Search

Background Data suggest selective internal radiotherapy (SIRT) in third-line or subsequent therapy for metastatic colorectal cancer has clinical benefit in patients with colorectal liver metastases with liver-dominant disease after chemotherapy. The FOXFIRE, SIRFLOX, and FOXFIRE-Global randomised studies evaluated the efficacy of combining first-line chemotherapy with SIRT using yttrium-90 resin microspheres in patients with metastatic colorectal cancer with liver metastases. The studies were designed for combined analysis of overall survival. Methods FOXFIRE, SIRFLOX, and FOXFIRE-Global were randomised, phase 3 trials done in hospitals and specialist liver centres in 14 countries worldwide (Australia, Belgium, France, Germany, Israel, Italy, New Zealand, Portugal, South Korea, Singapore, Spain, Taiwan, the UK, and the USA). Chemotherapy-naive patients with metastatic colorectal cancer (WHO performance status 0 or 1) with liver metastases not suitable for curative resection or ablation were randomly assigned (1: 1) to either oxaliplatin-based chemotherapy (FOLFOX: leucovorin, fluorouracil, and oxaliplatin) or FOLFOX plus single treatment SIRT concurrent with cycle 1 or 2 of chemotherapy. In FOXFIRE, FOLFOX chemotherapy was OxMdG (oxaliplatin modified de Gramont chemotherapy; 85 mg/m(2) oxaliplatin infusion over 2 h, L-leucovorin 175 mg or D,L-leucovorin 350 mg infusion over 2 h, and 400 mg/m(2) bolus fluorouracil followed by a 2400 mg/m(2) continuous fluorouracil infusion over 46 h). In SIRFLOX and FOXFIRE-Global, FOLFOX chemotherapy was modified FOLFOX6 (85 mg/m(2) oxaliplatin infusion over 2 h, 200 mg leucovorin, and 400 mg/m(2) bolus fluorouracil followed by a 2400 mg/m(2) continuous fluorouracil infusion over 46 h). Randomisation was done by central minimisation with four factors: presence of extrahepatic metastases, tumour involvement of the liver, planned use of a biological agent, and investigational centre. Participants and investigators were not masked to treatment. The primary endpoint was overall survival, analysed in the intention-to-treat population, using a two-stage meta-analysis of pooled individual patient data. All three trials have completed 2 years of follow-up. FOXFIRE is registered with the ISRCTN registry, number ISRCTN83867919. SIRFLOX and FOXFIRE-Global are registered with ClinicalTrials.gov, numbers NCT00724503 (SIRFLOX) and NCT01721954 (FOXFIRE-Global). Findings Between Oct 11, 2006, and Dec 23, 2014, 549 patients were randomly assigned to FOLFOX alone and 554 patients were assigned FOLFOX plus SIRT. Median follow-up was 43.3 months (IQR 31.6-58.4). There were 411 (75%) deaths in 549 patients in the FOLFOX alone group and 433 (78%) deaths in 554 patients in the FOLFOX plus SIRT group. There was no difference in overall survival (hazard ratio [HR] 1.04, 95% CI 0.90-1.19; p=0.61). The median survival time in the FOLFOX plus SIRT group was 22.6 months (95% CI 21.0-24.5) compared with 23.3 months (21.8-24.7) in the FOLFOX alone group. In the safety population containing patients who received at least one dose of study treatment, as treated, the most common grade 3-4 adverse event was neutropenia (137 [24%] of 571 patients receiving FOLFOX alone vs 186 (37%) of 507 patients receiving FOLFOX plus SIRT). Serious adverse events of any grade occurred in 244 (43%) of 571 patients receiving FOLFOX alone and 274 (54%) of 507 patients receiving FOLFOX plus SIRT. 10 patients in the FOLFOX plus SIRT group and 11 patients in the FOLFOX alone group died due to an adverse event; eight treatment-related deaths occurred in the FOLFOX plus SIRT group and three treatment-related deaths occurred in the FOLFOX alone group. Interpretation Addition of SIRT to first-line FOLFOX chemotherapy for patients with liver-only and liver-dominant metastatic colorectal cancer did not improve overall survival compared with that for FOLFOX alone. Therefore, early use of SIRT in combination with chemotherapy in unselected patients with metastatic colorectal cancer cannot be recommended. To further define the role of SIRT in metastatic colorectal cancer, careful patient selection and studies investigating the role of SIRT as consolidation therapy after chemotherapy are needed. Copyright (C) The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.

