Adherence Outcomes and Risk Factors Predicting Nonadherence to Active Surveillance in Patients With Stage 1 Testicular Germ Cell Tumors.

PURPOSE: Adherence to active surveillance in patients with stage 1 testicular cancers may be influenced by factors affecting capacity and motivation to attend appointments. The aims of this study were to assess adherence to active surveillance and analyze factors which may impact adherence. PATIENTS AND METHODS: A retrospective cohort study was conducted in patients diagnosed with stage 1 testicular cancer between 2005 and 2020, and managed with active surveillance at 3 institutions in South Western Sydney, Australia. Adherence with active surveillance was followed to 2023 and patients were subsequently classified into 3 groups: "Optimal," "Adequate" or "Loss to follow-up" (LTFU). Factors for adherence were analyzed using multivariable logistic regression. Disease recurrence was analyzed using multivariable Cox regression. RESULTS: In 125 patients, adherence with active surveillance was assessed as "Optimal" in 64 (51%), "Adequate" in 14 (11%), and LTFU in 47 (38%). Multivariable analysis demonstrated that patients had higher odds of being in the "Optimal" or "Adequate" categories if they were from a culturally and linguistically diverse background (OR 4.86, P = .026), nonsmokers (OR 7.63, P = .0002), not employed (OR 4.93, P = .0085), had a partner (OR 2.74, P = .0326), or were diagnosed after June 2016 (OR 5.22, P = .0016). Recurrence occurred in 21 patients (17%). The risk of recurrence increased with the presence of multiple pathological risk factors (HR 5.77, P = .0032), if patients were unemployed (HR 2.57, P = .032), or if they had "Optimal" or "Adequate" adherence (HR 12.74, P = .0136). CONCLUSION: Adherence with active surveillance was poorer in this cohort of stage 1 testicular cancer patients. Patients from culturally and linguistically diverse backgrounds and those who were nonsmokers, unemployed, with a partner, and later date of diagnosis, were more likely to be adherent with active surveillance.

Real-world tolerance and outcomes of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer-Does dose intensity matter?

INTRODUCTION: Fluoropyrimidine and oxaliplatin-based adjuvant chemotherapy delivered as 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX), or capecitabine and oxaliplatin (CAPOX) is the standard of care for resected stage III colon cancer. Without randomized trial data, we compared real-world dose intensity, survival outcomes, and tolerability of these regimens. METHODS: Records of patients treated with FOLFOX or CAPOX in the adjuvant setting for stage III colon cancer across four institutions in Sydney during 2006-2016 were reviewed. The relative dose intensity (RDI) of fluoropyrimidine and oxaliplatin of each regimen, disease-free survival (DFS), overall survival (OS), and incidence of grade ≥2 toxicities were compared. RESULTS: Characteristics of patients receiving FOLFOX (n = 195) and CAPOX (n = 62) were evenly matched. FOLFOX patients had a higher mean RDI for both fluoropyrimidine (85% vs. 78%, p < 0.01) and oxaliplatin (72% vs. 66%, p = 0.06). In spite of a lower RDI, CAPOX patients trended toward a better 5-year DFS (84% vs. 78%, HR = 0.53, p = 0.068) and similar OS (89% vs. 89%, HR = 0.53, p = 0.21) compared to the FOLFOX group. This difference was most pronounced in the high-risk (T4 or N2) group where 5-year DFS was 78% versus 67% (HR = 0.41, p = 0.042). Patients receiving CAPOX experienced more grade ≥2 diarrhea (p = 0.017) and hand-foot syndrome (p < 0.001) but not peripheral neuropathy or myelosuppression. CONCLUSION: In a real-world setting, patients who received CAPOX had similar OS rates when compared to those receiving FOLFOX in the adjuvant setting in spite of lower RDI. In the high-risk population, CAPOX appears to demonstrate a superior 5-year DFS over FOLFOX.

Real-World Outcomes of FLOT versus CROSS Regimens for Patients with Oesophagogastric Cancers.

