Surgery (RMH) - Research Publications
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ItemHow accurate are medical oncologists' impressions of management of metastatic colorectal cancer in Australia?(WILEY, 2018-04)AIM: Current efforts to understand patient management in clinical practice are largely based on clinician surveys with uncertain reliability. The TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) database is a multisite registry collecting comprehensive treatment and outcome data on consecutive metastatic colorectal cancer (mCRC) patients at multiple sites across Australia. This study aims to determine the accuracy of oncologists' impressions of real-word practice by comparing clinicians' estimates to data captured by TRACC. METHODS: Nineteen medical oncologists from nine hospitals contributing data to TRACC completed a 34-question survey regarding their impression of the management and outcomes of mCRC at their own practice and other hospitals contributing to the database. Responses were then compared with TRACC data to determine how closely their impressions reflected actual practice. RESULTS: Data on 1300 patients with mCRC were available. Median clinician estimated frequency of KRAS testing within 6 months of diagnosis was 80% (range: 20-100%); the TRACC documented rate was 43%. Clinicians generally overestimated the rates of first-line treatment, particularly in patients over 75 years. Estimate for bevacizumab in first line was 60% (35-80%) versus 49% in TRACC. Estimated rate for liver resection varied substantially (5-35%), and the estimated median (27%) was inconsistent with the TRACC rate (12%). Oncologists generally felt their practice was similar to other hospitals. CONCLUSIONS: Oncologists' estimates of current clinical practice varied and were discordant with the TRACC database, often with a tendency to overestimate interventions. Clinician surveys alone do not reliably capture contemporary clinical practices in mCRC.
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ItemExamining the impact of regular aspirin use and PIK3CA mutations on survival in stage 2 colon cancer(WILEY, 2017-01)BACKGROUND/AIM: Data suggest aspirin improves survival in colorectal cancer (CRC) harbouring PIK3CA mutations. The impact of aspirin is thought predominantly to be through an anti-inflammatory effect. The aim of this study is to explore the effect of aspirin use on survival in a real-world cohort of stage 2 colon cancer (CC) patients. METHODS: A prospective CRC database identified patients diagnosed with stage 2 CC between 2000 and 2011. PIK3CA mutation status was determined by next generation sequencing. Neutrophil-lymphocyte ratio greater than 5 at diagnosis represented systemic inflammation. Chart review was used to record regular aspirin use at diagnosis. Clinico-pathological features and survival data were available. Survival analyses used the Cox proportional hazards method. RESULTS: Of 488 patients with stage 2 CC, 95 patients were aspirin users and 70 patients had PIK3CA mutations. Aspirin users were more likely to be older (median: 76.4 years vs 68.3 years, P < 0.001), to be less fit (American Society of Anaesthetists Score 3-4: 58% vs 31%, P < 0.001) and to have systemic inflammation (neutrophil-lymphocyte ratio > 5: 39% vs 27%, P = 0.027). Regular aspirin use did not significantly improve recurrence-free survival. In the PIK3CA mutated group, there was a trend towards improved recurrence-free survival (hazard ratio: 0.45, P = 0.42). CONCLUSIONS: Our study did not demonstrate a significant survival advantage from aspirin use in stage 2 PIK3CA mutated CC. The 'real-world' nature of our cohort and the subsequent uncontrolled differences in age and fitness in aspirin users are likely to have contributed to this result. Defining the true impact of aspirin in CRC requires prospective randomised clinical trials.