Background Pain management can be challenging in frail older people with cancer due to drug–drug interactions and heightened susceptibility to adverse drug events. Objective To investigate the relationship between analgesic use and pain by frailty status in older outpatients with cancer. Methods A total of 385 consecutive patients aged 70 years and over who presented to an outpatient oncology clinic between January 2009 and July 2010 completed structured assessments of analgesic use (opioids, paracetamol or non-steroidal anti-inflammatory drugs), pain (10-point visual analogue scale) and clinical factors. Frailty was derived using modified Fried’s frailty phenotype. Logistic regression was used to compute adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) for the relationship between analgesic use and pain for each frailty group (robust, pre-frail or frail). Results For robust outpatients (n = 101), there was weak evidence for a 30 % relative increase in the adjusted odds of analgesic use between outpatients who differed by one unit of pain score (95 % CI 0.995−1.71, p = 0.0532). For pre-frail outpatients (n = 190), there was evidence for a negative quadratic relationship (adjusted OR for the quadratic coefficient: 0.952, 95 % CI 0.910−0.993, p = 0.0244). For frail outpatients (n = 94), there was an 8 % relative increase in the adjusted odds of analgesic use between outpatients who differed by one unit of pain score, but no statistical evidence for association (95 % CI 0.934−1.26; p = 0.298). Conclusions These findings can be considered for the ongoing development of safe, effective strategies for analgesic use in older outpatients with cancer.

Immune evasion is a recently defined hallmark of cancer, and immunotherapeutic approaches that stimulate an immune response to tumours are gaining recognition. However tumours may evade the immune response and resist immune-targeted treatment by promoting an immune-suppressive environment and stimulating the differentiation or recruitment of immunosuppressive cells. Myeloid-derived suppressor cells (MDSC) have been identified in a range of cancers and are often associated with tumour progression and poor patient outcomes. Pancreatic cancer in particular supports MDSC differentiation via the secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF), and MDSC are believed to contribute to the profoundly immune-suppressive microenvironment present in pancreatic tumours. MDSC-targeted therapies that deplete or inhibit this cell population have been proposed as a way to shift the balance in favour of a tumour-clearing immune response. In this study, we have modelled MDSC differentiation and function in vitro and this has provided us with the opportunity to test a range of potential MDSC-targeted therapies to identify candidates for further investigation. Using in vitro modelling we show here that the combination of GM-CSF-signalling blockade and gemcitabine suppresses both the MDSC phenotype and the inhibition of T-cell function by MDSC. Refereed/Peer-reviewed

Polypharmacy is often defined as use of ‘five-or-more-medications’. However, the optimal polypharmacy cut-point for predicting clinically important adverse events in older people with cancer is unclear. The aim was to determine the sensitivities and specificities of a range of polypharmacy cut-points in relation to a variety of adverse events in older people with cancer. Methods: Data on medication use, falls and frailty criteria were collected from 385 patients aged ≥70 years presenting to a medical oncology outpatient clinic. Receiver operating characteristic (ROC) curves were produced to examine sensitivities and specificities for varying definitions of polypharmacy in relation to exhaustion, falls, physical function, Karnofsky Performance Scale (KPS) and frailty. Sub-analyses were performed when stratifying by age, sex, comorbidity status and analgesic use. Results: Patients had a mean age of 76.7 years. Using Youden’s index, the optimal polypharmacy cut-point was 6.5 medications for predicting frailty (specificity 67.0 %, sensitivity 70.0 %), physical function (80.2 %, 49.3 %) and KPS (69.8 %, 52.1 %), 5.5 for falls (59.2 %, 73.0 %) and 3.5 for exhaustion (43.4 %, 74.5 %). For polypharmacy defined as five-or-more-medications, the specificities and sensitivities were frailty (44.9 %, 77.5 %), physical function (58.0 %, 69.7 %), KPS (47.7 %, 69.4 %), falls (44.5 %, 75.7 %) and exhaustion (52.6 %, 64.1 %). The optimal polypharmacy cut-points were similar when the sample was stratified by age, sex, comorbidity status and analgesic use. Conclusions: Our results suggest that no single polypharmacy cut-point is optimal for predicting multiple adverse events in older people with cancer. In this population, the common definition of five-or-more-medications is reasonable for identifying ‘at-risk’ patients for medication review. Refereed/Peer-reviewed

