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Inorganic arsenic (NaAsO 2 ) is a naturally occurring metalloid found in water resources globally and in the United States at concentrations exceeding the U.S. Environmental Protection Agency Maximum Contamination Level of 10 ppb. While exposure to arsenic has been linked to cancer, cardiovascular disease, and skin lesions, the impact of arsenic exposure on wound healing is not fully understood. Cultured dermal fibroblasts exposed to NaAsO 2 displayed reduced migration (scratch closure), proliferation, and viability with a lowest observable effect level (LOEL) of 10 µM NaAsO 2 following 24 h exposure. An enrichment of Matrix Metalloproteinase 1 ( MMP1 ) transcripts was observed at a LOEL of 1 µM NaAsO 2 and 24 h exposure . In vivo, C57BL/6 mice were exposed to 10 µM NaAsO 2 in their drinking water for eight weeks, then subjected to two full thickness dorsal wounds. Wounds were evaluated for closure after 6 days. Female mice displayed a significant reduction in wound closure and higher erythema levels, while males showed no effects. Gene expression analysis from skin excised from the wound site revealed significant enrichment in Arsenic 3-Methyltransferase ( As3mt) and Estrogen Receptor 2 ( Esr2) mRNA in the skin of female mice . These results indicate that arsenic at environmentally relevant concentrations may negatively impact wound healing processes in a sex-specific manner.

We have previously reported that the cortical bone thinning seen in mice lacking the Wnt signaling antagonist Sfrp4 is due in part to impaired periosteal apposition. The periosteum contains cells which function as a reservoir of stem cells and contribute to cortical bone expansion, homeostasis, and repair. However, the local or paracrine factors that govern stem cells within the periosteal niche remain elusive. Cathepsin K (Ctsk), together with additional stem cell surface markers, marks a subset of periosteal stem cells (PSCs) which possess self-renewal ability and inducible multipotency. Sfrp4 is expressed in periosteal Ctsk-lineage cells, and Sfrp4 global deletion decreases the pool of PSCs, impairs their clonal multipotency for differentiation into osteoblasts and chondrocytes and formation of bone organoids. Bulk RNA sequencing analysis of Ctsk-lineage PSCs demonstrated that Sfrp4 deletion down-regulates signaling pathways associated with skeletal development, positive regulation of bone mineralization, and wound healing. Supporting these findings, Sfrp4 deletion hampers the periosteal response to bone injury and impairs Ctsk-lineage periosteal cell recruitment. Ctsk-lineage PSCs express the PTH receptor and PTH treatment increases the % of PSCs, a response not seen in the absence of Sfrp4 . Importantly, in the absence of Sfrp4 , PTH-dependent increase in cortical thickness and periosteal bone formation is markedly impaired. Thus, this study provides insights into the regulation of a specific population of periosteal cells by a secreted local factor, and shows a central role for Sfrp4 in the regulation of Ctsk-lineage periosteal stem cell differentiation and function.

Abstract: The high prevalence of diabetes in Alabama and the limited diabetes education available to patients in that state suggest that new interventions are needed. To that end, the authors developed a project to assess whether the use of telehealth technology to deliver diabetes self-management education and support (DSMES) in a small group setting is an effective and acceptable way to increase access to such education by underserved individuals. Certified diabetes educators, RNs, and telehealth services at three rural county health departments in Alabama implemented a DSMES program. Data were collected from participant registration forms, pre- and postintervention surveys, and telehealth surveys to assess participants' baseline and postintervention diabetes knowledge, self-care, and sense of self-efficacy. Blood pressure, glycated hemoglobin (HbA1c) levels, and weight were also measured before and after the intervention. Forty-two people attended the DSMES program and participated in its evaluation. The findings demonstrated that for this sample, telehealth was an effective and acceptable way to conduct DSMES. The substantial improvements in health status, coupled with the fact that most participants had never participated in a DSMES program before, highlight the untapped potential of such programs to increase access to diabetes education in underserved areas., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Although quality of life (QOL) is an important clinical end point, cancer drugs are often approved based on overall survival (OS) or putative surrogate end points such as progression-free survival (PFS) without QOL data., Objective: To ascertain whether cancer drug trials that show improvement in OS or PFS also improve global QOL of patients with cancer compared with the control treatment, as well as to assess how unchanged or detrimental QOL outcomes are reported in trial publications., Design, Setting, and Participants: This retrospective cohort study included all patients with cancer in the advanced setting who were enrolled into phase 3 randomized clinical trials (RCTs) of cancer drugs reporting QOL data and published in English language in a PubMed-indexed journal in the calendar year 2019. The systematic search of PubMed was conducted in July 2020., Main Outcomes and Measures: Association of QOL outcomes with OS and PFS, framing of unchanged QOL outcomes in trial publications, and the association of favorable framing with industry funding of the trials., Results: A total of 45 phase 3 RCTs enrolling 24 806 participants (13 368 in the experimental arm and 11 438 in the control arm) met the inclusion criteria and were included in the study analyses. Improvement in global QOL with the experimental agent was reported in 11 (24%) RCTs. The RCTs with improved QOL were more likely to also show improved OS vs trials with unimproved QOL (7 of 11 [64%] trials vs 10 of 34 [29%] trials; χ2 = 4.13; P = .04); there was no such association observed for PFS (6 of 11 [55%] trials vs 17 of 34 [50%] trials, χ2 = 0.03; P = .87). Six trials reported worsening QOL, of which 3 (50%) were trials of targeted drugs, and 11 trials reported improvement in QOL, of which 6 (55%) were trials of immunotherapy drugs. Of the 34 trials in which QOL was not improved compared with controls, 16 (47%) reported these results in a positive frame, an observation statistically significantly associated with industry funding (χ2 = 6.35; P = .01)., Conclusions and Relevance: In this cohort study, a small proportion of RCTs of cancer drugs showed benefit in global QOL with the experimental agent. These results showed an association between QOL benefit and OS benefit but no such association with PFS benefit. Trials that failed to show improved QOL often reported their QOL outcomes more favorably. Non-immunotherapy-targeted drugs led to worse QOL more often than did cytotoxic agents.

