Showing papers by "Bishal Gyawali published in 2018"

Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global Burden of Disease Study.

Abstract: Importance The increasing burden due to cancer and other noncommunicable diseases poses a threat to human development, which has resulted in global political commitments reflected in the Sustainable Development Goals as well as the World Health Organization (WHO) Global Action Plan on Non-Communicable Diseases. To determine if these commitments have resulted in improved cancer control, quantitative assessments of the cancer burden are required. Objective To assess the burden for 29 cancer groups over time to provide a framework for policy discussion, resource allocation, and research focus. Evidence Review Cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs) were evaluated for 195 countries and territories by age and sex using the Global Burden of Disease study estimation methods. Levels and trends were analyzed over time, as well as by the Sociodemographic Index (SDI). Changes in incident cases were categorized by changes due to epidemiological vs demographic transition. Findings In 2016, there were 17.2 million cancer cases worldwide and 8.9 million deaths. Cancer cases increased by 28% between 2006 and 2016. The smallest increase was seen in high SDI countries. Globally, population aging contributed 17%; population growth, 12%; and changes in age-specific rates, −1% to this change. The most common incident cancer globally for men was prostate cancer (1.4 million cases). The leading cause of cancer deaths and DALYs was tracheal, bronchus, and lung cancer (1.2 million deaths and 25.4 million DALYs). For women, the most common incident cancer and the leading cause of cancer deaths and DALYs was breast cancer (1.7 million incident cases, 535 000 deaths, and 14.9 million DALYs). In 2016, cancer caused 213.2 million DALYs globally for both sexes combined. Between 2006 and 2016, the average annual age-standardized incidence rates for all cancers combined increased in 130 of 195 countries or territories, and the average annual age-standardized death rates decreased within that timeframe in 143 of 195 countries or territories. Conclusions and Relevance Large disparities exist between countries in cancer incidence, deaths, and associated disability. Scaling up cancer prevention and ensuring universal access to cancer care are required for health equity and to fulfill the global commitments for noncommunicable disease and cancer control.

Autologous Transplantation for Newly Diagnosed Multiple Myeloma in the Era of Novel Agent Induction: A Systematic Review and Meta-analysis.

Abstract: Importance The role of high-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) in patients with multiple myeloma continues to be debated in the context of novel agent induction. Objective To perform a systematic review, conventional meta-analysis, and network meta-analysis of all phase 3 randomized clinical trials (RCTs) evaluating the role of HDT/ASCT. Data Sources We performed a systematic literature search of Cochrane Central, MEDLINE, and Scopus from January 2000 through April 2017 and relevant annual meeting abstracts from January 2014 to December 2016. The following search terms were used: “myeloma” combined with “autologous,” “transplant,” “myeloablative,” or “stem cell.” Study Selection Phase 3 RCTs comparing HDT/ASCT with standard-dose therapy (SDT) using novel agents were assessed. Studies comparing single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation and tandem transplantation were included for network meta-analysis. Data Extraction And Synthesis For the random effects meta-analysis, we used hazard ratios (HRs) and corresponding 95% CIs. Main Outcomes and Measures The primary outcome was progression-free survival (PFS). Overall survival (OS), complete response, and treatment-related mortality were secondary outcomes. Results A total of 4 RCTs (2421 patients) for conventional meta-analysis and 5 RCTs (3171 patients) for network meta-analysis were selected. The combined odds for complete response were 1.27 (95% CI, 0.97-1.65;P = .07) with HDT/ASCT when compared with SDT. The combined HR for PFS was 0.55 (95% CI, 0.41-0.74;P Conclusions and Relevance The results of the conventional meta-analysis and network meta-analysis of all the phase 3 RCTs showed that HDT/ASCT was associated with superior PFS with minimal toxic effects compared with SDT. Both tandem HDT/ASCT and single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone were superior to single HDT/ASCT alone and SDT for PFS, but OS was similar across the 4 approaches. Longer follow-up may better delineate any OS benefit; however, is likely to be affected by effective postrelapse therapy.

ReDO_DB: the repurposing drugs in oncology database.

