Treatment and outcomes of metastatic colorectal cancer patients in public and private hospitals: results from the South Australian Metastatic Colorectal Cancer Registry.

BACKGROUND: Studies have reported significant differences in baseline characteristics and outcomes of metastatic colorectal cancer (mCRC) patients when managed in private versus public hospitals. AIMS: To compare disease, treatment and survival outcomes of patients with mCRC in public versus private hospitals in South Australia (SA). METHODS: Analysis of prospectively collected data from the SA mCRC Registry. Patterns of care and outcome data according to location of care and socioeconomic status based on Index of Relative Socio-Economic Advantage and Disadvantage were analysed. RESULTS: A total of 3470 patients' data was analysed during February 2006-January 2015. The majority (70%) of patients received treatment in public hospitals. Patients in the upper 50% for Index of Relative Socio-Economic Advantage and Disadvantage score were more likely to receive treatment at a private hospital (41.2% vs 21.56%) compared to <50%. Public patients had higher burden of disease (10.49% vs 7.41%, P = 0.005). Public patients received less treatment compared to the private patients (odds ratio = 0.48 (0.38-0.61), P = 0.01) and rates of surgical resections were lower in public patients. After adjusting for the covariates, public patients survive 1.33 months (P = 0.025) shorter than private patients with follow-up time of 5 years. Patients receiving metastasectomy and more than three lines of treatment were shown to have the greatest survival benefit. CONCLUSION: Public patients have a higher burden of disease and in comparison are less likely to receive systemic therapy and have lower survival than patients treated in private hospitals.

A Pilot Study of Self-Management-based Nutrition and Physical Activity Intervention in Cancer Survivors.

Exercise and a healthy diet are beneficial after cancer, but are not uniformly adopted by cancer survivors. This study reports on the feasibility, acceptability, and effectiveness of a self-management-based nutrition and exercise intervention for Australian cancer survivors. Adult survivors (n  =  25) during curative chemotherapy (stratum 1[S1]; n  =  11) or post-treatment (stratum 2 [S2]; n  =  14) were recruited prospectively from a single center. The Flinders Living Well Self-Management Program™ (FLW Program) was utilized to establish patient-led nutrition and exercise goals and develop a tailored 12-wk intervention plan. Fortnightly reviews occurred with assessments at baseline, 6 and 12 wk. A recruitment and retention rate of 38% and 84% were observed. Both strata maintained total skeletal muscle mass. Small reductions in body mass index, hip circumference, and percentage body fat, and small increases in hand grip strength and exercise capacity among subjects in both strata were observed. No significant differences were observed between strata; however, significant increases in exercise capacity and global health status for S2 were observed from baseline to 12 wk. FLW Program is a feasible mode of delivering nutrition and exercise intervention to cancer survivors and it appears that there are no barriers to implementing this program early during chemotherapy. Hence, the additive effect of gains achieved over a longer duration is promising and this should be explored in randomized controlled trials adequately powered to observe clinically and statistically significant improvements in relevant outcomes.

Survival improvements associated with access to biological agents: Results from the South Australian (SA) metastatic colorectal cancer (mCRC) registry.

Background Randomized controlled trials evaluating biological therapy have shown improvements in survival from metastatic colorectal cancer (mCRC). Subjects in the trials represent a selected proportion of mCRC patients. We have the potential to assess the impact of biological therapy on mCRC outcomes, particularly the effect of bevacizumab, from a population-based clinical registry by comparing two time cohorts with differences in therapy accessibility. Material and methods A retrospective cohort study was performed by analyzing the South Australian (SA) mCRC registry data based on diagnosis in two time periods: 1 February 2006-31 May 2009 (Cohort A) versus 1 June 2009-30 June 2014 (Cohort B). The demarcation for these cohorts was chosen to reflect the change in accessibility of bevacizumab from July 2009. Results Between February 2006 and June 2014, 3308 patients were identified through the SA mCRC registry: 1464 (44%) in Cohort A and 1844 (56%) in Cohort B. 61 and 59% patients in Cohort A and B, respectively received systemic therapy (p = 0.26). Major differences in clinical characteristics were: biological therapy use 18 versus 33% (p < 0.001) and clinical trial enrolment 12 versus 7% (p < 0.001). Uptake of bevacizumab was: first-line 9 versus 42% and second-line 6 versus 16%. Median overall survival (mOS) for the entire group was: 13.1 versus 17.1 months (HR 0.80; 95% CI 0.74-0.87). Evaluation restricted to patients receiving systemic therapy was 20.5 versus 25.2 months (HR 0.80; 95% CI 0.72-0.89). Multivariate analysis indicated that biological therapy and Cohort B were associated with improved mOS. Conclusion The expected rise in bevacizumab administration was observed in Cohort B. Its use in first-line therapy remained relatively low even after the reimbursement, potentially reflecting real world practice where comorbidities, primary in-situ and age may contraindicate its use. mOS improvement over time was attributed to increased access to biological therapy, especially bevacizumab and possibly advance in peri-operative and supportive care.