Existing literature has described the projected increase in cancer incidence and the associated deficiencies in the cancer workforce. However, there is currently a lack of research into the necessary policy and planning steps that can be taken to mitigate this issue. Herein, we review current literature in this space and highlight the importance of implementing oncology workforce registries. We propose the establishment of cancer workforce registries using the WHO Minimum Data Set for Health Workforce Registry by adapting the data set to suit the multidisciplinary nature of the cancer workforce. The cancer workforce registry will track the trends of the workforce, so that evidence can drive decisions at the policy level. The oncology community needs to develop and optimize methods to collect information for these registries. National cancer societies are likely to continue to lead such efforts, but ministries of health, licensing bodies, and academic institutions should contribute and collaborate., Competing Interests: Scott R. BerryStock and Other Ownership Interests: Oncology EducationConsulting or Advisory Role: Merck, MD Briefcase, Apo Biologix, AmgenOther Relationship: Cancerlink/Oncology Education Felipe RoitbergHonoraria: Boehringer Ingelheim, Sanofi, Roche, MSD Oncology, AstraZeneca, Nestle health science, Dr Reddy's, Oncologia BrazilConsulting or Advisory Role: MSD OncologyResearch Funding: Roche, Boehringer Ingelheim, MSD, Bayer, AstraZeneca, TakedaNo other potential conflicts of interest were reported.

Importance: Single-agent immune checkpoint inhibition has not shown activities in advanced refractory colorectal cancer (CRC), other than in those patients who are microsatellite-instability high (MSI-H)., Objective: To evaluate whether combining programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition improved patient survival in metastatic refractory CRC., Design, Setting, and Participants: A randomized phase 2 study was conducted in 27 cancer centers across Canada between August 2016 and June 2017, and data were analyzed on October 18, 2018. Eligible patients had histologically confirmed adenocarcinoma of the colon or rectum; received all available standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab if appropriate; cetuximab or panitumumab if RAS wild-type tumors; regorafenib if available); were aged 18 years or older; had adequate organ function; had Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease., Interventions: We randomly assigned patients to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg durvalumab every 28 days, or best supportive care alone (BSC) in a 2:1 ratio., Main Outcomes and Measures: The primary end point was overall survival (OS) and a 2-sided P<.10 was considered statistically significant. Circulating cell-free DNA from baseline plasma was used to determine microsatellite instability (MSI) and tumor mutation burden (TMB)., Results: Of 180 patients enrolled (121 men [67.2%] and 59 women [32.8%]; median [range] age, 65 [36-87] years), 179 were treated. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (hazard ratio [HR], 0.72; 90% CI, 0.54-0.97; P = .07). Progression-free survival was 1.8 months and 1.9 months respectively (HR, 1.01; 90% CI, 0.76-1.34). Grade 3 or 4 adverse events were significantly more frequent with immunotherapy (75 [64%] patients in the treatment group had at least 1 grade 3 or higher adverse event vs 12 [20%] in the BSC group). Circulating cell-free DNA analysis was successful in 168 of 169 patients with available samples. In patients who were microsatellite stable (MSS), OS was significantly improved with durvalumab and tremelimumab (HR, 0.66; 90% CI, 0.49-0.89; P = .02). Patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) had the greatest OS benefit (HR, 0.34; 90% CI, 0.18-0.63; P = .004)., Conclusions and Relevance: This phase 2 study suggests that combined immune checkpoint inhibition with durvalumab plus tremelimumab may be associated with prolonged OS in patients with advanced refractory CRC. Elevated plasma TMB may select patients most likely to benefit from durvalumab and tremelimumab. Further confirmation studies are warranted., Trial Registration: ClinicalTrials.gov Identifier: NCT02870920.