Abstract: Repurposing is a drug development strategy that seeks to use existing medications for new indications. In oncology, there is an increased level of activity looking at the use of non-cancer drugs as possible cancer treatments. The Repurposing Drugs in Oncology (ReDO) project has used a literature-based approach to identify licensed non-cancer drugs with published evidence of anticancer activity. Data from 268 drugs have been included in a database (ReDO_DB) developed by the ReDO project. Summary results are outlined and an assessment of clinical trial activity also described. The database has been made available as an online open-access resource (http://www.redo-project.org/db/).

Awareness, prevalence, treatment, and control of type 2 diabetes in a semi-urban area of Nepal: Findings from a cross-sectional study conducted as a part of COBIN-D trial.

Abstract: Background Type 2 diabetes is an escalating public health problem in Nepal. The current study aims to assess the prevalence, associated factors, awareness, treatment, and control of type 2 diabetes in a semi-urban area of Nepal. Methods A population-based cross-sectional survey was conducted including 2,310 adults aged 25 years or above from a semi-urban area of Lekhnath Municipality of Nepal, during October 2016 to April 2017 using the World Health Organization (WHO) STEPS approach. Data on demographics, behavioral risk factors, blood pressure, anthropometric measurements (weight, height, waist and hip circumference), and fasting blood glucose were collected by face-to-face interviews during a door-to-door visit. Participants were considered to have type 2 diabetes if they had previously been diagnosed by a physician and/or were on antidiabetic medications and/or had fasting blood glucose ≥ 7.0 mmol/L. Participants were classified as being aware of their diabetes conditions if they had earlier been told that they had type 2 diabetes. Treatment of diabetes among those aware was if participants received any kind of medication treatment or counseling, and control of diabetes among those treated was defined as fasting blood glucose level was <7.0 mmol/L. Odds Ratio (OR) with 95% Confidence Interval (CI) was used to determine the strength of association. Results The prevalence of type 2 diabetes was 11.7% (95% CI: 10.5–13.1). Among type 2 diabetes participants, 65% were aware of their disease, 94% of those who were aware received treatment, and 21% of the treated subjects had their diabetes under control. Factors significantly associated with type 2 diabetes were older age (OR = 3.2 for age group 45–54 years, OR = 3.8 for age group 55–64 years), Janajati ethnicity (OR = 1.4), abdominal obesity (OR = 2.3), being overweight or obese (OR = 1.4), and hypertension (OR = 2.0), while protective factors included being a female (OR = 0.4), medium physical activity (OR = 0.3), high physical activity (OR = 0.2), and not having family history of diabetes (OR = 0.3). Conclusions The study revealed a high prevalence of type 2 diabetes among adults. Older age, male gender, Janajati ethnicity, abdominal obesity, overweight or obesity, hypertension, low physical activity, and family history of diabetes were associated with type 2 diabetes. Immediate public health and individual measures are warranted to reduce further burden of type 2 diabetes.

Efficacy, Safety, and Regulatory Approval of Food and Drug Administration-Designated Breakthrough and Nonbreakthrough Cancer Medicines.

Abstract: Purpose The breakthrough therapy program was established in 2012 to expedite the development and review of new medicines. We evaluated the times to approval, efficacy, and safety of breakthrough-designated versus non-breakthrough-designated cancer drugs approved by the US Food and Drug Administration (FDA). Methods We studied all new cancer drugs approved by the FDA between January 2012 and December 2017. Regulatory and therapeutic characteristics (time to FDA approval, pivotal trial efficacy end point, novelty of mechanism of action) were compared between breakthrough-designated and non-breakthrough-designated cancer drugs. Random-effects meta-regression was used to assess the association between breakthrough therapy designation and hazard ratios for progression-free survival (PFS), response rates (RRs) for solid tumors, serious adverse events, and deaths not attributed to disease progression. Results Between 2012 and 2017, the FDA approved 58 new cancer drugs, 25 (43%) of which received breakthrough therapy designation. The median time to first FDA approval was 5.2 years for breakthrough-designated drugs versus 7.1 years for non-breakthrough-designated drugs (difference, 1.9 years; P = .01). There were no statistically significant differences between breakthrough-designated and non-breakthrough-designated drugs in median PFS gains (8.6 v 4.0 months; P = .11), hazard ratios for PFS (0.43 v 0.51; P = .28), or RRs for solid tumors (37% v 39%; P = .74). Breakthrough therapy-designated drugs were not more likely to act via a novel mechanism of action (36% v 39%; P = 1.00). Rates of deaths (6% v 4%; P = .99) and serious adverse events (38% v 36%; P = 0.93) were also similar in breakthrough-designated and non-breakthrough-designated drugs. Conclusion Breakthrough-designated cancer drugs were associated with faster times to approval, but there was no evidence that these drugs provide improvements in safety or novelty; nor was there a statistically significant efficacy advantage when compared with non-breakthrough-designated drugs.