Comparable survival outcome of metastatic colorectal cancer in Indigenous and non-Indigenous patients: Retrospective analysis of the South Australian metastatic colorectal cancer registry.

OBJECTIVE: This study aims to investigate disparities in demographics, disease characteristics, treatment and overall survival between South Australian (SA) Indigenous and non-Indigenous patients with metastatic colorectal cancer (mCRC). DESIGN: This employs a retrospective population study using the SA mCRC registry. SETTING: The SA mCRC registry identifies mCRC patients from hospital encounters, histopathology reports, medical oncology letters, clinician notification, attendances at multidisciplinary meetings and death audits by the SA Cancer Registry. PARTICIPANTS: A total of 2865 adult mCRC patients including 14 Indigenous patients were identified through the SA mCRC registry between February 2006 and August 2013. Patients were linked to the SA Cancer Registry to obtain Indigenous status. MAIN OUTCOME MEASURES: Demographic, disease and treatment characteristics were compared using Chi-squared test and t-test; while overall survival defined as time to any cause of death was analysed using Cox regression. RESULTS: No difference was observed for clinical characteristics, except for a higher proportion of Indigenous patients receiving chemotherapy (85.7% versus 58.5%; P = 0.04). The rate of liver surgery was similar across the two groups (21.0% versus 15.1%; P = 0.40). The median overall survivals were equivalent (11.9 months versus 15.1 months; hazard ratio = 1.00; 95% confidence interval for hazard ratio, 0.54-1.86). CONCLUSIONS: Clinical characteristics and survival outcomes were similar between Indigenous and non-Indigenous patients captured on the SA mCRC registry, and outcome of those who have an access to comprehensive cancer care appeared independent of Indigenous status and in line with large clinical trials. Underestimation of Indigenous cases due to their lower utilisation of cancer service could not be excluded and ultimately the accurate reporting of these patients is crucial.

Safety, Efficacy, and Pharmacokinetics of SHR-A1811, a Human Epidermal Growth Factor Receptor 2-Directed Antibody-Drug Conjugate, in Human Epidermal Growth Factor Receptor 2-Expressing or Mutated Advanced Solid Tumors: A Global Phase I Trial.

PURPOSE: SHR-A1811 is an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab, a cleavable linker, and a topoisomerase I inhibitor payload. We assessed the safety, tolerability, antitumor activity, and pharmacokinetics of SHR-A1811 in heavily pretreated HER2-expressing or mutated advanced solid tumors. METHODS: This global, multi-center, first-in-human, phase I trial was conducted at 33 centers. Patients who had HER2-expressing or mutated unresectable, advanced, or metastatic solid tumors and were refractory or intolerant to standard therapies were enrolled. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg once every 3 weeks. The primary end points were dose-limiting toxicity, safety, and the recommended phase II dose. RESULTS: From September 7, 2020, to February 27, 2023, 307 patients who had undergone a median of three (IQR, 2-5) previous treatment regimens in the metastatic setting received SHR-A1811 treatment. As of data cutoff (February 28, 2023), one patient from the 6.4 mg/kg group experienced dose-limiting toxicities (pancytopenia and colitis). The most common grade 3 or higher adverse events (AEs) included decreased neutrophil count (119 [38.8%]) and decreased WBC count (70 [22.8%]). Interstitial lung disease occurred in only eight (2.6%) patients. Serious AEs and deaths occurred in 70 (22.8%) and 13 (4.2%) patients, respectively. SHR-A1811 led to objective responses in 59.9% (184/307) of all patients, 76.3% (90/118) of HER2-positive breast cancer, 60.4% (55/91) of HER2 low-expressing breast cancer, and 45.9% (39/85 with evaluable tumor responses) of the 98 nonbreast tumors. CONCLUSION: SHR-A1811 exhibited acceptable tolerability, promising antitumor activity, and a favorable pharmacokinetic profile in heavily pretreated advanced solid tumors. The recommended phase II dose of 4.8 or 6.4 mg/kg was selected for various tumor types.