Introduction: Treatment of oesophageal (OC), gastro-oesophageal junction (GOJ), and gastric cancer (GC) includes either neoadjuvant Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) for OC or GOJ or perioperative 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for OC, GOJ, and GC adenocarcinomas. This study aims to describe the real-world outcomes of patients with GC, GOJ, and OC treated with FLOT or CROSS and identify variables associated with efficacy through exploratory analysis. We also aimed to evaluate the comparison of FLOT and CROSS for the treatment of OC and GOJ adenocarcinomas. Methods: This is a retrospective observational study of patients with locally advanced OC, GOJ, or GC treated with FLOT or CROSS between January 2015 and June 2021 in 5 cancer centres across Sydney, Australia. Long-rank test was used to compare survival estimated between subgroups. Hazard ratios for univariate and multivariate analyses were estimated with Cox proportional regression. Results: The study included 168 patients. The 24-month relapse-free survival (RFS) and overall survival (OS) for FLOT were 59% and 69%, respectively. The median RFS was 29.6 months and median OS was not reached. For CROSS, the 24-month RFS and OS were 55% and 63% with a median RFS and OS of 28.5 and 40.2 months, respectively. There was no difference in OS and RFS between the treatments. FLOT was less tolerable than CROSS with more dose reductions, treatment discontinuation, and clinically relevant grade 3 and 4 toxicity. Neutrophil lymphocyte ratio was associated with survival for both treatments. Conclusion: Similar efficacy outcomes were seen in this real-world population compared to the clinical trials for FLOT and CROSS.

Multigene panel next generation sequencing in metastatic colorectal cancer in an Australian population.

BACKGROUND: Next generation sequencing (NGS) is increasingly used in standard clinical practice to identify patients with potentially actionable mutations. Stratification of NGS mutation tiers is currently based on the European Society of Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT[E]) Tier I-V & X. Allele frequency is also increasingly recognised as an important prognostic tool in advanced cancer. The aim of this study was to determine the genomic mutations in metastatic colorectal cancer (CRC) in an Australian multicultural population and their influence on survival outcomes. METHODS: Next generation sequencing with the 50-gene panel Oncomine Precision Assay™ was used on 180 CRC tissue samples obtained across six Sydney hospitals between June 2021 and March 2022. RESULTS: From 180 samples, 147 (82%) had at least one gene mutation identified with 68 (38%) having two or more concurrent mutations. Tier I variants included RAS wild-type [EI] in 73 (41%) and BRAF V600E [EIA] in 27 (15%). Non-tier I variants include 2 (1%) ERBB2 amplification [EIIB], 26 (15%) PIK3CA hotspot mutations [EIIIA] and 9 (5%) MET focal amplifications [EIIIA]. NGS testing revealed an additional 22% of cases with Tier II & III mutations. 43% of patients also presented with potentially actionable Tier III & IV mutations. Patients with concurrent TP53 and RAS mutations had significantly reduced overall survival (6.1 months versus 21.1 months, p <0.01). High KRAS allele frequency, as defined by those with over 20% variant allele frequency (VAF), also demonstrated reduced overall survival (12.1 months versus 42.9 months, p = 0.04). CONCLUSIONS: In addition to identifying patients with genomic alterations suitable for clinically proven standard of care therapeutic options, the 50 gene NGS panel has significant potential in identifying potentially actionable non-tier 1 mutations and therefore may become future standard clinical practice.

Circulating Tumour Cell Associated MicroRNA Profiles Change during Chemoradiation and Are Predictive of Response in Locally Advanced Rectal Cancer.

Locally advanced rectal cancer (LARC) has traditionally been treated with trimodality therapy consisting of neoadjuvant radiation +/- chemotherapy, surgery, and adjuvant chemotherapy. There is currently a clinical need for biomarkers to predict treatment response and outcomes, especially during neoadjuvant therapy. Liquid biopsies in the form of circulating tumour cells (CTCs) and circulating nucleic acids in particular microRNAs (miRNA) are novel, the latter also being highly stable and clinically relevant regulators of disease. We studied a prospective cohort of 52 patients with LARC, and obtained samples at baseline, during treatment, and post-treatment. We enumerated CTCs during chemoradiation at these three time-points, using the IsofluxTM (Fluxion Biosciences Inc., Alameda, CA, USA) CTC Isolation and detection platform. We then subjected the isolated CTCs to miRNA expression analyses, using a panel of 106 miRNA candidates. We identified CTCs in 73% of patients at baseline; numbers fell and miRNA expression profiles also changed during treatment. Between baseline and during treatment (week 3) time-points, three microRNAs (hsa-miR-95, hsa-miR-10a, and hsa-miR-16-1*) were highly differentially expressed. Importantly, hsa-miR-19b-3p and hsa-miR-483-5p were found to correlate with good response to treatment. The latter (hsa-miR-483-5p) was also found to be differentially expressed between good responders and poor responders. These miRNAs represent potential predictive biomarkers, and thus a potential miRNA-based treatment strategy. In this study, we demonstrate that CTCs are present and can be isolated in the non-metastatic early-stage cancer setting, and their associated miRNA profiles can potentially be utilized to predict treatment response.