A Comparison of Response Patterns for Progression-Free Survival and Overall Survival Following Treatment for Cancer With PD-1 Inhibitors: A Meta-analysis of Correlation and Differences in Effect Sizes

Abstract: Importance Based on efficacy results from pivotal randomized clinical trials, PD-1 (programmed cell death 1) inhibitors, such as nivolumab and pembrolizumab, have been approved to treat various cancers. Response patterns with varying effects on progression-free survival (PFS) and overall survival (OS) have been reported for these drugs. Objective To compare 2 outcomes for PD-1 inhibitors: the correlation between PFS and OS and the differences in treatment effect size between PFS and OS. Data Sources A systematic search of PubMed, Google Scholar, the Cochrane Library, Web of Science, and conference abstracts for randomized clinical trials of nivolumab and pembrolizumab published in English. Study Selection Randomized clinical trials of nivolumab or pembrolizumab in adults with solid-tissue cancers with a nonimmunotherapy control. Data Extraction and Synthesis Two reviewers screened the studies for selection and extracted data on medians and hazard ratios (HRs) for PFS and OS. A pooled meta-analysis was conducted. Main Outcomes and Measures Across all trials, correlation coefficients between median PFS and median OS and between PFS benefit and OS benefit as well as the HRs of PFS and OS were assessed. The difference in treatment effect sizes between PFS and OS was assessed using a ratio of HRs (rHR). Subgroup analyses were conducted to observe differences based on drug, tumor type, and timing of therapy. Results Ten randomized clinical trials that included 4653 patients and met inclusion criteria were identified, as were 2 others (comprising 764 patients) in which nivolumab or pembrolizumab was used following treatment with ipilimumab. The correlations between median PFS and median OS (r = 0.676;R2 = 0.457;P = .09) and the correlations between the change in PFS and the change in OS (r = 0.474;R2 = 0.225;P = .28) were not significant. However, the correlation between HRs of PFS and OS was significant (r = 0.637;R2 = 0.406;P = .048). Using random-effects meta-analysis, the protective effects of treatment were greater for OS than for PFS (pooled rHR, 1.18; 95% CI, 1.06-1.31;P = .002). There was no statistical evidence for heterogeneity across the studies (Q = 6.24;P = .72;I2 = 0%). Subgroup analyses showed some differences in the treatment effect sizes based on drug type, tumor type, and line of therapy. Conclusions and Relevance There was no significant correlation between OS and PFS in terms of medians and gains in medians, but their HRs were significantly correlated. The protective effects of treatment were greater for OS than for PFS. Traditional Response Evaluation Criteria in Solid Tumors–based PFS cannot capture the benefit of PD-1 inhibitors in patients with solid tumors, and OS should remain the gold standard.

Socioeconomic and health system factors associated with lower utilization of hematopoietic cell transplantation in older patients with acute myeloid leukemia

Abstract: Receipt of hematopoietic cell transplantation (HCT) can improve overall survival in older patients with intermediate or high-risk acute myeloid leukemia (AML); however, utilization of HCT is poor. It is important to understand the factors that affect the receipt of HCT in a real-world setting among the older patients. We utilized the National Cancer Database to determine receipt of HCT in older patients (61–75 years) with intermediate or high-risk AML reported between 2003 and 2012. Multivariate logistic regression analysis was used to determine factors associated with receipt of HCT. Only 5.5% of older patients (n = 17,555) underwent HCT. Factors associated with a lower likelihood of receiving HCT included receipt of care in a non-academic hospital, race other than white, older age, Charlson comorbidity score of ≥1, uninsured status, Medicaid or Medicare insurance, and lower educational status. The receipt of HCT in older patients is low and varies based on biological as well as non-biologic factors, such as hospital type, insurance, and educational status. Nationwide efforts to improve access to HCT for appropriate patients are necessary.

A prospective survey of comprehensive score for financial toxicity in Japanese cancer patients: report on a pilot study.