Background: In Ontario, FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GnP) have been publicly funded for first-line unresectable locally advanced pancreatic cancer (uLAPC) or metastatic pancreatic cancer (mPC) since April 2015. We examined the real-world effectiveness and safety of FFX vs GnP for advanced pancreatic cancer, and in uLAPC and mPC., Methods: Patients receiving first-line FFX or GnP from April 2015 to March 2017 were identified in the New Drug Funding Program database. Baseline characteristics and outcomes were obtained through the Ontario Cancer Registry and other population-based databases. Overall survival (OS) was assessed using Kaplan-Meier and weighted Cox proportional hazard models, weighted by the inverse propensity score adjusting for baseline characteristics. Weighted odds ratio (OR) for hospitalization and emergency department visits (EDV) were estimated from weighted logistic regression models., Results: For 1130 patients (632 FFX, 498 GnP), crude median OS was 9.6 and 6.1 months for FFX and GnP, respectively. Weighted OS was improved for FFX vs GnP (HR = 0.77, 0.70-0.85). Less frequent EDV and hospitalization were observed in FFX (EDV: 67.8%; Hospitalization: 49.2%) than GnP (EDV: 77.7%; Hospitalization: 59.3%). More frequent febrile neutropenia-related hospitalization was observed in FFX (5.8%) than GnP (3.3%). Risk of EDV and hospitalization were significantly lower for FFX vs GnP (EDV: OR = 0.68, P = .0001; Hospitalization: OR = 0.76, P = .002), whereas the risk of febrile neutropenia-related hospitalization was significantly higher (OR = 2.12, P = .001). Outcomes for uLAPC and mPC were similar., Conclusion: In the real world, FFX had longer OS, less frequent all-cause EDV and all-cause hospitalization, but more febrile neutropenia-related hospitalization compared to GnP., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Evidence from a retrospective analysis of multiple large phase iii trials suggested that primary tumour location (ptl) in RAS wild-type metastatic colorectal cancer (wt RAS mcrc) might have predictive value with respect to response to drug therapies. Recent studies also show a potential preferential benefit for epidermal growth factor inhibitors (egfris) for left-sided tumours. In the present study, we aimed to determine the incremental cost-effectiveness ratio (icer) for the first-line use of an egfri for patients with left-sided wt RAS mcrc., Methods: We developed a state-transition model to determine the cost effectiveness of alternative treatment strategies in patients with left-sided mcrc:■ Standard of care■ Use of an egfri in first-line therapyThe cohort for the study consisted of patients diagnosed with unresectable wt RAS mcrc with an indication for chemotherapy and previously documented ptl. Model parameters were obtained from the published literature and calibration. The perspective was that of a provincial ministry of health in Canada. We used a 5-year time horizon and an annual discount rate of 1.5%., Results: Selecting patients for first-line egfri treatment based on left-sided location of their colorectal primary tumour was more effective than the standard of care, resulting in an increase in quality-adjusted life-years (qalys) of 0.226 (or 0.644 life-years gained). However, the strategy was also more expensive, costing an average of $60,639 more per patient treated. The resulting icer was $268,094 per qaly. A 35% price reduction in the cost of egfri would be needed to make this strategy cost-effective at a willingness-to-pay threshold (wtp) of $100,000 per qaly., Conclusions: Selective use of an egfri based on ptl was more cost-effective than unselected use of those agents; however, based on traditional wtp thresholds, it was still not cost-effective. While awaiting the elucidation of more precise predictive biomarkers that might improve cost-effectiveness, the price of egfris could be reduced to meet the wtp threshold., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: WWLW has received research support from the BioCanRx network and the Canadian Liver Foundation; SRB has served on advisory boards for Amgen and Lilly. The remaining authors have no conflicts to disclose., (2019 Multimed Inc.)

Following publication of the original article [1], the author has requested us to make a correction in the Results section of the Abstract and in the Discussion sections as explained below.

Background: Given the high levels of sedentary time and treatment-related side effects in prostate cancer survivors (PCS), interventions targeting sedentary behavior (SED) may be more sustainable compared to physical activity (PA)., Purpose: To examine the feasibility of a web-based intervention (RiseTx) for reducing SED and increasing moderate-to-vigorous physical activity (MVPA) among PCS undergoing ADT. Secondary outcomes include changes in SED, MVPA, light intensity PA, and quality of life., Methods: Forty-six PCS were recruited from two cancer centres in Toronto, Ontario, Canada between July 2015-October 2016. PCS were given an activity tracker (Jawbone), access to the RiseTx website program, and provided with a goal of increasing walking by 3000 daily steps above baseline levels over a 12-week period. A range of support tools were progressively released to reduce SED time (e.g., self-monitoring of steps) during the five-phase program. Objective measures of SED, MVPA, and daily steps were compared across the 12-week intervention using linear mixed models., Results: Of the 46 PCS enrolled in the study, 42 completed the SED intervention, representing a 9% attrition rate. Measurement completion rates were 97 and 65% at immediately post-intervention and 12-week follow-up for all measures, respectively. Overall adherence was 64% for total number of logins (i.e., > 3 visits each week). Sample mean age was 73.2 ± 7.3 years, mean BMI was 28.0 ± 3.0 kg/m 2 , mean number of months since diagnosis was 93.6 ± 71.2, and 72% had ADT administered continuously. Significant reductions of 455.4 weekly minutes of SED time were observed at post-intervention (p = .005). Significant increases of + 44.1 for weekly minutes of MVPA was observed at immediately post-intervention (p = .010). There were significant increases in step counts of + 1535 steps from baseline to post-intervention (p < .001)., Conclusions: RiseTx was successful in reducing SED and increasing MVPA in PCS. PCS were satisfied with the intervention and its components. Additional strategies may be needed though for maintenance of behavior change. The next step for RiseTx is to replicate these findings in a larger, randomized controlled trial that will have the potential for reducing sedentary time among PCS., Trial Registration: NCT03321149 (ClinicalTrials.gov Identifier).

