Search

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC). BRCA reversion mutations are a known mechanism of acquired resistance to PARP inhibitors in multiple cancer types, although their impact and prevalence in mCRPC remain unknown.To examine the prevalence of BRCA reversion mutations in the plasma of patients with BRCA+ mCRPC after progression on rucaparib.Men with BRCA+ mCRPC enrolled in Trial of Rucaparib in Prostate Indications 2 (TRITON2) were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected at the end of treatment after confirmed progression before May 5, 2020, was queried for BRCA reversion mutations using next-generation sequencing (NGS).The association of clinical efficacy and postprogression genomics was measured in 100 patients with BRCA+ mCRPC treated with rucaparib.No baseline BRCA reversion mutations were observed in 100 BRCA+ patients. NGS identified somatic BRCA reversion mutations in 39% (39/100) of patients after progression. Reversion rates were similar for BRCA2 and BRCA1, irrespective of germline or somatic status, but higher in samples with a high tumor DNA fraction. Most patients with reversions (74%, 29/39) had two or more reversion mutations occurring subclonally at lower allele frequencies than the original BRCA mutations. The incidence of BRCA reversion mutations increased with the duration of rucaparib treatment. The frequency of reversion mutations was higher in patients with an objective (58%) or a prostate-specific antigen (69%) response compared with those without either (39% and 29%, respectively).These findings suggest that BRCA reversion mutations are a significant mechanism of acquired resistance to rucaparib in patients with BRCA+ mCRPC, with evidence of subclonal convergence promoting systemic resistance.Men with BRCA mutated metastatic castration-resistant prostate cancer enrolled in TRITON2 were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected after radiographic or prostate-specific antigen progression before May 5, 2020, was analyzed by next-generation sequencing and queried for BRCA reversion mutations.

Patients in randomized controlled trials (RCTs) must be successfully randomized to reduce or eliminate bias. Because pre-treatment symptoms have prognostic significance in cancer patients, qualitative and quantitative tools were developed to assess similarity of baseline pre-treatment symptoms across different treatment arms of RCTs as one measure of randomization success. Clinician-reported symptom data from two colorectal cancer RCTs, CO.20 and CO.17, were used to demonstrate the utility of a qualitative visualization tool and quantitative machine learning K-means tool, which grouped patients into clusters using baseline symptoms. Qualitatively, reflection bar graphs (RBGs) visualized potential imbalances in baseline symptoms (i) across treatment arms and (ii) by corresponding patient clusters identified within each treatment arm. RBGs found that the treatment arms for both RCTs had similar symptom profiles, while the lack of significant differences in the proportions of patients in each cluster across treatment arms further confirmed successful randomization. This paper details the creation of visualization, machine-learning, and statistical tools to compare baseline symptoms across RCT treatment arms, demonstrating that the CO.20 and CO.17 trials were successfully randomized by baseline symptoms and are comparable. These tools can therefore be implemented easily to ensure an extra layer of quality assurance of the randomization process for study assessment.

The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood.We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use.Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not.A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).

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.

Background Complementary medicines (CM) are frequently used by patients with cancer. Controversy exists over the effectiveness and risk that CM may add to conventional cancer therapy. The incidence of CM use among patients enrolled in phase III clinical trials is unknown. Methods Medication lists from 6 international phase III clinical trials were retrospectively reviewed to identify patients using CM. Patients had metastatic breast, colorectal, or lung cancers. Quality of life, adverse events, overall survival, and progression-free survival were compared between CM users and non-users. Baseline differences between groups were adjusted with propensity score matching groups. Results Seven hundred and six of 3446 patients (20.5%) used at least one CM. CM use was highest among patients with breast cancer (35.6%). CM users had more favorable baseline prognostic factors (ECOG 0-1, non-smoking status, younger age, and fewer metastases). CM use was associated with lower rates of adverse events (50% vs. 62%, P = .002) and quality of life was similar between both groups. After adjustment with propensity score matching, CM use was also associated with longer overall survival in patients with lung cancer (adjusted hazard ratio 0.80, 95%CI, 0.68-0.94, P =.0054). However, several key control variables like EGFR status were not available. Conclusion One in 5 patients in phase III clinical trials report using CM. CM was not associated with worse cancer-specific outcomes. However, CM users had more favorable baseline prognostic factors, and likely other confounders that may have contributed to improved outcomes observed in the lung cohort. Physicians should monitor for CM use and potential interactions with clinical trial drugs.

BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is highly lethal. Combination chemotherapy regimens improve overall survival (OS). Historically, only one third of mPDAC patients in Victoria received chemotherapy (1) . AIM: To describe current Australian chemotherapy utilisation and outcomes in patients with mPDAC using the multi-site PURPLE (Pancreatic cancer: Understanding Routine Practice and Lifting End Results) registry. METHODS: PURPLE collects longitudinal data on consecutive patients with pancreatic cancer seen since January 2016. Data was collated for patients with mPDAC from six Victorian sites, and analysed descriptively. RESULTS: Three-hundred-and-sixty-three patients with mPDAC were identified. Median age was 70 years (20-94). First line chemotherapy was administered in 195 patients (54%). Prevalent regimens included gemcitabine-nab-paclitaxel (71%), gemcitabine alone (10%) and FOLFIRINOX (6%). Sixty-two of 195 (32%) patients who received first line treatment have proceeded to second line chemotherapy. Chemotherapy treated patients were younger (69 versus 73 years, p