Abstract: Background Financial toxicity (FT) has a negative impact on the quality of life and survival of patients with cancer. The comprehensive score for FT (COST) questionnaire is a tool to measure FT which has already been validated in patients with cancer in the United States. However, the feasibility and validity of assessing FT using the COST questionnaire have not been established in non-US healthcare settings, including that in Japan. Methods This is a prospective pilot survey to ascertain the feasibility of using the COST questionnaire to evaluate FT in Japanese patients with advanced solid cancer who had been receiving chemotherapy for at least 2 months. The COST questionnaire was translated into Japanese using Functional Assessment of Chronic Illness Therapy methodology. Results Of the 12 patients approached, 11 (92%) responded to the questionnaire. The median COST score was 22 (range, 6-29; mean ± SD, 20.18 ± 8.17). Five (45%) and two (18%) patients suffered grade 1 (COST score 14-25) and grade 2 (COST score 1-13) FT, respectively. The COST measure demonstrated good internal consistency with a Cronbach α of 0.87. Conclusions The COST measure demonstrated good feasibility in measuring FT in the Japanese healthcare setting. Despite the existing universal health insurance system and ceiling amount for high-cost medical expenses, some Japanese patients experienced meaningful FT during chemotherapy. A prospective study is already underway to confirm the preliminary results (UMIN: 000025043).

Reporting harms more transparently in trials of cancer drugs

Abstract: Studies of cancer drugs often use terms that downplay the seriousness of adverse events. Bishal Gyawali and colleagues call for greater clarity and transparency

Diabetes management training for female community health volunteers in Western Nepal: an implementation experience

Abstract: In the backdroup of a rapidly increasing burden of diabetes in Nepal, a community-based diabetes management program is implemented involving female community health volunteers (FCHVs) under the government run FCHVs program. FCHVs received an intensive one-week training workshop on prevention, control and management of diabetes. The training program was implemented and evaluated to enhance diabetes knowledge of FCHVs and matched according to their literacy level. A range of teaching methods were applied, including desk review, active participation, lectures, presentations, discussions, role plays, demonstration and field test. Evaluation of the knowledge attained was done by testing before and after the workshop. Major milestones in the development of the training module were presented from desk review and ending in stakeholder’s participation in reviewing and revising the training package. The qualitative interview transcripts of FCHVs were analyzed thematically. A 5-day training package was developed through a desk review of interventions using community health workers (CHWs) on diabetes management from similar settings. Training module included home-based blood glucose monitoring and home-based health education on life style counselling delivered through a participatory learning approach. There were 20 participants with a mean age of 47 years (SD ± 5.7). The overall assessment of knowledge of diabetes before-after the training, evaluated by the Diabetes Knowledge Questionnaire (DKQ) showed increases in mean score from 40.4% before training to a mean score of 63.3% after training (Paired t-test: t = − 11.1, P < 0.001, and Wilcoxon test for paired samples: z = − 3.930, P = 0.0001). Focus group discussions (FGDs) revealed that FCHVs had a favorable perception of the training program’s effectiveness. If FCHVs are appropriately trained they may be instrumental in providing counseling and screening for diabetes management in their communities.

Reinforcing the social compromise of accelerated approval.

Abstract: Accelerated approval enables investigational drugs to reach the US market on the basis of their demonstrated effects in unvalidated surrogate measures, only reasonably likely to predict clinical response. To fulfil the social compromise, regulators should ensure that confirmatory trials testing clinically meaningful end points are already underway at the time of approval.

Community-based intervention for management of diabetes in Nepal (COBIN-D trial): study protocol for a cluster-randomized controlled trial.