Importance: Recent data have suggested that disease biology and outcome of colon cancer may differ between right-sided and left-sided tumors. However, the literature on the prognostic value of tumor laterality is conflicting., Objective: To explore differences in laterality based on disease characteristics and outcomes in a population-based cohort of early-stage colon cancer., Design, Setting, and Participants: This investigation was a population-based retrospective cohort study of patients with early-stage colon cancer from the province of Ontario, Canada. Electronic records of treatment were linked to the Ontario Cancer Registry to identify all patients with colon cancer who underwent resection between January 1, 2002, and December 31, 2008. The date of the final analysis was October 20, 2016. The study population included a 25% random sample of all patients with resected stage I to III disease. Right-sided colon cancer was defined as any tumor arising in the cecum, ascending colon, hepatic flexure, or transverse colon. Left-sided colon cancer was defined as any tumor arising in the splenic flexure, descending colon, sigmoid colon, or rectosigmoid colon., Main Outcomes and Measures: Overall survival (OS) and cancer-specific survival (CSS) measured from the time of resection., Results: This study identified 6365 patients with early-stage colon cancer (48.7% [3098 of 6365] female). Their median age was 72 years, and 51.7% (3291 of 6365) had right-sided disease. Stage distribution was 18.3% (1163 of 6365) stage I, 38.4% (2446 of 6365) stage II, and 43.3% (2756 of 6365) stage III. Patients with right-sided colon cancer were more likely to be older (median age, 73 vs 70 years; P < .001) and female (54.4% [1790 of 3291] vs 42.6% [1308 of 3074], P < .001) and have greater comorbidity. Right-sided cancers were more likely to be T4 (19.2% [631 of 3291] vs 15.9% [490 of 3074], P < .001) and poorly differentiated (21.1% [695 of 3291] vs 9.6% [295 of 3074], P < .001) but less likely to be node positive (42.0% [1383 of 3291] vs 44.7% [1373 of 3074], P = .03) compared with left-sided disease. In adjusted analyses, there was no difference in long-term survival for right-sided compared with left-sided colon cancer: the hazard ratios were 1.00 (95% CI, 0.92-1.08) for OS and 1.00 (95% CI, 0.91-1.10) for CSS. These results were consistent when the survival analyses were restricted to stage III disease: the hazard ratios were 1.03 (95% CI, 0.93-1.14) for OS and 1.10 (95% CI, 0.97-1.24) for CSS., Conclusions and Relevance: In this population-based cohort of early-stage resected colon cancer, disease laterality was not associated with long-term OS or CSS.

Aim: The Alabama Health Action Coalition is a state coalition whose purpose is to enable access to high-quality, safe, and patient-centered health care for all Alabamians by leading change in nursing and health care., Background: The Alabama Health Action Coalition has four focus areas: advancing nursing education, improving nursing workforce data, promoting diversity among nursing and health care professionals, and fostering a culture of health., Method: From 2012 to 2014, the Advancing Education Taskforce and Health Workforce Committee initiated processes to maximize resources, track changes in workforce data, and provide support for goal achievement., Results: Outcomes included an increase in the number of nurses with a BSN and higher degrees from 35 percent to 50 percent, nearing national averages., Conclusion: Tracking of trends continues with 2016 data. This growth is particularly important in a state with a large, underserved population and high percentage of rural areas.

Purpose: Abiraterone acetate (AA), used to treat metastatic castration-resistant prostate cancer (mCRPC), inhibits androgen biosynthesis by blocking cytochrome P450 (CYP) 17A1. It also inhibits other cytochromes involved in the metabolism of various widely used medications. As such, there is presumably a high potential for drug-drug interactions (DDIs) that can diminish the efficacy of AA or concurrent medications, or increase the risk of DDI-related adverse events (AEs). However, the scale of AA-associated DDIs is currently unknown., Methods: We conducted a retrospective review of pharmacy records and electronic patient charts to retrieve individual drug histories and on-treatment AEs of mCRPC patients beginning AA therapy in a tertiary care setting. Potential DDIs were analyzed using two commercial databases, Lexicomp and Micromedex., Results: Eighty-four informative patients were identified. Sixty-five patients (77 %) and 44 patients (52 %) were flagged for one or more potential DDIs by the Lexicomp and Micromedex databases, respectively. One hundred eighty-four potential DDIs were identified overall, with a median of 1 DDI per patient in both databases. Possibly due to rigorous DDI screening before AA treatment initiation, we did not identify a definite instance of DDI-related AEs., Conclusions: The use of commercial DDI databases suggests a substantial risk of potentially consequential DDIs in mCRPC patients undergoing AA therapy. However, prospective investigations with larger patient populations are required to better establish the clinical relevance of these DDIs.