B-Raf proto-oncogene (BRAF)-V600E mutations (BRAFmt) in colorectal cancer (CRC) predominantly occur in right-side (RS) primaries. In metastatic CRC (mCRC), there is substantial overlap between the reported features of BRAFmt and of an RS primary. To explore the significance of BRAFmt in a left-side (LS) primary, we analysed data from a multi-site mCRC registry. Tumours distal to the splenic flexure were considered LS. Of 3380 patients enrolled from June 2009 to June 2020, 214 (13%) of 1657 with known status were BRAFmt: 127 (24%) of 524 RS and 87 (8%) of 1133 LS. LS versus RS BRAFmt were younger (mean 59.5 vs. 65.1 years; p = 0.01), whereas sex (48 vs. 59% female; p = 0.13), mismatch repair-deficiency (dMMR) (16 vs. 21%; p = 0.47), and overall survival (OS) (median 15.1 vs. 17.7 months; p = 0.98) were similar. LS BRAFmt versus LS BRAF wildtype (wt) were of similar age (59.5 vs. 61.3 years; p = 0.28) with more females (48 vs. 37%; p = 0.04), more dMMR (16 vs. 1%; p < 0.0001), and inferior OS (median 15.1 vs. 36.6 months; p < 0.0001). Initial treatment with chemotherapy plus an epidermal growth factor receptor inhibitor produced median progression-free survival (PFS) of 4.3 versus 12.3 months (p = 0.20) for LS BRAFmt (n = 9) versus LS BRAFwt (n = 104). Initial chemotherapy and bevacizumab produced a median PFS of 7.6 versus 11.6 months (p = 0.02) for LS BRAFmt (n = 36) versus LS BRAFwt (n = 438), respectively. LS BRAFmt cancers share many features with RS BRAFmt cancers, including poor survival outcomes. Mature data on the activity of BRAF-targeted therapies in the first-line setting are eagerly awaited.

BACKGROUND: Evidence supporting dose modifications to reduce serious treatment-related adverse events of antineoplastic therapy is limited and frequently based on clinical trial protocols, which are not always generalisable to community patients. eviQ is an online resource with treatment protocols and recommendations for dose modification formulated by expert opinion and evidence-based review. Original recommended haematological thresholds to delay treatment were: neutrophil count

We investigate differences in spousal reports of intimate partner violence (IPV) against women and men using a sample of 800 couples in rural Kenya. We find that up to one-third of couples disagree but that disagreement varies by violence type and victim's gender. We study the role of gender attitudes in explaining this heterogeneity. We find that couples with more gender-unequal attitudes are more likely to agree on violence against women and less likely to agree on violence against men. This suggests that gender norms govern reporting by the victim. Thus, discrepancies may result even if perpetrators report accurately.

Trifluridine/tipiracil is available on the Australian Pharmaceutical Benefits Scheme for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-vascular endothelial growth factor agents and anti-epidermal growth factor receptor agents. This article reviews trifluridine/tipiracil clinical data and presents practical information on its use in the management of refractory mCRC in Australia. Whereas the primary mechanism of action of fluoropyrimidines such as fluorouracil (5-FU) and capecitabine is enzyme inhibition of nucleotide synthesis, trifluridine/tipiracil primarily acts by incorporation into DNA, resulting in DNA dysfunction. Trifluridine/tipiracil has activity in patients with 5-FU-resistant tumors and can be considered in patients with prior intolerance or toxicity to 5-FU. In the pivotal phase III RECOURSE trial evaluating trifluridine/tipiracil in chemotherapy-refractory mCRC, efficacy benefits were observed across all a priori prognostic subgroups including those defined by age (≥65 and ≥75 years), geographical origin, primary tumor site or KRAS status. Trifluridine/tipiracil therapy benefits appropriately selected patients who have an ECOG performance status of 0 or 1, with no more than mild hepatic impairment or mild-to-moderate renal impairment, and who are capable of adhering to oral therapy safely. Appropriate dosing, monitoring for adverse events and effective management of side effects are essential.

This study uses incentive-compatible techniques to obtain valuations of 14 common poverty reduction interventions from (probable) aid recipients. Recipients’ valuations for these interventions are highly heterogeneous both across interventions and across recipients of the same intervention. Valuation for interventions does not correlate with overall poverty or with perceived need for specific interventions, suggesting that targeting individuals with high valuations based on recipient characteristics is difficult. Through simulations, this study assesses how various allocation mechanisms—cash transfers and voting—compare in generating recipient surplus in the allocation of aid. When markets function and constraints on joint private contributions to public goods do not bind, cash transfers generate considerably more recipient surplus than voting. Even when cash transfers cannot enable public goods and some services, they may still outperform voting at very low resource levels. However, as resource levels increase, voting dominates cash transfers from a surplus-maximization perspective.

After antigenic activation, quiescent naive CD4+ T cells alter their metabolism to proliferate. This metabolic shift increases production of nucleotides, amino acids, fatty acids, and sterols. Here, we show that histone deacetylase 3 (HDAC3) is critical for activation of murine peripheral CD4+ T cells. HDAC3-deficient CD4+ T cells failed to proliferate and blast after in vitro TCR/CD28 stimulation. Upon T-cell activation, genes involved in cholesterol biosynthesis are upregulated while genes that promote cholesterol efflux are repressed. HDAC3-deficient CD4+ T cells had reduced levels of cellular cholesterol both before and after activation. HDAC3-deficient cells upregulate cholesterol synthesis appropriately after activation, but fail to repress cholesterol efflux; notably, they overexpress cholesterol efflux transporters ABCA1 and ABCG1. Repression of these genes is the primary function for HDAC3 in peripheral CD4+ T cells, as addition of exogenous cholesterol restored proliferative capacity. Collectively, these findings demonstrate HDAC3 is essential during CD4+ T-cell activation to repress cholesterol efflux.