Abstract: Type 2 diabetes is one of the fastest emerging chronic diseases in low- and middle-income countries. Population-based approaches, such as involvement of lay health workers offering culturally appropriate diabetes health promotion, may be the blueprint for the management of type 2 diabetes. This study aims to examine the effectiveness of a family-based home health education intervention on type 2 diabetes provided by female community health volunteers (FCHVs) in a semi-urban area of Lekhnath Municipality of Nepal. The COmmunity-Based INtervention for management of Diabetes in Nepal (COBIN-D) trial is a community-based, open-label, two-armed, cluster-randomized trial with seven randomly selected intervention and seven wait-list control clusters. A total of 112 subjects with type 2 diabetes will be recruited from the intervention clusters and 112 subjects from the wait-list control clusters. Based on the Health Belief Model and Social Support Theory, a 12-month family-based lifestyle intervention will be administered through FCHVs. Wait-list control clusters will continue to manage their glycemic condition as usual and their intervention will be delayed for 12 months. Participants will be measured at the beginning of the study and 12 months later. The primary outcome measure of the study will be difference in mean change (from baseline to 1 year) in fasting blood glucose between the two study arms. Impacts will be estimated using intention-to-treat analysis. The COBIN-D is the first study investigating the effect of family-based home health education and screening on blood sugar levels in adults by FCHVs at community level in Nepal. The perspective of this study is to develop and implement, in collaboration with the community, a community-based, culturally sensitive diabetes prevention and control program. It is anticipated that the study can act as a feasible and affordable tool for evidence-based integrated care for improvement of diabetes management and outcomes in Nepal as well as in other low- and middle-income countries. ClinicalTrials.gov, Identifier: NCT03304158 . Registered retrospectively on 03 October 2017.

Negative phase 3 randomized controlled trials: Why cancer drugs fail the last barrier?

Abstract: Dear Editor, Cancer drugs have a very poor probability of successfully transitioning from a Phase 1 study to FDA approval. One study estimated that only 5.1% drugs make this successful journey with the transitions from Phase 2 to Phase 3 being the most challenging to success. Failure of a new drug at Phase 3 stage of development is often disappointing to patients and investigators, and absorbs scarce resources, since phase 3 trials are also traditionally quite expensive. Hence, it’s important to understand why cancer drugs fail in Phase 3 trials. We searched all the negative Phase 3 randomized controlled trials (RCTs) published between January 1, 2016 and December 31, 2016 in the New England Journal of Medicine (NEJM), Lancet, Lancet Oncology and Journal of Clinical Oncology (JCO)—the top journals that publish cancer drug trials based on impact factor. A trial was considered negative if the primary endpoint was not met. For this analysis, we included only the RCTs testing a new drug that had not yet been approved by the FDA for the specific indication being studied. We then searched the literature, without any restrictions and including relevant conference abstracts, for any preceding Phase 2 trials supporting the conduct of these negative Phase 3 RCTs. The outcomes of this search were categorized as “Yes, positive” if a previous positive Phase 2 was available, “Yes, negative” if this Phase 3 RCT was conducted despite a previous negative Phase 2, “Not done” if no previous Phase 2 trials were found, “yes, inconclusive” if the previous Phase 2 couldn’t be objectively discerned as positive or negative and “Earlier trial” if this was a trial in early lines of therapy or an adjuvant trial of a drug already approved for later lines the same disease. A phase 2 trial was considered positive, negative or inconclusive based on whether the primary endpoint was met, unmet or not stated. In 2016, NEJM and Lancet published no negative cancer drug RCTs. Of the 24 and 25 Phase 3 RCTs published by Lancet Oncology and JCO respectively in 2016, 9 and 17 were negative Phase 3 RCTs of which 16 (71 9) trials involving 20,775 patients were those of new cancer drugs (Table 1). Of these 16 RCTs, 4 (25%) were “earlier trials,” i.e. they tested a drug approved for metastatic setting in adjuvant setting or an already approved drug for early lines of therapy in the same disease. One RCT (6.3%) was conducted without any previous Phase 2. For 5 RCTs (31.3%), there were only inconclusive previous Phase 2 studies because the criteria for considering them as positive were not prospectively defined. Three RCTs (18.8%) were conducted despite negative previous Phase 2 trials. Only 3 RCTs (18.8%) were conducted on the basis of previous positive Phase 2 trials (Fig. 1). Fifteen RCTs reported OS data of which 5 (33.3%) had a hazard ratio of >1 for overall survival—one of them was statistically significant implying harm. Although negative trials are important to advance our knowledge, a trial of a new cancer drug at Phase 3 stage of development represents use of substantial human, financial and logistic resources. These failed Phase 3 RCTs also contribute to the high Research & Development costs. Therefore, it is important to consider whether it is ethical to conduct large phase 3 RCTs of new cancer drugs despite evidence of lack of efficacy in phase 2. Although some previous studies have shown that negative Phase 3 trials are being conducted without Phase 2, we found that Phase 3 RCTs were also conducted despite a preceding negative Phase 2. Previous studies have also shown that the response rates of drugs fall in Phase 3 versus Phase 2 trials, hence the chances for success of a drug that has already failed a Phase 2 is low. Because every cancer drug approval represents a potentially multibillion dollar market, current market provides incentives to undertake overpowered Phase 3 RCTs designed to detect marginal significances. The Institutional Review Boards and approval authorities should take proactive steps to discourage Phase 3 RCTs that don’t have positive data from previous Phase 2, especially those Phase 3 that are being planned despite negative Phase 2. Another important step would be to define when a Phase 2 would be considered positive a priori, because a significant proportion of Phase 2 trials in our study were inconclusive. The limitations of our study are that the selected studies may not be representative of all negative Phase 3 RCTs of cancer drugs because many such studies are never published. Because our sample included negative Phase 3 RCTs published in top cancer journals, we believe our estimates are conservative and that the actual percentage of negative Phase Le tt er to th e E di to r