Haematological and nutritional prognostic biomarkers for patients receiving CROSS or FLOT.

Background: Neoadjuvant carboplatin and paclitaxel with radiotherapy (CROSS) and perioperative docetaxel, oxaliplatin, calcium folinate and fluorouracil (FLOT) are widely used for gastric (GC), gastro-oesophageal junction (GOJ) and oesophageal cancers (OC). Prognostic and predictive markers for response and survival outcomes are lacking. This study evaluates dynamic neutrophil-lymphocyte ratios (NLR), platelet-lymphocyte ratios (PLR), albumin and body mass index (BMI) as predictors of survival, response and toxicity. Methods: This multi-centre retrospective observational study across 5 Sydney hospitals included patients receiving CROSS or FLOT from 2015 to 2021. Haematological results and BMI were recorded at baseline and pre-operatively, and after adjuvant treatment for FLOT. Toxicities were also recorded. An NLR ≥2 and PLR ≥200 was used to stratify patients. Univariate and multivariate analyses were performed to determine predictors of overall survival (OS), disease free survival (DFS), rates of pathological complete response (pCR) and toxicity. Results: One hundred sixty-eight patients were included (95 FLOT, 73 FLOT). A baseline NLR ≥2 was predictive for worse DFS (HR 2.78, 95% CI: 1.41-5.50, P<0.01) and OS (HR 2.90, 95% CI: 1.48-5.67, P<0.01). Sustained elevation in NLR was predictive for DFS (HR 1.54, 95% CI: 1.08-2.17, P=0.01) and OS (HR 1.65, 95% CI: 1.17-2.33, P<0.01). An NLR ≥2 correlated with worse pCR rates (16% for NLR ≥2, 48% for NLR <2, P=0.04). A baseline serum albumin <33 was predictive of worse DFS and OS with a HR of 6.17 (P=0.01) and 4.66 (P=0.01) respectively. Baseline PLR, BMI, and dynamic changes in these markers were not associated with DFS, OS or pCR rates. There was no association of the aforementioned variables with toxicity. Conclusions: This demonstrates that a high inflammatory state represented by an NLR ≥2, both at baseline and sustained, is prognostic and predictive of response in patients receiving FLOT or CROSS. Baseline hypoalbuminaemia is predictive of poorer outcomes.

Health-Related Quality of Life during Chemoradiation in Locally Advanced Rectal Cancer: Impacts and Ethnic Disparities.

Aims: There is limited data on health-related quality of life (HRQoL) in locally advanced rectal cancer. We assessed HRQoL before, during and after neoadjuvant chemoradiation, correlated this to corresponding clinician-reported adverse events (CR-AEs) and explored disparities between patients of Asian ethnicity versus Caucasians. Correlation between HRQoL and treatment response was also assessed. Methods: A consecutive sample of patients was recruited. HRQoL was assessed with the EORTC QLQ-C30 before chemoradiation, week three of chemoradiation and one-week pre-surgery. Clinical variables including CR-AEs were recorded at these time-points. Patients self-reported socio-demographic variables. Treatment response was assessed by the tumour regression grade. HRQoL data were analysed with multilevel models. Results: Fifty-one patients were recruited. HRQoL completion rates were ≥86%. Cognitive and role functioning worsened significantly during treatment. Emotional, role and social functioning improved significantly at pre-surgery. Fatigue and nausea/vomiting worsened during treatment while fatigue, appetite loss, diarrhoea and financial difficulties improved from treatment to pre-surgery. Almost 30% of the cohort were Asian ethnicity. Differences were found in multiple HRQoL domains between Asians and Caucasians, with Asians faring worse. Significant differences were evident in physical, role and cognitive functioning, and in seven out of the 8 symptom scales. The correlation between patient-reported outcomes and clinician-reported outcomes was weak, with diarrhoea having the strongest correlation (r = 0.58). Vomiting during treatment correlated with poor response, whilst baseline constipation correlated with good response. Conclusion: Chemoradiation for locally advanced rectal cancer affects multiple HRQoL domains. Our findings highlight the importance of psychological aspects of treatment. Significant differences were identified between the Asian and Caucasian populations, with Asians consistently performing worse. Poor correlations between patient and clinician reporting strongly support the inclusion of patient-reported outcomes in clinical studies. HRQoL domains of vomiting and constipation are potential biomarkers of treatment response.

Decline in Left Ventricular Ejection Fraction Following Anthracyclines Predicts Trastuzumab Cardiotoxicity.