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ItemThe impact of bevacizumab in metastatic colorectal cancer with an intact primary tumor: Results from a large prospective cohort study(WILEY, 2017-08)BACKGROUND: Debate continues regarding the benefits versus risks of initial resection of the primary tumor in metastatic colorectal cancer (mCRC) patients with an asymptomatic primary tumor. Although the benefit of the anti-vascular endothelial growth factor agent bevacizumab alongside first-line chemotherapy in mCRC is established, the impact of bevacizumab on the intact primary tumor (IPT) is less well understood. METHODS: Data from an Australian mCRC registry were used to assess the impact of bevacizumab-based regimens in the presence of an IPT, to see if this differs from effects in resected primary tumor (RPT) patients and to understand the safety profile of bevacizumab in patients with IPT. Progression-free survival (PFS), overall survival (OS) and safety endpoints were analyzed. RESULTS: Of 1204 mCRC patients, 826 (69%) were eligible for inclusion. Bevacizumab use was similar in both arms (IPT (64%) versus RPT (70%)); compared with chemotherapy alone, bevacizumab use was associated with significantly longer PFS (IPT: 8.5 months vs 4.7 months, P = 0.017; RPT: 10.8 months vs 5.8 months, P < 0.001) and OS (IPT: 20 months vs 14.8 months, P = 0.005; RPT: 24.4 months vs 17.3 months, P = 0.004)).1 Bevacizumab use in an IPT was associated with more GI perforations (4.5% vs 1.8%, P = 0.210) but less frequent bleeding (1.5% vs 5.3%, P = 0.050) and thrombosis (1.5% vs 2.7%, P = 0.470), versus chemotherapy alone. Median survival was equivalent between patients that did or did not experience bevacizumab-related adverse events - 20.0 months versus 19.9 months, hazard ratio = 0.98, P = 0.623.1 CONCLUSIONS: The addition of bevacizumab significantly improved survival outcomes in mCRC with an IPT. The occurrence of bevacizumab-related adverse events did not significantly impact survival outcomes.
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ItemChemotherapy and biologic use in the routine management of metastatic colorectal cancer in Australia: is clinical practice following the evidence?(WILEY, 2019-04)BACKGROUND: Emerging evidence on the optimal use of chemotherapy and biologics in patients with metastatic colorectal cancer should impact management in routine care. Recent studies have demonstrated benefits for initial triplet chemotherapy (5-fluorouracil, oxaliplatin and irinotecan, FOLFOXIRI) and for initial treatment with an epidermal growth factor receptor inhibitor (EGFRi) in patients with a RAS wild-type tumour and a left-sided primary tumour. AIM: To explore evolving pattern of metastatic colorectal cancer care over time in Australia. METHODS: We analysed data from the Treatment of Recurrent and Advanced Colorectal Cancer registry. RESULTS: From July 2009 to December 2017, 2552 metastatic colorectal cancer patients were entered into the Treatment of Recurrent and Advanced Colorectal Cancer registry. Of 1585 patients who initially underwent chemotherapy, treatment was with a doublet in 76%. FOLFOXIRI was given to 22 patients (1.4%), mostly young patients and those with potentially resectable disease. Along with first-line chemotherapy, 61% received bevacizumab, while 3.3% received an EGFRi, predominantly over the last 2 years. Within the KRAS wild-type left-sided tumour cohort, EGFRi use increased from 9% in 2015 to 37% in 2017. Across treatment sites, there was a wide variation in the utilisation of FOLFOXIRI and EGFRi therapy; bevacizumab use was more consistent. A clear impact on survival outcomes from these regimens is not evident, potentially due to multiple confounders. CONCLUSION: Doublet chemotherapy + bevacizumab remains the dominant initial strategy, with limited uptake of triplet chemotherapy and of EGFRi. Potential explanations include uncertainty about the significance of post hoc analyses for EGFRi and concerns regarding adverse events for both strategies.
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ItemRe-inventing the randomized controlled trial in medical oncology: The registry-based trial(WILEY, 2018-12)Substantial progress has recently been made in optimizing the management of cancer patients, resulting in major gains in survival and quality of life. Much of this progress has resulted from the serial testing of promising treatment strategies, typically using prospective randomized controlled trials to compare outcomes achieved with the new approach versus the current standard(s) of care. However, there is an ever-expanding list of important questions that are difficult to investigate, particularly with respect to determining the optimal sequencing and combination of proven active agents. With the rapidly growing list of clinical, pathologic and molecular characteristics that promise to predict treatment benefit and/or risk for defined patient subsets, many new questions regarding how best to personalize our approach to treatment selection are emerging. These questions can be investigated in the context of registry-based randomized clinical trials. Recently, the potential of registry-based randomized clinical trials was demonstrated in cardiology, highlighting the ability to rapidly recruit large numbers of patients to a trial addressing an important clinical question, with minimal cost and high external validity. In this review, we discuss the challenges and limitations of conventional clinical trials in multidisciplinary cancer care, describe the potential advantages of registry-based randomized trials, and highlight several registry-based oncology studies that are already underway to demonstrate the feasibility of this approach.