Does the oncology community have a rejection bias when it comes to repurposed drugs

Abstract: Among the various measures proposed to combat the challenge of financial toxicity in cancer care, an important strategy is the use of lower-priced drugs instead of expensive alternatives. However, the oncology community seems to either ignore or more readily reject cheaper drugs in cancer care compared to more expensive alternatives. In this commentary, we present three examples of lower-priced drugs rejected or ignored by the oncology community and contrast this with three expensive drugs where persistent optimism remained despite negative clinical trial results. We argue that all drugs be held to the same rigorous standards - this not only includes skepticism in the absence of sound evidence, but also the suspension of premature judgement as has happened in the cases of repurposed drugs.

Rethinking community based strategies to tackle health inequities in South Asia.

Abstract: A long term strategy is vital to build on the impact of community health workers in achieving universal health coverage, say Zulfiqar Bhutta and colleagues

Primary Febrile Neutropenia Prophylaxis for Patients Who Receive FEC-D Chemotherapy for Breast Cancer: A Systematic Review.

Abstract: PurposeDespite widespread use of fluorouracil, epirubicin, cyclophosphamide, docetaxel (FEC-D) chemotherapy in breast cancer, the optimal strategy for primary febrile neutropenia (FN) prophylaxis remains unknown. A systematic review was therefore performed.MethodsEmbase, Ovid MEDLINE, PubMed, Cochrane Database of Systematic Reviews, Cochrane Register of Controlled Trials, and conference proceedings were searched from 1946 to April 2016 for trials that reported the effectiveness of primary FN prophylaxis with FEC-D chemotherapy. Outcome measures were incidence of FN; treatment-related hospitalizations; chemotherapy dose delays, reductions, and discontinuations; and adverse events from prophylaxis.ResultsOf 2,205 identified citations, eight studies (n = 1,250) met our eligibility criteria. Three additional studies (n = 293) were identified from a prior systematic review. Three randomized controlled trials (n = 576), one phase IV single-arm trial (n = 69), one prospective observational study (n = 37), and si...

Efficacy of Prophylactic Treatment for Oxycodone-Induced Nausea and Vomiting Among Patients with Cancer Pain (POINT): A Randomized, Placebo-Controlled, Double-Blind Trial.

Abstract: Background Although opioid-induced nausea and vomiting (OINV) often result in analgesic undertreatment in patients with cancer, no randomized controlled trials have evaluated the efficacy of prophylactic antiemetics for preventing OINV. We conducted this randomized, placebo-controlled, double-blind trial to evaluate the efficacy and safety of prophylactic treatment with prochlorperazine for preventing OINV. Materials and methods Cancer patients who started to receive oral oxycodone were randomly assigned in a 1:1 ratio to receive either prochlorperazine 5 mg or placebo prophylactically, given three times daily for 5 days. The primary endpoint was the proportion of patients who had a complete response (CR) during the 120 hours of oxycodone treatment. CR was defined as no emetic episode and no use of rescue medication for nausea and vomiting during 5 days. Key secondary endpoints were the proportion of patients with emetic episodes, proportion of patients with moderate or severe nausea, quality of life, and proportion of treatment withdrawal. Results From November 2013 through February 2016, a total of 120 patients were assigned to receive prochlorperazine (n = 60) or placebo (n = 60). There was no significant difference in CR rates (69.5% vs. 63.3%; p = .47) or any secondary endpoint between the groups. Patients who received prochlorperazine were more likely to experience severe somnolence (p = .048). Conclusion Routine use of prochlorperazine as a prophylactic antiemetic at the initiation of treatment with opioids is not recommended. Further research is needed to evaluate whether other antiemetics would be effective in preventing OINV in specific patient populations. Implications for practice Prophylactic prochlorperazine seems to be ineffective in preventing opioid-induced nausea and vomiting (OINV) and may cause adverse events such as somnolence. Routine use of prophylactic prochlorperazine at the initiation of treatment with opioids is not recommended. Further research is needed to evaluate whether other antiemetics would be effective in preventing OINV in specific patient populations.