Clinical trials have strict eligibility criteria, potentially limiting external validity. However, while often discussed this has seldom been explored, particularly across cancer types and at variable time frames posttrial completion. We examined comprehensive registry data (January 2014 to June 2019) for standard first-line treatments for metastatic colorectal cancer (CRC), advanced pancreatic cancer (PC), metastatic HER2-amplified breast cancer (BC) and castrate-resistant prostate cancer (CaP). Registry patient characteristics and outcomes were compared to the practice-changing trial. Registry patients were older than the matched trial cohort by a median of 2-6 years (all P =

B-Raf proto-oncogene (BRAF)-V600E mutations (BRAFmt) in colorectal cancer (CRC) predominantly occur in right-side (RS) primaries. In metastatic CRC (mCRC), there is substantial overlap between the reported features of BRAFmt and of an RS primary.To explore the significance of BRAFmt in a left-side (LS) primary, we analysed data from a multi-site mCRC registry. Tumours distal to the splenic flexure were considered LS.Of 3380 patients enrolled from June 2009 to June 2020, 214 (13%) of 1657 with known status were BRAFmt: 127 (24%) of 524 RS and 87 (8%) of 1133 LS. LS versus RS BRAFmt were younger (mean 59.5 vs. 65.1 years; p = 0.01), whereas sex (48 vs. 59% female; p = 0.13), mismatch repair-deficiency (dMMR) (16 vs. 21%; p = 0.47), and overall survival (OS) (median 15.1 vs. 17.7 months; p = 0.98) were similar. LS BRAFmt versus LS BRAF wildtype (wt) were of similar age (59.5 vs. 61.3 years; p = 0.28) with more females (48 vs. 37%; p = 0.04), more dMMR (16 vs. 1%; p0.0001), and inferior OS (median 15.1 vs. 36.6 months; p0.0001). Initial treatment with chemotherapy plus an epidermal growth factor receptor inhibitor produced median progression-free survival (PFS) of 4.3 versus 12.3 months (p = 0.20) for LS BRAFmt (n = 9) versus LS BRAFwt (n = 104). Initial chemotherapy and bevacizumab produced a median PFS of 7.6 versus 11.6 months (p = 0.02) for LS BRAFmt (n = 36) versus LS BRAFwt (n = 438), respectively.LS BRAFmt cancers share many features with RS BRAFmt cancers, including poor survival outcomes. Mature data on the activity of BRAF-targeted therapies in the first-line setting are eagerly awaited.

BACKGROUND: Metastatic colorectal cancer (mCRC) patients with a right-sided primary (RC) have an inferior survival to mCRC arising from a left-sided primary (LC). Previous analyses have suggested multiple factors contribute. METHODS: The Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Registry prospectively captured data on consecutive mCRC patients. RC were defined as tumors proximal to the splenic flexure; LC were those at and distal to the splenic flexure and included rectal cancers. Patient, tumor, treatment, and survival data were analyzed stratified by side. RESULTS: Of 2306 patients enrolled from July 2009-March 2018, 747 (32%) had an RC. Patients with RC were older, more likely to be female and have a Charlson score ≥3. RC were more frequently BRAF mutated, deficient in mismatch repair, associated with peritoneal metastases, and less likely to receive chemotherapy. Progression-free survival on first-line systemic therapy was inferior for RC patients (8.1 vs. 10.8 months, hazard ratio [HR] for progression in RC 1.38, P

Randomized controlled trials, which randomly allocate benefits to a treatment group and not a control group, ascribe differences in post-treatment welfare to the benefits being allocated. However, it is possible that potential recipients' welfare is not only affected by the receipt of the program, but also by the allocation mechanism (procedural utility). In this paper, we ask whether potential recipients support or oppose random allocation of financial benefits, by allowing them to reward or punish an allocator conditional on her choice of allocation mechanism: direct allocation to one recipient vs. randomization among potential recipients. We find that when potential recipients have equal endowments, they on average reward the allocator for randomizing. When instead there is inequality in the potential recipients' endowments, the relatively poorer recipients punish allocators who randomize, while the relatively richer potential recipients neither reward nor punish the allocator for randomizing. Our results suggest that an allocator who chooses to randomize between potential recipients with unequal endowments imposes a social cost on the relatively poorer potential recipients.

This paper uses a large-scale field experiment in India to study attitudinal, behavioral, and cognitive constraints that can stymie the link between financial education and financial outcomes. The study complements financial education with (i) financial incentives on a financial literacy test to affect participant motivation, (ii) financial goal setting to provide a psychological nudge, and (iii) personalized financial counseling to enhance the intensity of treatment. The analysis finds no impact of financial incentives on learning but significant effects of both goal setting and counseling on real financial outcomes. These results identify important complements to financial education that can bridge the gap between financial knowledge and behavior change. Data and the online appendix are available at https://doi.org/10.1287/mnsc.2017.2819 . This paper was accepted by Amit Seru, finance.