Detection of methylated BCAT1 and IKZF1 after curative-intent treatment as a prognostic indicator for colorectal cancer recurrence.

BACKGROUND: The risk of recurrence after completion of curative-intent treatment of colorectal cancer (CRC) is hard to predict. Post-treatment assaying for circulating tumor DNA (ctDNA) is an encouraging approach for stratifying patients for therapy, but the prognostic value of this approach is less explored. This study aimed to determine if detection of methylated BCAT1 and IKZF1 following completion of initial treatment identified patients with a poorer recurrence-free survival (RFS). METHODS: 142 CRC stage I-III cases with at least 2 years of follow up (unless recurrence was evident sooner) and a methylated BCAT1/IKZF1 test result between 2 weeks and 12 months after completion of initial treatment were eligible for study inclusion. The association between BCAT1/IKZF1 and RFS was assessed by the log-rank (Mantel-Cox) method. Cox proportional hazard regression analysis was used for multivariable survival analysis. RESULTS: Thirty-three (23.2%) had recurrence at a median 1.6y (interquartile range: 0.8-2.4). Methylated BCAT1/IKZF1 was detected in 19 of the 142 patients (13.4%) and was associated with a significant risk of recurrence (hazard ratio [HR] 5.7, 95%CI: 1.9-17.3, p = 0.002). Three-year RFS for patients with or without detectable methylated BCAT1/IKZF1 was 56.5% and 83.3%, respectively. Multivariable analysis showed that detection of methylated BCAT1/IKZF1 (HR = 2.6, p = 0.049) and site of the primary tumor (HR = 4.2, p = 0.002) were the only significant prognostic indicators of poor RFS. CONCLUSIONS: BCAT1/IKZF1 methylation testing after curative-intent treatment is an independent prognostic indicator for RFS and identifies a subgroup at high risk. Personalized surveillance is warranted for patients with these ctDNA biomarkers detectable after curative-intent treatment.

Survival outcomes for patients with colorectal cancer with synchronous liver only metastasis.

BACKGROUND: Colorectal cancer with synchronous liver-only metastasis is managed with a multimodal approach, however, optimal sequencing of modalities remains unclear. METHODS: A retrospective review of all consecutive rectal or colon cancer cases with synchronous liver-only metastasis was conducted from the South Australian Colorectal Cancer Registry from 2006 to 2021. This study aimed to investigate how order and type of treatment modality affects overall survival. RESULTS: Data of over 5000 cases were analysed (n = 5244), 1420 cases had liver-only metastasis. There were a greater number of colon than rectal primaries (N = 1056 versus 364). Colonic resection was the preferred initial treatment for the colon cohort (60%). In the rectal cohort, 30% had upfront resection followed by 27% that had chemo-radiotherapy as 1st line therapy. For the colon cohort, there was an improved 5-year survival with surgical resection as initial treatment compared to chemotherapy (25% versus 9%, P < 0.001). In the rectal cohort, chemo-radiotherapy as the initial treatment was associated with an improved 5-year survival compared to surgery or chemotherapy (40% versus 26% versus 19%, P = 0.0015). Patients who were able to have liver resection had improved survival, with 50% surviving over 5 years compared to 12 months in the non-resected group (P < 0.001). Primary rectal KRAS wildtype patients who underwent liver resection and received Cetuximab had significantly worse outcomes compared to KRAS wildtype patients who did not (P = 0.0007). CONCLUSIONS: Where surgery is possible, resection of liver metastasis and primary tumour improved overall survival. Further research is required on the use of targeted treatments in patients undergoing liver resection.

The Management of Unresectable, Advanced Gastrointestinal Stromal Tumours.

Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal tract mesenchymal tumours. Tyrosine kinase inhibitors (TKIs) have transformed the management of advanced GIST. Imatinib was the first TKI to gain approval as management for patients with advanced GIST, establishing a new standard of care. Since then, as a result of several trials including the GRID and INVICTUS studies, we now have five lines of approved targeted therapy, including imatinib, sunitinib, regorafenib, ripretinib and avapritinib for the treatment of unresectable, advanced GISTs. In this review, the Australasian Gastrointestinal Trials Group (AGITG) provide an overview of the key trials that have changed clinical practice, discuss the molecular drivers of GISTs, the importance of molecular testing and directing therapy according to molecular targets, as well as future strategies in the management of advanced GISTs.

Update on optimal management for pancreatic cancer: expert perspectives from members of the Australasian Gastrointestinal Trials Group (AGITG) with invited international faculty.