Purpose: Patients with unresectable wild-type KRAS metastatic colorectal cancer benefit from fluoropyrimidines (FP), oxaliplatin (O), irinotecan (I), bevacizumab (Bev), and epithelial growth factor receptor inhibitors (EGFRI). The most cost-effective regimen remains unclear., Methods: A Markov model was constructed to examine the costs and outcomes of three treatment strategies: strategy A (reference strategy): EGFRI monotherapy in third line ([3L]; ie, first-line [1L]: Bev + FOLFIRI [FP + I] or FOLFOX [FP + O]; second line [2L]: FOLFIRI/FOLFOX; 3L: EGFRI); strategy B: EGFRI and I in 3L (ie, 1L: Bev + FOLFIRI/FOLFOX; 2L: FOLFIRI/FOLFOX; 3L: EGFRI + I); and strategy C: EGFRI in 1L (ie, 1L: EGFRI + FOLFIRI/FOLFOX; 2L: Bev + FOLFIRI/FOLFOX; 3L: best supportive care). Efficacy data of the treatments were obtained from the literature. Health system resource use information was derived from chart review and the literature. Using Euro-QOL 5 Dimensions, utilities were obtained by surveying medical oncologists and costs from the Ontario Ministry of Health and the literature. The perspective of the Canadian public health care system was used over a 5-year time horizon with a 5% discount in 2012 Canadian dollars., Results: All three strategies had similar efficacy, but strategy C was most expensive. The incremental cost-effectiveness ratios (ICERs) for strategies B and C compared with A were 119,623 and 3,176,591, respectively. The model was primarily driven by the acquisition cost of the drugs. Strategy B was most cost effective when the willingness-to-pay threshold was > $130,000 per quality-adjusted life-year. Sensitivity analysis showed that strategy C would be cost-effective only when the progression-free survival of EGFRI is better than Bev in 1L with hazard ratio < 0.23 at willingness-to-pay of $150,000 per quality-adjusted life-year., Conclusion: First-line use of EGFRI in metastatic colorectal cancer is not cost effective at its current pricing relative to Bev., (Copyright © 2016 by American Society of Clinical Oncology.)

Purpose/objectives: To describe and understand the perceptions of sedentary behavior (SED) and the interests and preferences for a SED intervention of men on androgen-deprivation therapy (ADT) within a two-phase (formative and intervention research) feasibility study., Research Approach: Qualitative, descriptive., Setting: Princess Margaret Cancer Centre and Odette Cancer Centre, both in Toronto, Ontario, Canada., Participants: 27 men on ADT., Methodologic Approach: Men were recruited from prostate cancer clinics. Nine focus groups were conducted from November 2013 to April 2014 until data saturation was reached. Probe questions assessed perceptions regarding SED and preferences for a mobile SED intervention. Data were transcribed verbatim, and a thematic analysis was conducted., Findings: Twenty-seven men with a mean age of 73.5 years (SD = 8.1 years) volunteered for the study. Most men were aware of the health risks associated with SED, but most discussed SED in terms of increasing physical activity (PA). Many men were interested in a mobile application to reduce SED and expressed that the design should be easy to use, have an alerting function to interrupt sitting, have the ability to track and monitor PA levels, be tailored to the individual, and involve social support., Conclusions: These findings will inform the development and evaluation of a novel SED intervention to improve health outcomes in this population., Interpretation: Oncology nurses may serve as a motivational factor in encouraging men on ADT to reduce SED.

Background: An important goal of intermittent strategies of delivering systemic treatment as first-line treatment of metastatic colorectal cancer (mCRC) is to maintain efficacy while improving patients' quality of life (QoL). Given the varying impact on efficacy demonstrated in individual randomized, controlled trials (RCTs), a systematic review and meta-analysis of RCTs of these intermittent strategies was carried out., Design: Relevant databases were systematically searched for the period 2000-2014. RCTs that compared a continuous versus intermittent strategy of delivering systemic treatment were identified by a systematic review. Overall survival (OS) hazard ratios (HRs) were extracted from the most recently reported trial results. The results of identified trials were clinically homogeneous so the data were pooled using Review Manager software (RevMan 5.1)., Results: Eleven RCTs were identified (n = 4 854). For the eight (n = 4508) trials with available HRs, the treatment patients received after induction was: none (five trials, n = 3036), fluoropyrimidine (one trial, n = 620), and biologic (two trials, n = 852). There were no statistically significant survival differences observed between the continuous and intermittent chemotherapy strategies. There was no statistically significant difference observed between continuous and intermittent strategies [HR = 1.03, 95% confidence interval (CI) 0.96-1.10, P = 0.38)]. Subgroup analyses demonstrated results were generally robust across induction and maintenance regimens. One subgroup analysis of the three trials (CAIRO3, OPTIMOX2, COIN, n = 2403) with combination treatment induction and no maintenance until progression revealed a statistically, but nonclinically significant benefit for continuous treatment (HR = 1.10, 95% CI 1.00-1.20, P = 0.049). QoL life was either the same in both arms in two trials (n = 912) or improved in the intermittent strategy arm in one trial (n = 1630)., Conclusion: Intermittent strategies of delivering systemic treatment of mCRC do not result in a clinically significant reduction in OS compared with a continuous strategy of delivery, and should be part of an informed discussion of treatment options with patients with mCRC., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@ oup.com.)