248 Background: Quality indicators (QI) are essential to monitor the efficacy of cancer care and to guide quality improvement, however many are derived from ‘expert consensus’ and are not validated against outcomes. Moreover, the majority of oncological QI are defined in the surgical setting, with only a paucity of QI for the treatment of metastatic disease. We aimed to define and validate novel QI for metastatic colorectal cancer (mCRC) based on therapeutic approaches associated with a proven survival benefit. Methods: Data was analysed from TRACC, a multisite Australian registry collecting prospective demographic, tumour, treatment and outcome data for mCRC. We identified all patients diagnosed across 11 hospitals and explored variation by site with regards to patient and tumour characteristics, first-line chemotherapy administration and resection of oligometastatic disease. Log-rank testing and Kaplan-Meier curves compare overall survival (OS) between sites, and Pearson correlation was used to assess associations with each QI. Results: We examined data from 3132 patients diagnosed with mCRC between July 2009 – April 2021. Median age was 66 years (range 62 – 71 years by site), ECOG 0-1 81% (range 69 – 96% by site), and Charlson Comorbidity Index ≤2 43% (33 – 59% by site). Multivariate analysis confirmed association of known adverse prognostic factors with inferior OS (poor ECOG, right sided primary, KRAS or BRAF mutation, all p 2 = 0.851), rate of liver resection (9.8 – 23.2% by site) was moderately correlated (R2 = 0.523), and rates of active treatment with first-line chemotherapy (63 - 90% by site) were weakly correlated (R2 = 0.209). Other proposed QI such as rates of lung metastases resection or chemotherapy administration in the elderly showed significant variation by site, but did not correlate with survival. Conclusions: There is significant variation in OS for patients with mCRC in these Australian hospitals, with major differences in treatment approaches. Treatment strategies known to improve survival outcomes, such as triplet FOLFOXIRI chemotherapy and resection of liver metastases, may be potential QI to benchmark and track quality improvement over time. Further analysis will determine the impact of baseline patient populations between sites, and to correlate these QI with other quality measures.

71 Background: For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. In Australia, TAS-102 was initially made available locally through patients self-funding, later via an industry sponsored Medicine Access Program (MAP) and then via the Pharmaceutical Benefits Scheme (PBS). This study aims to investigate the efficacy and safety of TAS-102 in real world Australian population. Methods: A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to all TRACC patients and those enrolled in the registration study (RECOURSE). Results: Across 13 sites, 107 patients were treated with TAS-102 (non-PBS n = 27, PBS n = 80), The median number of patients per site was 7 (range: 1-17). The median age was 60 years (range: 31-83), compared to 67 for all TRACC patients and 63 for RECOURSE. Comparing registry TAS-102 and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 39% vs 49% were RAS wild type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median clinician assessed progression-free survival was 3.3 compared to RECIST defined PFS of 2 months in RECOURSE study, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths in the real-world series, where TAS102 dose at treatment initiation was at clinician discretion. In the RECOURSE study there was a 4% febrile neutropenia rate and one treatment-related death. Conclusions: TRACC registry patients treated with TAS102 were younger than both TRACC patients overall and those from the RECOURSE trial. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS. However overall survival outcomes achieved with TAS102 in real world patients were comparable to findings from this pivotal trial with an acceptable rate of major adverse events.

84 Background: The optimal management of isolated distant lymph node metastases (IDLNM) in metastatic colorectal cancer (mCRC) is not clearly established. Small case series and prior data from the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) registry support the use of radical treatment with curative intent (local resection, chemo-radiation or stereotactic radiotherapy), which may lead to better outcomes in mCRC patients with IDLNM. Aims: This study investigates the clinical characteristics and outcomes of mCRC patients with IDLNM treated with systemic therapies plus locoregional therapy with curative intent versus systemic therapies with palliative intent. Methods: Clinical data were collected and reviewed from the TRACC registry, a prospective, comprehensive registry for mCRC from multiple tertiary hospitals across Australia from 01/07/2009 to 30/06/2020. Clinicopathological characteristics, treatment modalities and survival outcomes were analyzed in patients with IDLNM and compared to patients with other organ metastases. Fisher exact test was used for significance tests and Kaplan Meier curves for survival analyses. Results: Of 3408 mCRC patients with a median follow-up of 38.0 months, 93 (2.7%) were found to have IDLNM. Compared to mCRC with other organ metastases, patients with IDLNM were younger (mean age: 62.1 vs 65.6 years, p=0.0200), more likely to have metachronous disease (57.0% vs 38.9%, p=0.0005), be KRAS wild-type (74.6% vs 53.9%, p=0.0012) and BRAF mutant (12.9% vs 6.2%, p=0.0100). There was no overall survival difference between with IDLNM and those with other organ metastases (median OS 27.24 vs 25.92 months, p=0.2300). Twenty-four patients (25.8%) with IDLNM received treatment with curative intent, with a trend towards improved overall survival compared to those with other organ metastases treated with curative intent (73.5 vs 62.7 months, p=0.8200). Amongst mCRC patients with IDLNM, those who received treatment with curative intent had a significantly better overall survival than those treated with palliative intent (73.5months vs 23.2 months, p=0.0070). Conclusions: Our findings suggest that there are differences in the patterns of presentation of IDLNM and other organ metastases. Radical treatment with curative intent options should be considered for mCRC patients with IDLNM where appropriate.

Objectives The elderly accounts for a large proportion of patients with metastatic colorectal cancer (mCRC). This study reviews patterns of care and outcomes for elderly patients with mCRC in the community setting. Materials and Methods Elderly patients (≥ 65 years) with mCRC on the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) registry were identified. Treatment, bevacizumab-related adverse events, and overall survival (OS) were analysed by age cohorts, comparing those aged 65–74 vs. 75–84 vs. ≥ 85 years and correlated with potential prognostic factors. Factors affecting chemotherapy and bevacizumab administration were analysed using logistic regression analysis. Results Of 1439 patients, 363, 352, and 106 were aged 65–74, 75–84, and ≥ 85 years, respectively. 584 (71%) patients received first-line chemotherapy, with chemotherapy use declining with advancing age (84%, 69%, and 34% in 65–74-, 75–84- and ≥ 85-year-olds, respectively). Seven (10%) patients aged ≥ 85 years were not treated with chemotherapy on the basis of age alone. Only 10 of 36 very elderly patients who received chemotherapy also received bevacizumab. Factors affecting bevacizumab administration included age, treatment location, and comorbidities. There was no impact of age on bevacizumab-related adverse events. Resection of metastatic disease occurred in 173 (21%) patients overall, with rates declining with age (26% vs. 21% vs. 6%). Conclusion Chemotherapy usage and resection of metastatic disease decline with advancing age. A minority of patients are not treated with systemic therapy due to advanced age alone. Our cohort suggests underutilisation of bevacizumab in older patients, but where given, toxicity rates did not increase with age.