INTRODUCTION: Pancreatic cancer remains a challenging malignancy due to the high proportion of patients diagnosed at advanced stages and the limited treatment options. This article discusses recent evidence in the management of both localized and advanced pancreatic cancer and offers an expert opinion on current best practice. AREAS COVERED: For patients with localized disease, the evidence for adjuvant chemotherapy is discussed as well as emerging neoadjuvant approaches for resectable, borderline resectable, and locally advanced disease. Advances in metastatic disease are discussed including cytotoxic chemotherapy, targeted therapies, and the role of genomic testing to identify patients with molecular alterations. Reviewed literature included journal publications, abstracts presented at major international oncology meetings, and ongoing clinical trials databases. EXPERT OPINION: Pancreatic cancer is a devastating diagnosis and despite recent advances has a very poor prognosis. Only a minority of patients, 20%, are diagnosed with potentially curable disease. The shifting paradigm toward neoadjuvant therapy may improve resectability and survival rates; however, robust evidence is required. Thus far, there has only been limited progress in advanced stage disease. Genomic testing may potentially identify more treatment targets although limited to small subgroups.

Management of early-stage gastro-esophageal cancers: expert perspectives from the Australasian Gastrointestinal Trials Group (AGITG) with invited international faculty.

Introduction: A multimodal approach in operable early-stage oesophago-gastric (OG) cancer has evolved in the last decade, leading to improvement in overall outcomes.Areas covered: A review of the published literature and conference abstracts was undertaken on the topic of optimal adjunctive chemotherapy or chemoradiotherapy in early-stage OG cancers. This review article focuses on the current evidence pertaining to neoadjuvant and perioperative strategies in curable OG cancers including the evolving landscape of immunotherapy and targeted drugs in this setting.Expert commentary: Adjunctive therapies in the form of preoperative chemo-radiotherapy (CRT) or chemotherapy and perioperative chemotherapy over surgery alone improve outcomes in patients with operable OG cancer. Although there are variations in practice around the world, a multi-disciplinary approach to patient care is of paramount importance. Immunotherapy and on treatment functional imaging are two examples of emerging strategies to improve the outcome for early-stage patients. A better understanding of the molecular biology of this disease may help overcome the problem of tumor heterogeneity and enable more rationally designed and targeted therapeutic interventions in the future.

Uncommon Anal Neoplasms.

Uncommon neoplasms of the anal canal are associated with significant diagnostic dilemma in clinical practice and a high index of suspicion and pathologic expertise is needed. The incidence is likely to increase, particularly of small, incidental lesions found because of use of more frequent colonoscopy and high-definition MRI. Generally treatment follows that of the same histologic subtype in other anatomic location. Surgical intervention is the cornerstone for cure in early/localized disease; however, removal of the anal canal is associated with significant morbidities and quality of life issues. A centralized global registry/database established under the auspices of the International Rare Care Initiative collaboration would be useful.

Metastatic Colorectal Cancer in Young Adults: A Study From the South Australian Population-Based Registry.

BACKGROUND: Colorectal cancer (CRC) is a common malignancy. There is growing evidence that CRC incidence is increasing in the younger population. There is controversy surrounding the prognosis of young patients with CRC. In this study we reviewed Australian patients with metastatic CRC (mCRC) who were younger than 40 years of age at the time of diagnosis of metastatic disease. To our knowledge this is the first study to focus on this age group with mCRC. PATIENTS AND METHODS: This was a retrospective study using data from the South Australian Metastatic Colorectal Cancer database. We compared patient and disease characteristics, management approaches, and outcomes for age groups < 40 and ≥ 40. A multivariate Cox proportional hazards model was fitted to compare the survival outcomes (death from all causes) between the 2 groups. RESULTS: From 3318 patients, 46 (1.4%) were younger than 40 years of age. In a comparison of patients in the younger than 40-year-old group with the older group, a greater proportion had synchronous metastatic disease (80.4% vs. 64.4%, respectively; P = .04) and disease originating from the left colon (71.7% vs. 61.7%, respectively; P = .035); also a larger proportion in the younger than 40-year-old group received chemotherapy compared with the older group (82.6% vs. 58.7%, respectively; P < .01). In the adjusted multivariate model, survival was not significantly different between the 2 groups (hazard ratio, 0.81; 95% confidence interval, 0.56-1.16; log rank P = .25). CONCLUSION: Young-onset mCRC patients, when defined as aged younger than 40 years, have equivalent survival compared with their older counterparts. This is despite differences in disease characteristics and management approach between the 2 groups.