OBJECTIVES: The aim of CATS (Cardiotoxicity of Adjuvant Trastuzumab Study) was to prospectively assess clinical, biochemical, and genomic predictors of trastuzumab-related cardiotoxicity (TRC). BACKGROUND: Cardiac dysfunction is a common adverse effect of trastuzumab. Studies to identify predictive biomarkers for TRC have enrolled heterogeneous populations and yielded mixed results. METHODS: A total of 222 patients with early-stage human epidermal growth factor receptor 2-positive breast cancer scheduled to receive adjuvant anthracyclines followed by 12 months of trastuzumab were prospectively recruited from 17 centers. Left ventricular ejection fraction (LVEF), troponin T, and N-terminal prohormone of brain natriuretic peptide were measured at baseline, post-anthracycline, and every 3 months during trastuzumab. Germline single-nucleotide polymorphisms in ERBB2, FCGR2A, and FCGR3A were analyzed. TRC was defined as symptomatic heart failure; cardiac death, arrhythmia, or infarction; a decrease in LVEF of >15% from baseline; or a decrease in LVEF of >10% to <50%. RESULTS: TRC occurred in 18 of 217 subjects (8.3%). Lower pre-anthracycline LVEF and greater interval decline in LVEF from pre- to post-anthracycline were each associated with TRC on multivariate analyses (odds ratio: 3.9 [p = 0.0001] and 7.9 [p < 0.0001] for a 5% absolute change in LVEF). Higher post-anthracycline N-terminal prohormone of brain natriuretic peptide level was associated with TRC on univariate but not multivariate analyses. There were no associations between troponin T or ERBB2/FGCR polymorphisms and TRC. Baseline LVEF and LVEF change post-anthracycline were used to generate a "low-risk TRC score" to identify patients with low TRC incidence. CONCLUSIONS: Low baseline LVEF and greater LVEF decline post-anthracycline were both independent predictors of TRC. The other biomarkers did not further improve the ability to predict TRC. (Cardiotoxicity of Adjuvant Trastuzumab [CATS]; NCT00858039).

Precision Medicine for Advanced Pancreas Cancer: The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) Trial.

PURPOSE: Personalized medicine strategies using genomic profiling are particularly pertinent for pancreas cancer. The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial was initially designed to exploit results from genome sequencing of pancreatic cancer under the auspices of the International Cancer Genome Consortium (ICGC) in Australia. Sequencing revealed small subsets of patients with aberrations in their tumor genome that could be targeted with currently available therapies. EXPERIMENTAL DESIGN: The pilot stage of the IMPaCT trial assessed the feasibility of acquiring suitable tumor specimens for molecular analysis and returning high-quality actionable genomic data within a clinically acceptable timeframe. We screened for three molecular targets: HER2 amplification; KRAS wild-type; and mutations in DNA damage repair pathways (BRCA1, BRCA2, PALB2, ATM). RESULTS: Tumor biopsy and archived tumor samples were collected from 93 patients and 76 were screened. To date 22 candidate cases have been identified: 14 KRAS wild-type, 5 cases of HER2 amplification, 2 mutations in BRCA2, and 1 ATM mutation. Median time from consent to the return of validated results was 21.5 days. An inability to obtain a biopsy or insufficient tumor content in the available specimen were common reasons for patient exclusion from molecular analysis while deteriorating performance status prohibited a number of patients from proceeding in the study. CONCLUSIONS: Documenting the feasibility of acquiring and screening biospecimens for actionable molecular targets in real time will aid other groups embarking on similar trials. Key elements include the need to better prescreen patients, screen more patients, and offer more attractive clinical trial options.

Migrant health in cancer: outcome disparities and the determinant role of migrant-specific variables.

BACKGROUND: Multiethnic societies face challenges in delivering evidence-based culturally competent health care. This study compared health-related quality of life and psychological morbidity in a hospital-based sample of first-generation migrants and Australian-born Anglo cancer patients, controlling for potential confounders related to migrant status. Further, it explored the relative contribution of ethnicity versus migrant-related variables. METHODS: Eligible participants, recruited via 16 oncology clinics in Australia, included those over the age of 18, diagnosed with cancer (any type or stage) within the previous 12 months and having commenced treatment at least 1 month previously. RESULTS: In total, 571 migrant patients (comprising 145 Arabic, 248 Chinese, and 178 Greek) and a control group of 274 Anglo-Australian patients participated. In multiple linear regression models adjusted for age, sex, education, marital status, socioeconomic status, time since diagnosis, and type of cancer, migrants had clinically significantly worse health-related quality of life (HRQL; 3.6-7.3 points on FACT-G, p < .0001), higher depression and anxiety (both p < .0001), and higher incidence of clinical depression (p < .0001) and anxiety (p = .003) than Anglo-Australians. Understanding the health system (p < .0001 for each outcome) and difficulty communicating with the doctor (p = .04 to .0001) partially mediated the impact of migrancy. In migrant-only analyses, migrant-related variables (language difficulty and poor understanding of the health system), not ethnicity, predicted outcomes. CONCLUSION: Migrants who develop cancer have worse psychological and HRQL outcomes than Anglo-Australians. Potential targets for intervention include assistance in navigating the health system, translated information, and cultural competency training for health professionals.

