to have ECOG performance status 0 (45%, 44%, 59% in ENZ, AA and DOC groups respectively p < 0.0001). Median TTF was significantly higher in those receiving ENZ (12.4 months) and AA (11.9 months) compared to DOC (8.3 months, p < 0.001). PSA50 response rates and OS were not statistically different. Time to developing CRPC > 12 months was independently associated with longer TTF (HR 0.67, p < 0.001) and OS (HR 0.49, p = 0.002). CONCLUSION: In our real-world population, ENZ and AA were common first-line systemic therapy choices, particularly among older patients and those with poorer performance status. Patients receiving ENZ and AA demonstrated superior TTF compared to DOC, while OS was not statistically different. Our findings highlight the important role of ARSIs, given the variability of access worldwide.