Purpose: Previous studies have shown hematologists and medical oncologists may not accept the financial limits set by governing agencies on patient access to oral chemotherapy. The purpose of this study was to capture the methods physicians used to overcome barriers to accessing chemotherapeutic regimens for their patients., Methods: A total of 640 medical oncologists and hematologists across Canada were surveyed using a 13-item Web-based survey tool. The survey was delivered by e-mail with three follow-up reminders. After a response period of 3 months, results were collated and analyzed with descriptive statistics., Results: Of the 640 invitations, 568 were successfully delivered, and 183 responses were received (response rate, 32.0%). Among respondents, 101 treated solid malignancies (55.2%), 49 treated nonsolid malignancies (26.8%), and 33 treated both (18.0%). To overcome funding barriers, participating oncologists enrolled patients onto clinical trials (90.5%), used compassionate access programs (96.1%), and made special requests to government (91.8%). Other methods included writing false claims on forms to fit funding criteria for drugs (31.1%) and using leftover drug supplies (31.0%). Physicians felt their inability to obtain unfunded medications had a negative impact on their patients' clinical outcomes (56.0%) and psychosocial quality of life (73.0%). Only 28.5% of physicians contacted their governing body with concerns about oral chemotherapy funding., Conclusion: Canadian physicians use numerous methods to obtain unfunded oral chemotherapies, including falsifying claims on access forms and submitting special requests to government agencies. Further study is warranted to explore the disconnection between policymakers and physicians with regard to funding of oral chemotherapies.

This vignette highlights the ethical issues surrounding restricted access to oncology drugs caused by drug shortages. A review of selected literature and a framework for creating institutional guidelines for reacting to shortage is provided.

Purpose: To evaluate Canadian medical oncologists' perspectives on how barriers to accessing new expensive cancer drugs have affected their practice and their opinions on the drug approval and funding processes., Methods: Canadian medical oncologists treating colorectal cancer (CRC) were surveyed by means of a self-administered, cross-sectional survey., Results: Of the 164 eligible oncologists, there were 68 respondents (41.4% response rate). Only 29.4% of physicians felt they had been using the ideal first-line chemotherapy regimen for patients with metastatic CRC. Although all considered bevacizumab to be a component of the ideal first-line regimen, only 18% could use bevacizumab routinely, and less than half (44.8%) always discussed its role with their patients. In terms of accessing unfunded drugs, most physicians agreed that private payment should be allowed for drugs to be delivered at their own centers (76.1%) or private infusion clinics (52.2%). Ninety-seven percent of physicians reported major concerns about the drug approval and funding processes, and 85% of physicians supported the establishment of a national drug formulary., Conclusions: Canadian medical oncologists are struggling to provide optimal cancer care for their patients with metastatic CRC as a result of nonuniform access to preferred therapeutic drugs. In face of these challenges, physicians have had to use clinical trials and private infusion clinics and, at times, may avoid discussing drugs with limited access. Many oncologists are dissatisfied with the existing funding mechanism and approval processes and support private payment for unfunded drugs.

Amid calls for physicians to become better stewards of the nation's health care resources, it is important to gain insight into how physicians think about the cost-effectiveness of new treatments. Expensive new cancer treatments that can extend life raise questions about whether physicians are prepared to make "value for money" trade-offs when treating patients. We asked oncologists in the United States and Canada how much benefit, in additional months of life expectancy, a new drug would need to provide to justify its cost and warrant its use in an individual patient. The majority of oncologists agreed that a new cancer treatment that might add a year to a patient's life would be worthwhile if the cost was less than $100,000. But when given a hypothetical case of an individual patient to review, the oncologists also endorsed a hypothetical drug whose cost might be as high as $250,000 per life-year gained. The results show that oncologists are not consistent in deciding how many months an expensive new therapy should extend a person's life before the cost of therapy is justified. Moreover, the benefit that oncologists demand from new treatments in terms of length of survival does not necessarily increase according to the price of the treatment. The findings suggest that policy makers should find ways to improve how physicians are educated on the use of cost-effectiveness information and to influence physician decision making through clinical guidelines that incorporate cost-effectiveness information.

Purpose: New anticancer drugs are improving outcomes for patients with cancer but at significant cost, and some publically funded health care systems have chosen not to fund these medications. Accessing these unfunded drugs concerns patients, challenges their physicians, and raises important policy and legal issues. We assessed Canadian medical oncologists' access to and attitudes toward accessing unfunded intravenous cancer drugs., Methods: Two hundred twenty-two Canadian medical oncologists outside of Québec were surveyed., Results: Response rate was 62% (138 of 222). Respondents could access unfunded cancer drugs (49% at their government-funded hospitals; 70% at nongovernment-funded private infusion clinics), but access varied across the country. A majority of respondents (52% to 67%) were comfortable with accessing unfunded drugs in their own institutions and uncomfortable with accessing these drugs in private clinics in Canada or the United States (52% to 61%), but substantial minorities had opposing opinions. The majority of respondents felt all methods of accessing unfunded intravenous cancer drugs should be available (76% in their own center; 60% in private clinics) and used these methods to access these medications (81% in their own institution; 62% in private clinics)., Conclusion: Access to effective but unfunded cancer drugs varies across Canada. Policymakers need to consider whether this is consistent with articulated values of the system and whether currently planned processes address these inconsistencies. Key stakeholders need to consider the merits of the different means of accessing these drugs to appropriately and fairly integrate access into publically funded health care systems like that of Canada and other systems like that of the United States, which could face similar limits in the future.