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ItemCirculating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study(PUBLIC LIBRARY SCIENCE, 2021-05)BACKGROUND: In patients with resectable colorectal liver metastases (CRLM), the role of pre- and postoperative systemic therapy continues to be debated. Previous studies have shown that circulating tumor DNA (ctDNA) analysis, as a marker of minimal residual disease, is a powerful prognostic factor in patients with nonmetastatic colorectal cancer (CRC). Serial analysis of ctDNA in patients with resectable CRLM could inform the optimal use of perioperative chemotherapy. Here, we performed a validation study to confirm the prognostic impact of postoperative ctDNA in resectable CRLM observed in a previous discovery study. METHODS AND FINDINGS: We prospectively collected plasma samples from patients with resectable CRLM, including presurgical and postsurgical samples, serial samples during any pre- or postoperative chemotherapy, and serial samples in follow-up. Via targeted sequencing of 15 genes commonly mutated in CRC, we identified at least 1 somatic mutation in each patient's tumor. We then designed a personalized assay to assess 1 mutation in plasma samples using the Safe-SeqS assay. A total of 380 plasma samples from 54 patients recruited from July 2011 to Dec 2014 were included in our analysis. Twenty-three (43%) patients received neoadjuvant chemotherapy, and 42 patients (78%) received adjuvant chemotherapy after surgery. Median follow-up was 51 months (interquartile range, 31 to 60 months). At least 1 somatic mutation was identified in all patients' tumor tissue. ctDNA was detectable in 46/54 (85%) patients prior to any treatment and 12/49 (24%) patients after surgery. There was a median 40.93-fold (19.10 to 87.73, P < 0.001) decrease in ctDNA mutant allele fraction with neoadjuvant chemotherapy, but ctDNA clearance during neoadjuvant chemotherapy was not associated with a better recurrence-free survival (RFS). Patients with detectable postoperative ctDNA experienced a significantly lower RFS (HR 6.3; 95% CI 2.58 to 15.2; P < 0.001) and overall survival (HR 4.2; 95% CI 1.5 to 11.8; P < 0.001) compared to patients with undetectable ctDNA. For the 11 patients with detectable postoperative ctDNA who had serial ctDNA sampling during adjuvant chemotherapy, ctDNA clearance was observed in 3 patients, 2 of whom remained disease-free. All 8 patients with persistently detectable ctDNA after adjuvant chemotherapy have recurred. End-of-treatment (surgery +/- adjuvant chemotherapy) ctDNA detection was associated with a 5-year RFS of 0% compared to 75.6% for patients with an undetectable end-of-treatment ctDNA (HR 14.9; 95% CI 4.94 to 44.7; P < 0.001). Key limitations of the study include the small sample size and the potential for false-positive findings with multiple hypothesis testing. CONCLUSIONS: We confirmed the prognostic impact of postsurgery and posttreatment ctDNA in patients with resected CRLM. The potential utility of serial ctDNA analysis during adjuvant chemotherapy as an early marker of treatment efficacy was also demonstrated. Further studies are required to define how to optimally integrate ctDNA analyses into decision-making regarding the use and timing of adjuvant therapy for resectable CRLM. TRIAL REGISTRATION: ACTRN12612000345886.
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ItemPrognostic significance of postsurgery circulating tumorDNAin nonmetastatic colorectal cancer: Individual patient pooled analysis of three cohort studies(WILEY, 2021-02-15)Studies in multiple solid tumor types have demonstrated the prognostic significance of ctDNA analysis after curative intent surgery. A combined analysis of data across completed studies could further our understanding of circulating tumor DNA (ctDNA) as a prognostic marker and inform future trial design. We combined individual patient data from three independent cohort studies of nonmetastatic colorectal cancer (CRC). Plasma samples were collected 4 to 10 weeks after surgery. Mutations in ctDNA were assayed using a massively parallel sequencing technique called SafeSeqS. We analyzed 485 CRC patients (230 Stage II colon, 96 Stage III colon, and 159 locally advanced rectum). ctDNA was detected after surgery in 59 (12%) patients overall (11.0%, 12.5% and 13.8% for samples taken at 4-6, 6-8 and 8-10 weeks; P = .740). ctDNA detection was associated with poorer 5-year recurrence-free (38.6% vs 85.5%; P < .001) and overall survival (64.6% vs 89.4%; P < .001). The predictive accuracy of postsurgery ctDNA for recurrence was higher than that of individual clinicopathologic risk features. Recurrence risk increased exponentially with increasing ctDNA mutant allele frequency (MAF) (hazard ratio, 1.2, 2.5 and 5.8 for MAF of 0.1%, 0.5% and 1%). Postsurgery ctDNA was detected in 3 of 20 (15%) patients with locoregional and 27 of 60 (45%) with distant recurrence (P = .018). This analysis demonstrates a consistent long-term impact of ctDNA as a prognostic marker across nonmetastatic CRC, where ctDNA outperforms other clinicopathologic risk factors and MAF further stratifies recurrence risk. ctDNA is a better predictor of distant vs locoregional recurrence.