Background Prior studies have suggested improved outcomes for cancer patients managed in private centres, despite universal healthcare within Australia. Aims To compare patient, disease, treatment and survival data for metastatic colorectal cancer (mCRC) managed in private versus public centres. Methods Analysis of prospectively collected registry data for consecutive patients with mCRC managed at 16 participating centres from July 2009. Results Data for 1065 patients were examined. Age, gender and Charlson comorbidity score were similar for public and private patients. Private patients were more commonly Eastern Cooperative Oncology Group performance score 0–1 (85% vs 78%, P = 0.008), in the highest Index of Relative Socioeconomic Advantage and Disadvantage quintile (57% vs 18%, P < 0.001) or had a single metastatic site (62% vs 54%, P = 0.009). Patients treated in private were more likely to receive chemotherapy (84% vs 70%, P < 0.001), bevacizumab (59% vs 50%, P = 0.008), be treated with curative intent (37% vs 26%, P < 0.001) and undergo metastasectomy (30% vs 22%, P = 0.001). These management differences remained statistically significant after adjusting for baseline characteristics. Management in the private setting was associated with superior overall survival (median 27.9 vs 20 months, hazard ratio 0.7, 95% confidence interval: 0.57 to 0.86, P = 0.001), significant in multivariate analysis adjusting for all baseline covariates. Conclusions Significant differences in baseline characteristics were noted for private versus public patients. However, these do not explain the higher rates of treatment delivery in the private setting, which likely contributed towards the observed survival difference. Further studies are required to determine if the increased likelihood of intervention in the private setting is driven by patient, clinician and/or institutional factors.

The treatment of metastatic colorectal cancer has evolved greatly in the last 15 years, involving combined chemotherapy protocols and, in more recent times, new biologic agents. Clinical benefit from the use of targeted therapy with bevacizumab, aflibercept, cetuximab, panitumumab and regorafenib in the treatment of metastatic colorectal cancer is now well established with median overall survival accepted as over 24 months, and with super selection for extended RAS patients higher again. The optimal timing of treatment options requires careful consideration of predictive biomarkers, and importantly the potential for interactions, to derive the maximal benefit. A group of colorectal subspecialty medical oncologists from Australia, the USA, the Netherlands and Germany met during ECCO 2013 to discuss current practice. Subsequent new data from the American Society of Clinical Oncology were also reviewed. This article reviews the evidence discussed in support of modern treatments for colorectal cancer and the decision-making behind the treatment choices, with their benefits and risks.

Background: The changing treatment landscape for metastatic colorectal cancer creates multiple potential treatment strategies. An Australian-centric database capturing comprehensive information across a range of treatment locations would create a valuable resource enabling multiple important research questions to be addressed. Aims: To establish a collection of a consensus dataset capturing treatment and outcomes at multiple public and private hospitals across Australia. Methods: An electronic database was developed by a panel of clinicians, to capture an agreed dataset for patients with newly diagnosed metastatic colorectal cancer. Of particular interest were clinician decision-making, the impact of comorbidities and the frequency of major adverse events. Results: Since July 2009, data collection has been established at six public and eight private hospitals across three Australian states and territories. Successful linkage and analysis, with support from BioGrid Australia, of selected data on the initial 864 patients demonstrates that data can be captured from diverse sites, including public and private practice, that multiple factors impact on treatment delivered and outcomes achieved and that comprehensive data on rare but important adverse events can be captured. As a clinical research tool, the project has been highly successful, generating multiple presentations at national and international conferences related to a diverse range of research questions. Conclusions: Multistate, project-specific data collection involving large numbers of patients is achievable. Providing invaluable insight into the routine clinical management of metastatic colorectal cancer in the era of targeted therapies, this also creates a significant resource for research, including many questions not being addressed by clinical trials.

Cetuximab-induced hypomagnesemia has been associated with improved clinical outcomes in advanced colorectal cancer (CRC). We explored this relationship from a randomized clinical trial of cetuximab plus best supportive care (BSC) versus BSC alone in patients with pretreated advanced CRC.Day 28 hypomagnesemia grade (0 versus ≥1) and percent reduction (20% versus ≥20%) of Mg from baseline was correlated with outcome.The median percentage Mg reduction at day 28 was 10% (-42.4% to 63.0%) for cetuximab (N = 260) versus 0% (-21.1% to 25%) for BSC (N = 251) [P0.0001]. Grade ≥1 hypomagnesemia and ≥20% reduction from baseline at day 28 were associated with worse overall survival (OS) [hazard ratio, HR 1.61 (95% CI 1.12-2.33), P = 0.01 and 2.08 (95% CI 1.32-3.29), P = 0.002, respectively] in multivariate analysis including grade of rash (0-1 versus 2+). Dyspnea (grade ≥3) was more common in patients with ≥20% versus20% Mg reduction (68% versus 45%; P = 0.02) and grade 3/4 anorexia were higher in patients with grade ≥1 hypomagnesemia (81% versus 63%; P = 0.02).In contrast to prior reports, cetuximab-induced hypomagnesemia was associated with poor OS, even after adjustment for grade of rash.