Affordability and Price Increases of New Cancer Drugs in Clinical Guidelines, 2007–2016

Abstract: In response to the rising cost of cancer drugs, the National Comprehensive Cancer Network (NCCN) recently developed a value framework, known as "Evidence Blocks," to grade the efficacy, safety, evidence quality, evidence consistency, and affordability of treatments included in its clinical guidelines. The value scores were available for 55 of the 69 new cancer drugs approved by the US Food and Drug Administration from 2007 to 2016. Overall, the treatment costs for 95% of new cancer medicines in NCCN clinical guidelines were scored as "very expensive" or "expensive". In multivariable ordered logistic regression models, there was no association between the affordability of new cancer drugs and efficacy and safety data available in clinical guidelines. Most guideline-recommended drugs were subject to annual list price increases exceeding inflation.

Duration of adjuvant immunotherapy-biologic, clinical and economic considerations.

Abstract: The financial impact of an extensive duration of adjuvant immunotherapy is severe. The clinical and biological rationale for this extensive duration is unclear. This study aims to understand the biologic and clinical rationale for the duration of treatment in designing adjuvant trials and to assess the economic impact of different treatment durations in adjuvant therapy. We searched http://www.clinicaltrials.gov for adjuvant immunotherapy clinical trials. Based on our inclusion and exclusion criteria, we identified 47 trials targeting PD-1, PD-L1, and CTLA-4. We examined the duration of these trials and performed a US based budget impact analysis of three representative trials based on various data sources. Most current adjuvant immunotherapy trials provide treatment for 1 year. Our budget impact analyses estimate that the cost per patient of 1 year treatment with nivolumab for melanoma is $165,000 while the cost of 3 years treatment with ipilimumab for melanoma is more than $1,850,000 assuming full duration of treatment. The annual cost for adjuvant treatment with nivolumab for melanoma is approximately $1.15 billion for the entire target population in the United States assuming full uptake. The necessary duration of adjuvant immunotherapy is unknown. The rationale for duration in current trials is not clear and may be longer than necessary. Non-inferiority trials testing shorter duration of therapies should be conducted. Appropriate mechanisms to fund such trials should be sought out by healthcare payers.

Cancer treatment in the last 6 months of life: when inaction can outperform action.

Abstract: When an investigational anticancer drug is being tested, demonstration of improvement in overall survival (OS) will generally lead to regulatory approval. However, the value that improvement in OS adds to patients' lives is guided largely by the context of the improvement and accompanying trade-offs. For example, when a patient's life expectancy is less than 6 months, many oncologists will not embark on any active cancer treatments. However, multiple new anticancer drugs have been approved recently after being tested in end-stage cancer patients and demonstrating median OS in the experimental arm close to 6 months. Such practice, particularly when the treatment is also accompanied by serious toxicities and cost, can undermine a peaceful life-death transition. In this commentary, we review regulatory approvals in the last 5 years and the ethical considerations involved in testing active cancer treatment in terminal cancer patients.

What Global Oncology Needs: Mutual Learning and More Funding.

Abstract: Although we have not yet agreed to an official definition of global oncology, one of the overarching themes of this emerging medical discipline is cancer control in lowand middle-income countries (LMICs), given that 65% of cancer deaths worldwide occur in these countries.1 Hence, to control the global cancer burden, it is important to address the burden of cancer in LMICs. However, it is also important to note that global oncology is not the concern of LMICs alone. Cancer respects no boundaries and neither should cancer control efforts.

Correction: Awareness, prevalence, treatment, and control of type 2 diabetes in a semi-urban area of Nepal: Findings from a cross-sectional study conducted as a part of COBIN-D trial (PLoS ONE (2018) 13:11 (e0206491) DOI: 10.1371/journal.pone.0206491)

Abstract: [This corrects the article DOI: 10.1371/journal.pone.0206491.].