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ItemNo Preview AvailableReal-world outcomes for neoadjuvant capecitabine versus infusional 5-fluorouracil in the treatment of locally advanced rectal cancer(WILEY, 2021-08)BACKGROUND: Neoadjuvant chemoradiation therapy is standard-of-care treatment for locally advanced rectal cancer (LARC). A pathological complete response (pCR) following chemoradiation therapy is an early indicator of treatment benefit and associated with excellent survival outcomes, with capecitabine largely replacing infusional 5-fluorouracil as the choice in routine care of LARC. AIMS: To analyse the uptake of capecitabine usage over time, and on the back of clinical trial data demonstrating equivalence between fluoropyrimidines, confirm that efficacy is maintained in the real-world setting. METHODS: We analysed data from a prospectively maintained colorectal cancer database at three Australian hospitals including patients diagnosed from January 2009 to December 2018. Pathological response was determined as either complete or incomplete and compared for patients receiving 5-FU or capecitabine. RESULTS: A total of 657 patients was analysed, 498 receiving infusional 5-FU and 159 capecitabine. Capecitabine use has markedly increased from approval in 2014 in Australia, now being used in more than 80% of patients. Patient characteristics were similar by treatment, including age, tumour location and pre-treatment stage. pCR was reported in 22/159 (13.8%) of capecitabine-treated patients and 118/380 (23.7%) that received 5-FU (P ≤ 0.01). More capecitabine-treated patients received post-operative oxaliplatin (44.2% vs 6.3%, P < 0.01). Two-year progression-free survival was similar (84.9% vs 88.0%, P = 0.34). CONCLUSIONS: Capecitabine is now the dominantly used neoadjuvant chemotherapy in LARC. Capecitabine use was associated with a lower rate of pCR versus infusional 5-FU, a difference not explained by examined patient or tumour characteristics. Poor treatment compliance with oral therapy in the real-world setting is one possible explanation.
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ItemNo Preview AvailableSimulating Progression-Free and Overall Survival for First-Line Doublet Chemotherapy With or Without Bevacizumab in Metastatic Colorectal Cancer Patients Based on Real-World Registry Data(ADIS INT LTD, 2020-11)BACKGROUND: Simulation models utilizing real-world data have potential to optimize treatment sequencing strategies for specific patient subpopulations, including when conducting clinical trials is not feasible. We aimed to develop a simulation model to estimate progression-free survival (PFS) and overall survival for first-line doublet chemotherapy with or without bevacizumab for specific subgroups of metastatic colorectal cancer (mCRC) patients based on registry data. METHODS: Data from 867 patients were used to develop two survival models and one logistic regression model that populated a discrete event simulation (DES). Discrimination and calibration were used for internal validation of these models separately and predicted and observed medians and Kaplan-Meier plots were compared for the integrated DES. Bootstrapping was performed to correct for optimism in the internal validation and to generate correlated sets of model parameters for use in a probabilistic analysis to reflect parameter uncertainty. RESULTS: The survival models showed good calibration based on the regression slopes and modified Hosmer-Lemeshow statistics at 1 and 2 years, but not for short-term predictions at 0.5 years. Modified C-statistics indicated acceptable discrimination. The simulation estimated that median first-line PFS (95% confidence interval) of 219 (25%) patients could be improved from 175 days (156-199) to 269 days (246-294) if treatment would be targeted based on the highest expected PFS. CONCLUSIONS: Extensive internal validation showed that DES accurately estimated the outcomes of treatment combination strategies for specific subpopulations, with outcomes suggesting treatment could be optimized. Although results based on real-world data are informative, they cannot replace randomized trials.