Microfinance, the provision of small individual and business loans, has experienced dramatic growth, reaching over 150 million borrowers worldwide. Much of the success of microfinance has been attributed to attempts to overcome the challenges of information asymmetries in uncollateralized lending. However, very little is known about the optimal contract structure of these loans, and there is substantial variation across lenders, even within a particular setting. This paper exploits a plausibly exogenous change in the liability structure offered by a microfinance program in India, which shifted from individual to group liability lending. We find evidence that the lending model matters: for the same borrower, the required monthly loan installments are 11 percent less likely to be missed under the group liability setting in comparison with individual liability. In addition, compulsory savings deposits are 20 percent less likely to be missed under group liability contracts. Copyright 2013, Oxford University Press.

The medical treatment of patients with metastatic colorectal cancer (mCRC) has evolved greatly in the past 10 years, involving complex combined chemotherapy protocols and, in more recent times, new biologic agents. Clinical benefit from the use of the targeted monoclonal antibodies bevacizumab, cetuximab, and panitumumab in the treatment of patients with mCRC is now well-established, but the optimal timing of their use requires careful consideration in order to derive the maximal benefit. Evidence to date suggests potentially distinct roles for bevacizumab and epidermal growth factor receptor–targeted biologic agents (cetuximab and panitumumab) in the treatment of patients with mCRC. This article reviews the evidence in support of modern treatments for mCRC and the decision making behind the treatment choices as well as their benefits and toxicities. An evidence-based algorithm is proposed that incorporates the use of these biologic agents early in the treatment of patients with initially nonresectable mCRC based on clearly defined tumor-related factors dependent on the immediate treatment goal. Real-world application of this algorithm is dependent on an individual countries' approval of access to new biologic agents.

Purpose National Cancer Institute of Canada Clinical Trials Group CO.17 demonstrated the antiepidermal growth factor receptor (anti-EGFR) monoclonal antibody cetuximab improves overall and progression-free survival in patients with advanced, chemotherapy-refractory colorectal cancer (CRC), particularly in patients with wild-type KRAS tumors. This article reports the health-related quality-of-life (HRQL) outcomes from CO.17. Patients and Methods Patients (N = 572) with pretreated EGFR-detectable advanced CRC were randomly assigned to cetuximab and best supportive care (BSC) or to BSC alone. HRQL primary end points assessed by the EORTC QLQ-C30 were physical function (PF) and global health status (GHS); mean changes from baseline to 8 and 16 weeks were assessed. Post hoc analysis by KRAS mutation status was performed. Results Questionnaire compliance was 94% at baseline, but it declined differentially (67% v 47% for cetuximab v BSC at 16 weeks). PF change scores were −3.9 for cetuximab and −8.6 for BSC (P = .046) at 8 weeks and were −5.9 and −12.5 for cetuximab and BSC, respectively, (P = .027) at 16 weeks. GHS change scores were −0.5 and −7.1 (P = .008) at 8 weeks and were −3.6 and −15.2 (P = .008) at 16 weeks for cetuximab and BSC, respectively. In patients who had tumors with wild-type KRAS status, cetuximab resulted in less PF deterioration at 8 weeks (−0.7 v −7.2; P = .11) and 16 weeks (−3.4 v −13.8; P = .008) compared with BSC. Patients with wild-type status who received cetuximab experienced improved GHS at 8 weeks, whereas patients who received BSC alone deteriorated (3.2 v −7.7; P = .002). Cetuximab preserved GHS at 16 weeks (−0.2 v −18.1; P < .001). No significant differences were noted between study arms for patients with mutated KRAS tumors. Conclusion Cetuximab offers important HRQL and survival benefits for pretreated patients with advanced, wild-type KRAS CRC.

Die Standardbehandlung eines Rektumkarzinoms wird immer noch von den Ergebnissen randomisierter, klinischer Studien definiert, die den optimalen Zeitpunkt und den Einsatz von adjuvanter Chemotherapie und Bestrahlung im Vergleich mit einer Operation untersuchen. Die klinischen Problemstellungen, fur die nur begrenztes aktuelles Datenmaterial als Hilfestellung bei der Entscheidungsfindung zur Verfugung steht, finden sich bei Patienten mit Rektumkarzinom im hoheren Alter und/oder signifikanten Begleiterkrankungen sowie bei Patienten, die eine Operation ablehnen. An sechs australischen Kliniken wurde eine retrospektive Analyse von Rektumkarzinompatienten, die aufgrund eines sehr hohen operativen Risikos oder Verweigerung einer Operation ausschlieslich mit Bestrahlung oder einer Radiochemotherapie behandelt worden waren, durchgefuhrt. Identifiziert wurden 48 Patienten mit einem medianen Alter von 76 Jahren (49–94 Jahre), die zwischen August 1998 und Juni 2005 behandelt worden waren. 24 Patienten (50%) wurden als medizinisch inoperabel eingestuft, und 24 Patienten lehnten eine Operation ab. Die Behandlung bestand bei 36 Patienten aus einer Radiochemotherapie (mit 5-Fluorouracil) und bei zwolf Patienten aus ausschlieslicher Bestrahlung; 93% fuhrten die geplante Behandlung bis zum Ende durch. Bei 56% wurde ein komplettes klinisches Ansprechen und bei 30% ein partielles Ansprechen festgestellt. Bei einem medianen Follow-up von 49 Monaten zeigte sich bei 18 Patienten ein Fortschreiten der Erkrankung; dies betraf zehn von 24 Patienten in der medizinisch inoperablen Gruppe sowie acht von 24 Patienten in der Gruppe, die eine Operation verweigerte. Von den 25 verstorbenen Patienten waren 16 an der fortschreitenden Erkrankung und neun an nicht karzinombezogenen Ursachen gestorben. Radiochemotherapie oder ausschliesliche Bestrahlung stellt eine sichere Alternative dar, die bei medizinisch als inoperabel eingestuften oder eine Operation verweigernden Patienten in einem signifikant langeren progressionsfreien Uberleben und Gesamtuberleben resultiert. Letztendlich wird die Erkrankung allerdings bei vielen Patienten fortschreiten.