Uncommon manifestations of Listeria monocytogenes infection.

BACKGROUND: Listeria monocytogenes causes gastroenteritis, meningitis and bacteraemia in immunocompromised, pregnant patients, the elderly as well in immunocompetent patients. Focal infections with this organism are uncommon, especially in sporadic (non-outbreak) setting, require high index of suspicion and are challenging to diagnose. We present 3 cases of Listeria monocytogenes presenting as focal infections to our hospitals, all of which are the first reported cases from Australia. CASE PRESENTATION: Three unrelated cases of unique focal infections caused by Listeria monocytogenes are presented. 1) A 73 year old Caucasian lady on immunosuppression for colorectal cancer presented with prosthetic knee joint septic arthritis, 2) An 83 year old Caucasian man presented with prosthetic vascular graft infection and 3) A 60 year old Asian man with perianal abscess. Except for case 1, the other cases had a prolonged duration of symptoms on presentation. Listeria was not thought to be causative organism in any of these cases until microbiological specimens isolated the organism. Matrix Associated Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) assisted in making an earlier diagnosis of the infection in all three cases. All of these patients had Listeria monocytogenes isolated from clinical specimens. They were managed with antibiotics and surgery with favourable outcomes. Public health investigations to determine any dietary association were done, however no intervention was thought to be necessary in any of the cases except provide dietary advice. The first two cases highlight the importance of microbiological sampling in serious infections for definitive antibiotic therapy to be administered. CONCLUSION: Sporadic focal infections with Listeria occur infrequently and are often not diagnosed till culture results from microbiological specimens become available. Dietary history should be an important aspect of thorough clinical history and food consumption advice is crucial in immunocompromised patients on similar lines as given to pregnant women about listeriosis.

Chemotherapy in rectal cancer: variation in utilization and development of an evidence-based benchmark rate of optimal chemotherapy utilization.

BACKGROUND: Published chemotherapy utilization rates for rectal cancer show considerable variation. Optimal chemotherapy utilization rates can serve as benchmarks to assess the quality of cancer care. The purpose of this study was to determine the optimal proportion of patients with rectal cancer who should receive chemotherapy at least once. PATIENTS AND METHODS: An optimal chemotherapy utilization tree was constructed using indications for chemotherapy identified from evidence-based treatment guidelines. Epidemiologic data were merged with treatment indications to calculate an optimal chemotherapy utilization rate; this rate was compared with reported actual rates of chemotherapy utilization. RESULTS: Chemotherapy is indicated at least once in 64% of patients with rectal cancer. Although the actual (Australian and United States data) and optimal utilization rates are comparable for patients presenting in stages II or III rectal cancer, actual utilization rates are higher than the optimal for stage I and lower than optimal for patients presenting in stage IV rectal cancer. CONCLUSION: Chemotherapy may be under-utilized in the initial management of patients presenting with metastatic rectal cancer.

Estimation of an optimal chemotherapy utilisation rate for colon cancer: an evidence-based benchmark for cancer care.

BACKGROUND: Optimal chemotherapy (CT) utilisation rates can serve as benchmarks to assess the quality of cancer care. This study aims to determine the optimal proportion of patients with colon cancer that should receive chemotherapy at least once. METHODS: An optimal chemotherapy utilisation tree was constructed using indications for chemotherapy identified from evidence-based treatment guidelines. Data on the proportion of patient and tumour-related attributes for which chemotherapy was indicated were obtained and merged with the treatment indications to calculate an optimal chemotherapy utilisation rate (CTU rate). This optimal rate was compared with reported actual rates of chemotherapy utilisation. RESULTS: Chemotherapy is indicated at least once in 55% of patients with colon cancer. While 89% of colon cancer patients presenting with Stage IV disease should optimally receive chemotherapy, 38-52% actually received chemotherapy as part of their initial treatment. CONCLUSION: The optimal chemotherapy utilisation rate can serve as an evidence-based benchmark in the planning and evaluation of chemotherapy services. Chemotherapy may be under-utilised in the initial management of patients presenting with metastatic colon cancer.