Purpose of Review: This review summarizes recent research on chronic obstructive pulmonary disease (COPD) among older adults., Recent Findings: Recent research on COPD and older adults addresses four key areas: diagnosis and screening, comorbidities, end-of-life care, and management. These key findings include the Rotterdam study's identification of the incidence rate of COPD in older adults being 9.2 per 1000 person-years; a new assessment of FEV1 cut-points associated with increased prevalence of respiratory symptoms and risk of death; development and validation of new mortality scales, the ADO (age, dyspnea, and airflow obstruction) index and the PILE score; older adults with COPD average 9 comorbidities, of which depression, cardiovascular diseases such as hypertension, and chronic renal failure are highly prevalent; nonrespiratory treatments such as proton pump inhibitors, angiotensin-converting enzyme inhibitors, and statins show promise in the management of COPD; and strength may be a protective factor for older adults with COPD., Summary: Findings suggest that more research on older adults and COPD suggest that aging is a determinant of the progression of disease and that management of this population requires different metrics and strategies.

Patients with advanced incurable cancer face complex physical, psychological, social, and spiritual consequences of disease and its treatment. Care for these patients should include an individualized assessment of the patient's needs, goals, and preferences throughout the course of illness. Consideration of disease-directed therapy, symptom management, and attention to quality of life are important aspects of quality cancer care. However, emerging evidence suggests that, too often, realistic conversations about prognosis, the potential benefits and limitations of disease-directed therapy, and the potential role of palliative care, either in conjunction with or as an alternative to disease-directed therapy, occur late in the course of illness or not at all. This article addresses the American Society of Clinical Oncology's (ASCO's) vision for improved communication with and decision making for patients with advanced cancer. This statement advocates an individualized approach to discussing and providing disease-directed and supportive care options for patients with advanced cancer throughout the continuum of care. Building on ASCO's prior statements on end-of-life care (1998) and palliative care (2009), this article reviews the evidence for improved patient care in advanced cancer when patients' individual goals and preferences for care are discussed. It outlines the goals for individualized care, barriers that currently limit realization of this vision, and possible strategies to overcome these barriers that can improve care consistent with the goals of our patients and evidence-based medical practice.

Purpose: To determine antitumor activity of cetuximab monotherapy in patients with refractory metastatic colorectal carcinoma (mCRC) with lack of specific membrane immunostaining for the epidermal growth factor receptor (EGFR)., Patients and Methods: Patients had immunohistochemical (IHC)-determined mCRC with absent EGFR immunostaining that progressed after receiving at least one standard, fluoropyrimidine-containing chemotherapeutic regimen. Absent EGFR immunostaining was defined as the IHC absence of specific membrane staining in ≥500 cancer cells examined in well-preserved tissue. The study was performed prior to results of studies linking cetuximab sensitivity to K-ras mutation status. Patients received 400 mg/m(2) of intravenous (i.v.) cetuximab followed by once-weekly i.v. cetuximab 250 mg/m(2) until disease progression or unacceptable toxicity. Patients were evaluated for objective response at least every 6 weeks. Kaplan-Meier estimates were calculated for duration of response, time to progression (TTP), and overall survival (OS)., Results: Seven (8.2%) of 85 mCRC patients whose tumors lacked EGFR immunostaining had major responses following cetuximab treatment. The median duration of response was 5.1 months. Median TTP and OS were 2.5 months and 10.0 months, respectively; the 1-year survival rate was 39.6%. The most frequently reported cetuximab-related adverse events were acneiform dermatitis, fatigue, headache, and dry skin., Conclusion: Cetuximab monotherapy produces objective antitumor activity in patients with mCRC that does not express EGFR as determined by IHC. The activity and safety profiles of cetuximab monotherapy in mCRC lacking EGFR immunostaining are similar to previous observations in EGFR IHC-positive disease that was not selected based on K-ras mutation status.

Purpose: Oncologists in the United States and Canada work in different health care systems, but physicians in both countries face challenges posed by the rising costs of cancer drugs. We compared their attitudes regarding the costs and cost-effectiveness of medications and related health policy., Methods: Survey responses of a random sample of 1,355 United States and 238 Canadian medical oncologists (all outside of Québec) were compared., Results: Response rate was 59%. More US oncologists (67% v 52%; P < .001) favor access to effective treatments regardless of cost, while more Canadians favor access to effective treatments only if they are cost-effective (75% v 58%; P < .001). Most (84% US, 80% Canadian) oncologists state that patient out-of-pocket costs influence their treatment recommendations, but less than half the respondents always or frequently discuss the costs of treatments with their patients. The majority of oncologists favor more use of cost-effectiveness data in coverage decisions (80% US, 69% Canadian; P = .004), but fewer than half the oncologists in both countries feel well equipped to use cost-effectiveness information. Majorities of oncologists favor government price controls (57% US, 68% Canadian; P = .01), but less than half favor more cost-sharing by patients (29% US, 41% Canadian; P = .004). Oncologists in both countries prefer to have physicians and nonprofit agencies determine whether drugs provide good value., Conclusion: Oncologists in the United States and Canada generally have similar attitudes regarding cancer drug costs, cost-effectiveness, and associated policies, despite practicing in different health care systems. The results support providing education to help oncologists in both countries use cost-effectiveness information and discuss drug costs with their patients.