The standard management of rectal cancer continues to be defined by the results of randomized, clinical trials exploring the optimal timing and use of adjuvant chemotherapy and radiation therapy in relation to surgery. The patient with rectal cancer who is elderly and/or has significant comorbidities and the patient who refuses surgery are clinical contexts for which there is limited current data to guide decision making. A retrospective analysis was performed at six Australian centers of patients with rectal cancer treated with radiation therapy or chemoradiation alone because of excessive operative risk or patient refusal of surgery. We identified 48 patients treated between August 1998 and June 2005 with a median age of 76 (range, 49–94) years. Twenty-four patients (50 percent) were considered medically inoperable and 24 patients refused surgery. Treatment was with chemoradiation (with 5-fluorouracil) in 36 patients and radiotherapy alone in 12 patients; 93 percent completed the planned therapy. A clinical complete response was seen in 56 percent and a partial response in 30 percent of patients. At a median follow-up of 49 months, 18 patients have disease progression, including 10 of 24 in the medically inoperable group and 8 of 24 in the refused surgery group. Of the 25 deceased patients, 16 died from progressive disease and 9 from noncancer causes. Chemoradiation or radiotherapy alone is a safe alternative that results in significant progression-free and overall survival times in patients who are considered medically inoperable or refuse to undergo surgery. Ultimately, however, many patients will progress.

Background: Hormone-refractory prostate cancer (HRPC) is associated with a poor prognosis and has historically been considered relatively chemoresistant. Emerging data demonstrate clinical benefit with the use of docetaxel in HRPC, culminating in two recent published phase III studies demonstrating survival benefit. Currently, docetaxel is registered but not reimbursed for HRPC in Australia. Aim: To retrospectively review prostate-specific antigen (PSA) response rate, and survival following the use of docetaxel for metastatic HRPC. Methods: Retrospective audit of the use of docetaxel for HRPC from 1 January 2001 to 1 April 2004 in three medical oncology practices. Demographic data, baseline PSA, ECOG (Eastern Cooperative Oncology Group) Performance Status, sites of disease, number of cycles received and PSA response rates were collected. Results: Thirty five patients (median age, 71 years; range, 50–88) had an ECOG status of 0 (eight), 1 (20) and 2 (seven). The mean duration from initial prostate cancer diagnosis to start of docetaxel was 5.4 years (range, 0.2–13.5 years). The mean baseline PSA doubling time, available for 29/35 patients, was 1.9 months (range, 0.4–4.9). The median number of metastatic sites was 1 (range, 1–4): bone (34 patients), lymph nodes (10), liver (seven) and lung (seven). Twelve patients were chemotherapy naive; 23 had received prior chemotherapy (21/23 received mitoxantrone). Twenty patients received docetaxel three times weekly; 15 were on weekly schedules. Their mean dose density was 23 mg/m2/week. Patients received an average of 3.2 months of treatment (range, 0.2–11.8). There were 170 recorded toxicities, 13 of which were grade 3–4, and two likely treatment-related deaths (sepsis). Twelve patients (34%) had >50% PSA response (four were chemotherapy naive); of these 12 responders, seven patients had a >75% PSA response (four chemotherapy naive). Median survival from start of docetaxel was 8 months with 37% alive at 12 months and 23% alive at 24 months. Conclusion: Docetaxel is active in HRPC (in both chemotherapy naive and exposed patients) with a predictable toxicity profile. More research is warranted to identify predictors of response and toxicity.

Aim: To prospectively evaluate the efficacy and safety of Selective Internal Radiation (SIR) Spheres (Sirtex Medical, Sydney, NSW, Australia) in patients with unresectable primary or secondary hepatic malignancies. Methods: We report our experience of SIR sphere therapy at three Australian centres. Patients with previously untreated colorectal cancer (CRC) received concurrent 5FU, other patients with CRC received 5-FU at investigator discretion and all other patients received SIR spheres alone. Results: Forty-six patients were enrolled between January 2002 and June 2003. The majority (32 patients) had metastatic colorectal cancer and five patients had hepatocellular carcinoma. The median age of patients was 64 years (range 46–78 years). Forty-three patients were evaluable for response. There were 12 partial responses, of which 10 were in patients with CRC. The median duration of response for all patients was 8.6 months (range 2–21 months). Overall treatment related toxicity was acceptable. Significant late toxicity included four cases of severe gastric ulceration, despite standard work-up and treatment by experienced interventional radiologists. Conclusion: In this series of patients, treatment with SIR-spheres has demonstrated modest activity, mostly observed in patients with CRC. Toxicity was substantial in a small number of patients. (Intern Med J 2005; 35: 222–227)

France has long been on the 'bleeding edge' of international terrorism. In the last 20 years in particular, it has suffered repeated waves of both international and domestic terror. As a result, France has developed, largely by costly trial and error, a fairly effective system for fighting terrorism at home. This system is uniquely French, tailored to France's particular threats, capacities and civic culture. Nonetheless, there are lessons from France's experience for other countries, including the United States. Three stand out: the advantages of a centralised and specialised judicial process; the importance of creating strong, trusting relationships between judicial and intelligence organisations; and the need to understand the interaction between counter-terrorism efforts at home and abroad.