Objective: The aim was to explore incidence, mortality and case survivals for invasive neuroendocrine cancers in an Australian population and consider cancer control implications. Methods: Directly age-standardised incidence and mortality rates were investigated from 1980 to 2006, plus disease-specific survivals. Results: Annual incidence per 100,000 increased from 1.7 in 1980–1989 to 3.3 in 2000–2006. A corresponding mortality increase was not observed, although numbers of deaths were low, reducing statistical power. Increases in incidence affected both sexes and were more evident for female lung, large bowel (excluding appendix), and unknown primary site. Common sites were lung (25.9%), large bowel (23.3%) (40.9% were appendix), small intestine (20.6%), unknown primary (15.0%), pancreas (6.5%), and stomach (3.7%). Site distribution did not vary by sex (p = 0.260). Younger ages at diagnosis applied for lung (p = 0.002) and appendix (p < 0.001) and older ages for small intestine (p < 0.001) and unknown primary site (p < 0.001). Five-year survival was 68.5% for all sites combined, with secular increases (p < 0.001). After adjusting for age and diagnostic period, survivals were higher for appendix and lower for unknown primary site, pancreas, and colon (excluding appendix). Conclusions: Incidence rates are increasing. Research is needed into possible aetiological factors for lung and large-bowel sites, including tobacco smoking, and excess body weight and lack of exercise, respectively; and Crohn’s disease as a possible precursor condition. Refereed/Peer-reviewed

Background: Registry data from four major public hospitals indicate trends in clinical care and survival from colorectal cancer over three decades, from 1980 to 2010. Materials and Methods: Kaplan-Meier product-limit estimates and Cox proportional hazards models were used to investigate disease-specific survival and multiple logistic regression analyses to explore first-round treatment trends. Results: Five-year survivals increased from 48% for 1980-1986 to 63% for 2005-2010 diagnoses. Survival increases applied to each ACPS stage (Australian Clinico-Pathological Stage), and particularly stage C (an increase from 38% to 68%). Risk of death from colorectal cancer halved (hazards ratio: 0.50 (0.45, 0.56)) over the study period after adjusting for age, sex, stage, differentiation, primary sub-site, health administrative region, and measures of socioeconomic status and geographic remoteness. Decreases in stage were not observed. Survivals did not vary by sex or place of residence, suggesting reasonable equity in service access and outcomes. Of staged cases, 91% were treated surgically with lower surgical rates for older ages and more advanced stage. Proportions of surgical cases having adjuvant therapy during primary courses of treatment increased for all stages and were highest for stage C (an increase from 5% in 1980-1986 to 63% for 2005-2010). Radiotherapy was more common for rectal than colonic cases. Proportions of rectal cases receiving radiotherapy increased, particularly for stage C where the increase was from 8% in 1980-1986 to 60% in 2005-2010. The percentage of stage C colorectal cases less than 70 years of age having systemic therapy as part of their first treatment round increased from 3% in 1980-1986 to 81% by 1995-2010. Based on survey data on uptake of adjuvant therapy among those offered this care, it is likely that all these younger patients were offered systemic treatment. Conclusions: We conclude that pronounced increases in survivals from colorectal cancer have occurred at major public hospitals in South Australia due to increases in stage-specific survivals. Use of adjuvant therapies has increased and the patterns of change accord with clinical guideline recommendations. Reasons for sub-optimal use of radiotherapy for rectal cases warrant further investigation, including the potential for limited rural access to impede uptake of treatments at metropolitan-based radiotherapy centres. Refereed/Peer-reviewed

Potentially inappropriate medication (PIM) use has been associated with an increase in adverse drug events, hospitalization and mortality. This study investigated the prevalence and factors associated with PIM use in patients presenting to a medical oncology outpatient clinic. Consecutive patients (n=385) aged ≥ 70 years referred to a medical oncology outpatient clinic between January 2009 and July 2010 completed a structured data collection instrument. The instrument assessed medication use, diagnoses, self-reported falls in the previous six months, pain (10-point visual analog scale [VAS]) and distress (10-point VAS). Frailty was defined using exhaustion, weight loss, Karnofsky Performance Scale, instrumental activities of daily living and physical function. PIM use was defined by the Beers Criteria. Logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with PIM use. In total, 26.5% (n=102) of the sample used ≥1 PIM. The five most prevalent classes of PIMs were benzodiazepines (n=34, 8.8%), tricyclic antidepressants (n=16, 4.2%), alpha-adrenoreceptor antagonists (prazosin) (n=15, 3.9%), propulsives (metoclopramide) (n=15, 3.9%) and non-steroidal anti-inflammatory drugs (n=14, 3.6%). In multivariate analyses, PIM use was associated with age 75-79 years (OR 1.83; 95%CI 1.02-3.26) compared to age 70-74 years, using ≥ 5 medications (OR 4.10; 95%CI 2.26-7.44) compared to