Background: Health care policies, including drug-funding policies, influence physician practice. Funding policies are especially important in the area of cancer care since cancer is a leading cause of death that is responsible for a significant level of health care expenditures. Recognizing the rising cost of cancer therapies, Cancer Care Ontario (CCO) established a funding process to provide access to new, effective agents through a "New Drug Funding Program" (NDFP). The purpose of this study is to describe oncologists' perceptions of the impact of NDFP priority setting decisions on their practice., Methods: This is a qualitative study involving semi-structured, in-depth interviews with 46 medical oncologists in Ontario. Oncologists were asked to describe the impact of CCO's NDFP drug funding decisions on their practice. Analysis of interview transcripts commenced with data collection., Results: Our key finding is that many of the medical oncologists who participated in this study did not accept limits when policy decisions limit access to cancer drugs they feel would benefit their patients. Moreover, overcoming those limits had a significant impact on oncologists' practice in terms of how they spend their time and energy and their relationship with patients., Conclusion: When priority setting decisions limit access to cancer medications, many oncologists' efforts to overcome those limits have a significant impact on their practice. Policy makers need to seriously consider the implications of their decisions on physicians, who may go to considerable effort to circumvent their policies in the name of patient advocacy.

Background and Aim: The gap between the demand for liver transplantation and organ donation rates has a major impact on waiting list mortality. Understanding the risk factors that predict liver transplant waiting list death may help optimize organ allocation policy and reduce waiting list deaths., Methods: We analyzed risk factors associated with waiting list mortality in the Liver Transplant Unit Victoria for the period 1988 through 2004., Results: The mean annual waiting list mortality for the period examined was 10.2% (10.6% for adult and 6.4% for pediatric patients). Factors associated with waiting list death included female sex, fulminant hepatic failure, primary non-function, blood group O, more urgent United Network for Organ Sharing (UNOS)-derived medical status, a Child-Turcotte-Pugh (CTP) score >or=11, a model for end-stage liver disease (MELD) score >or=20, and a pediatric end-stage liver disease score >or=20. UNOS-derived medical status, CTP class, and MELD score were significant at the multivariate level., Conclusions: Disease severity scores, such as MELD, predict the risk of liver transplantation waiting list mortality. Use of such scores in organ allocation in Australian liver transplant units may result in reduced waiting list mortality.

Methods for accurately characterizing aerosols are required for detecting biological warfare agents. Currently, fluorescence-based biological agent sensors provide adequate detection sensitivity but suffer from high false-alarm rates. Combining single-particle fluorescence analysis with laser-induced breakdown spectroscopy (LIBS) provides additional discrimination and potentially reduces false-alarm rates. A transportable UV laser-induced fluorescence-cued LIBS test bed has been developed and used to evaluate the utility of LIBS for biological-agent detection. Analysis of these data indicates that LIBS adds discrimination capability to fluorescence-based biological-agent detectors. However, the data also show that LIBS signatures of biological agent simulants are affected by washing. This may limit the specificity of LIBS and narrow the scope of its applicability in biological-agent detection.

Minimization of death while waiting for liver transplantation involves accurate prioritization according to clinical status and appropriate allocation of donor livers. Clinical judgment in the Liver Transplant Unit Victoria (LTUV) was compared with Model for End-Stage Liver Disease (MELD) in a retrospective analysis of the LTUV database over the 2-year period August 1, 2002, through July 31, 2004. A total of 1,118 prioritization decisions occurred. Decisions were concordant in 758 (68%), comparing priorities assigned by clinical judgment with those assigned by MELD, P < 0.01. A total of 263 allocation decisions occurred. Decisions were concordant in 190 (72%) and 203 (77%) of the cases, comparing donor liver allocation with prioritization by MELD and clinical judgment, respectively. Of the 52 patients allocated a liver, only 23 would have been allocated on the basis of MELD while 29 had been prioritized on the waiting list in the week prior to transplantation. A total of 10 patients died on the waiting list in the 2-year period (annual adult waiting list mortality is 9.3%). Patients who subsequently died waiting were 3 times as likely to be prioritized by MELD as clinical judgment (29% vs. 9%, respectively). One half (3 of 6) of the patients who could have received a donor liver but who died waiting would have been allocated the organ on the basis of MELD. In conclusion, an allocation process based on MELD rather than clinical judgment would significantly alter organ allocation in Australia and may reduce waiting list mortality.

Background: Advance directives are an important part of end of life care, but current advance directive documents do not address the specific issues facing cancer patients. The authors' purpose was: 1) to develop a cancer specific advance directive, 2) determine whether oncology outpatients find this directive more acceptable than a generic advance directive, and 3) describe oncology outpatient preferences for life-sustaining treatment., Methods: A cancer specific advance directive ("The Cancer Living Will"; the full text of the updated version is available at the University of Toronto Joint Centre for Bioethics website [URL: www.utoronto.ca/jcb]) was developed in four steps: 1) literature search, 2) key informant interviews, 3) focus groups, and 4) evaluation of face and content validity. Subsequently, 91 volunteer oncology patients were given copies of the cancer specific advance directive and the generic advance directive ("The University of Toronto Centre for Bioethics Living Will") from which it was adapted. Acceptability of the advance directive was measured by determining the participants' preferred directive. Participants recorded their treatment preferences in both the cancer specific and generic advance directives., Results: Of 60 patients who returned their questionnaires, 50 expressed a preference for the advance directive. Thirty-two patients (64%; 95% confidence interval (CI), 49-77%) preferred the disease specific Cancer Living Will and 18 patients (36%; 95% CI, 23-51%) preferred the generic Centre for Bioethics Living Will. Most participants who preferred the Cancer Living Will did so because it was more specific and relevant to their situation., Conclusions: The authors have developed and evaluated a cancer specific advance directive that they believe can be recommended for clinical use with cancer patients.