BACKGROUND The authors combined cisplatin and carboplatin together with cyclophosphamide to maximize platinum dose intensity in patients with advanced epithelial ovarian cancer (AOC). METHODS The authors treated 26 consecutive, newly diagnosed patients with International Federation of Gynecology and Obstetrics (FIGO) Stage III/IV AOC with carboplatin, 600 mg/m2, on Day 1; cyclophosphamide, 250 mg/m2, on Day 1; and cisplatin, 100 mg/m2, on Day 8 every 4 weeks with or without pretreatment with amifostine (range, 740-1140 mg/m2). Platinum dose intensity was estimated using a 4:1 conversion for equipotent doses of cisplatin and carboplatin for expression as cisplatin dose equivalents (CDE). RESULTS The mean administered CDE was 49.4 mg/m2/week, which was 79% of the planned dose. Hematologic toxicity was severe, with FIGO Grade 3-4 anemia in 81% of patients, Grade 3-4 neutropenia in 92% of patients, and Grade 4 thrombocytopenia in 96% of patients. Eleven patients (42%) were admitted to the hospital for febrile neutropenia and there was 1 toxic death. Sensory neuropathy ≥ Grade 2 occurred in 10 patients (38%), ototoxicity ≥ Grade 2 occurred in 18 patients (69%), and 6 patients (23%) required long term hearing aids. Elevations in serum creatinine ≥ Grade 2 occurred in 7 patients (27%) and ≥ Grade 2 hypomagnesemia was noted in 23 patients (88%). Other Grade 3 toxicities were nausea (42%), emesis (38%), fatigue (15%), mucositis (4%), and respiratory toxicities (4%). Twenty-two of 26 patients (85%) had a clinical response (19 with a complete response [CR] and 3 with a partial response). Pathologic CR was demonstrated in 10 of 26 patients (38%) and residual microscopic disease in 4 of 26 patients (15%) for a total pathologic response rate of 53%. The median progression free survival was 13.5 months and the median overall survival was 37.2 months at a median potential follow-up of 79.3 months. Three of 26 patients remained free of disease at 66, 71, and 103 months, respectively. CONCLUSIONS Although dose intensive combination platinum treatment combined with cyclophosphamide in patients with AOC is active, it also is associated with substantial toxicity. Cancer 1998;83:1980-1988. © 1998 American Cancer Society.

To compare and contrast the clinical outcomes in critically ill patients with acute renal failure managed with either acute continuous hemodiafiltration or conventional dialytic therapies.Retrospective review of the medical records of 167 consecutive cases of acute renal failure treated at a single center (July 1982-July 1991). Scoring for illness severity (APACHE II, number of failing organs) and assessment of outcome in terms of biochemical control of azotemia, ARF therapy-related morbidity, and overall morbidity and mortality.Tertiary institution.167 consecutive critically ill patients with multiorgan failure and acute renal failure.84 patients received conventional dialytic therapy (CDT) (1982-1988) and 83 acute continuous hemodiafiltration (ACHD) (1988-1991). The etiology of ARF and illness severity indices were similar in both groups (organ failure scores: CDT 3.9 vs. ACHD 4.1; NS). All patients were critically ill, with more severely ill patients within the ACHD groups (mean APACHE II score: CDT 25.8 vs. ACHD 28.1; p.01). There were no significant differences in pretreatment serum creatinine, glucose, bicarbonate and phosphate, white cell and platelet counts, incidence of disseminated intravascular coagulation, prevalence of sepsis, or evidence of pulmonary and/or peripheral edema. Overall survival was 29.8% for the CDT groups and 41% for the ACHD group (NS). When patients were stratified by severity of illness, survival in those with 2 to 4 failing organs was significantly greater in the ACHD group (CDT 31.1% vs. ACHD 53.8%; p.025). Similarly, overall survival in patients with intermediate APACHE II scores (24 to 29) was significantly better in those treated with ACHD (CDT 12.5% vs. ACHD 46.4%; p.025). During the course of ARF, in comparison to CDT, ACHD was associated with greater overall reductions in serum creatinine, and in phosphate and plasma urea, and an increased net nutritional intake.ACHD provided biochemical and outcome indicator advantages over conventional dialytic therapy. In patients with 2 to 4 failing organs or an intermediate APACHE II score (24 to 29) a significant survival advantage was demonstrated for ACHD over CDT. Although this study is a retrospective analysis, with all the inherent limitations of such studies, it suggests that ACHD is the treatment of choice for ARF in the critically ill, with maximum benefits seen in those with 2 to 4 failing organs and/or intermediate APACHE II scores.

We present results from six randomized control trials of an integrated approach to improve livelihoods among the very poor. The approach combines the transfer of a productive asset with consumption support, training, and coaching plus savings encouragement and health education and/or services. Results from the implementation of the same basic program, adapted to a wide variety of geographic and institutional contexts and with multiple implementing partners, show statistically significant cost-effective impacts on consumption (fueled mostly by increases in self-employment income) and psychosocial status of the targeted households. The impact on the poor households lasted at least a year after all implementation ended. It is possible to make sustainable improvements in the economic status of the poor with a relatively short-term intervention.

The prevention of postoperative infection complications in a patient with chronic idiopathic neutropenia treated with granulocyte colony stimulating factor (G-CSF) is reported. A 48-year-old woman who presented with chronic idiopathic neutropenia causing life-long recurrent infections, and postoperative suppurative wound infections, presented for elective coronary artery surgery. The patient was successfully treated with G-CSF, resulting in a significantly higher neutrophil count and no infection complications in the peri-operative period. Peri-operative G-CSF therapy in patients with chronic idiopathic neutropenia is effective in increasing the total neutrophil count, and decreasing infection complications.