Refereed/Peer-reviewed

Background: Inequalities in survival from colorectal cancer (CRC) across socioeconomic groups and by area ofresidence have been described in various health care settings. Few population-wide datasets which includeclinical and treatment information are available in Australia to investigate disparities. This study examinessocio-demographic differences in survival for CRC patients in South Australia (SA), using a population-widedatabase derived via linkage of administrative and surveillance datasets. Methods: The study population comprised all cases of CRC diagnosed in 2003-2008 among SA residentsaged 50-79 yrs in the SA Central Cancer Registry. Measures of socioeconomic status (area level), geographicalremoteness, clinical characteristics, comorbid conditions, treatments and outcomes were derived through recordlinkage of central cancer registry, hospital-based clinical registries, hospital separations, and radiotherapy services data sources. Socio-demographic disparities in CRC survival were examined using competing risk regression analysis. Results: Four thousand six hundred and forty one eligible cases were followed for an average of 4.7 yrs, during whichtime 1525 died from CRC and 416 died from other causes. Results of competing risk regression indicated higher risk ofCRC death with higher grade (HR high v low =2.25, 95 % CI 1.32-3.84), later stage (HR C v A = 7.74, 95 % CI 5.75-10.4),severe comorbidity (HR severe v none =1.21, 95 % CI 1.02-1.44) and receiving radiotherapy (HR = 1.41, 95 % CI 1.18-1.68).Patients from the most socioeconomically advantaged areas had significantly better outcomes than those from the leastadvantaged areas (HR =0.75, 95 % 0.62-0.91). Patients residing in remote locations had significantly worse outcomes thanmetropolitan residents, though this was only evident for stages A-C (HR = 1.35, 95 % CI 1.01-1.80). These disparities were not explained by differences in stage at diagnosis between socioeconomic groups or area of residence. Nor were they explained by differences in patient factors, other tumour characteristics, comorbidity, or treatment modalities. Conclusions: Socio-economic and regional disparities in survival following CRC are evident in SA, despite havinga universal health care system. Of particular concern is the poorer survival for patients from remote areas withpotentially curable CRC. Reasons for these disparities require further exploration to identify factors that can beaddressed to improve outcomes. Refereed/Peer-reviewed

Background: Registry data from four major public hospitals indicate trends over three decades from 1980 to 2010 in treatment and survival from colorectal cancer with distant metastases at diagnosis (TNM stage IV). Materials and Methods: Kaplan-Meier product-limit estimates and Cox proportional hazards models for investigating disease-specific survival and multiple logistic regression analyses for indicating first-round treatment trends. Results: Two-year survivals increased from 10% for 1980-84 to 35% for 2005-10 diagnoses. Corresponding increases in five-year survivals were from 3% to 16%. Time-to-event risk of colorectal cancer death approximately halved (hazards ratio: 0.48 (0.40, 0.59) after adjusting for demographic factors, tumour differentiation, and primary sub-site. Survivals were not found to differ by place of residence, suggesting reasonable equity in service provision. About 74% of cases were treated surgically and this proportion increased over time. Proportions having systemic therapy and/or radiotherapy increased from 12% in 1980-84 to 61% for 2005-10. Radiotherapy was more common for rectal than colonic cases (39% vs 7% in 2005-10). Of the cases diagnosed in 2005-10 when less than 70 years of age, the percentage having radiotherapy and/or systemic therapy was 79% for colorectal, 74% for colon and 86% for rectum (& 'RS)) cancers. Corresponding proportions having: systemic therapies were 75%, 71% and 81% respectively; radiotherapy were 24%, 10% and 46% respectively; and surgery were 75%, 78% and 71% respectively. Based on survey data on uptake of offered therapies, it is likely that of these younger cases, 85% would have been offered systemic treatment and among rectum (&RS) cases, about 63% would have been offered radiotherapy. Conclusions: Pronounced increases in survivals from metastatic colorectal cancer have occurred, in keeping with improved systemic therapies and surgical interventions. Use of radiotherapy and/or systemic therapy has increased markedly and patterns of change accord with clinical guideline recommendations. Refereed/Peer-reviewed