Apalutamide plus Androgen Deprivation Therapy for Metastatic Castration-Sensitive Prostate Cancer: Analysis of Pain and Fatigue in the Phase 3 TITAN Study.

PURPOSE: We performed an exploratory analysis of prostate cancer-related pain and fatigue on health-related quality of life in patients with metastatic castration-sensitive prostate cancer receiving apalutamide (240 mg/day) or placebo, with continuous androgen deprivation therapy (ADT), in the phase 3, randomized, double-blind, placebo controlled TITAN trial (NCT02489318). MATERIALS AND METHODS: Patient-reported outcomes for pain and fatigue were evaluated using the Brief Pain Inventory-Short Form and Brief Fatigue Inventory. Time to deterioration (TTD) was estimated by Kaplan-Meier method; hazard ratios and 95% confidence intervals were calculated using Cox proportional hazards model. General estimating equations for logistic regression estimated treatment-related differences in the likelihood of worsening pain or fatigue. RESULTS: Compliance for completing the Brief Pain Inventory-Short Form and Brief Fatigue Inventory was high (96% to 97%) in the first year. Median followup times were similar between treatments (19 to 22 months). Median pain TTD was longer with apalutamide than placebo for "pain at its least in the last 24 hours" (28.7 vs 21.8 months, respectively; p=0.0146), "pain interfered with mood" (not estimable vs 22.4 months; p=0.0017), "pain interfered with walking ability" (28.7 vs 20.2 months; p=0.0027), "pain interfered with relations" (not estimable vs 23.0 months; p=0.0139) and "pain interfered with sleep" (28.7 vs 20.9 months; p=0.0167). Likelihood for fatigue and worsening fatigue were similar between groups. CONCLUSIONS: Patients with metastatic castration-sensitive prostate cancer receiving apalutamide plus ADT vs placebo plus ADT reported consistently favorable TTD of pain. No difference for change in fatigue was observed with apalutamide vs placebo.

Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study.

BACKGROUND: In the phase 3 TITAN study, the addition of apalutamide to androgen deprivation therapy (ADT) significantly improved the primary endpoints of overall survival and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer. We aimed to assess health-related quality of life (HRQOL) in TITAN, including pain and fatigue. METHODS: In this randomised, placebo-controlled, double-blind, phase 3 study, patients with metastatic castration-sensitive prostate cancer (defined as not receiving ADT at the time of metastatic disease progression) aged 18 years and older, receiving continuous ADT (selected at the investigator's discretion), and with an Eastern Cooperative Oncology Group performance status score of 0 or 1 were randomly assigned (1:1), using an interactive web response system, to receive oral apalutamide (four 60 mg tablets, once daily) or matching placebo. Previous localised disease treatment or previous docetaxel for metastatic castration-sensitive prostate cancer were allowed. Randomisation was stratified by Gleason score at diagnosis, region, and previous docetaxel treatment. Randomisation was done using randomly permuted blocks (block size of four). Investigators, research staff, sponsor study team, and patients were masked to the identities of test and control treatments. Patient-reported outcomes were prespecified exploratory endpoints and were the Brief Pain Inventory-Short Form (BPI-SF), Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and EuroQoL 5D questionnaire 5 level (EQ-5D-5L). BPI and BFI were completed for 7 consecutive days (days -6 to 1 inclusive of each cycle visit), then at months 4, 8, and 12 in follow-up. FACT-P and EQ-5D-5L were completed during cycles 1-7, then every other cycle until the end of treatment, and at months 4, 8, and 12 in follow-up. Analyses were based on the intention-to-treat population. Missing patient-reported outcome assessments were calculated as the expected number of assessments for a visit minus the actual number of assessments received for that visit. For time-to-event endpoints, when median values could not be calculated because less than 50% of patients had degradation, 25th percentiles were compared. This study is registered with ClinicalTrials.gov, number NCT02489318, and is ongoing. FINDINGS: Between Dec 9, 2015, and July 25, 2017, 1052 eligible patients were enrolled randomly assigned to apalutamide (n=525) or placebo (n=527). Data cutoff for this analysis of patient-reported outcomes was Nov 23, 2018. Median follow-up for time to pain-related endpoints ranged from 19·4 to 22·1 months. Patients were mostly asymptomatic at baseline: on the BPI-SF pain severity scale of 0-10, median pain scores (indicating worst pain in the past 24 h) were 1·14 (IQR 0-3·17) in the apalutamide group and 1·00 (0-2·86) in the placebo group, and median worst fatigue scores on the BFI were 1·29 (IQR 0-3·29) in the apalutamide group and 1·43 (0·14-3·14) in the placebo group. Patient experience of pain and fatigue (intensity and interference) did not differ between the groups for the duration of treatment. Median time to worst pain intensity progression was 19·09 months (95% CI 11·04-not reached) in the apalutamide group versus 11·99 months (8·28-18·46) in the placebo group (HR 0·89 [95% CI 0·75-1·06]; p=0·20). Median time to pain interference progression was not reached in either group (95% CI 28·58-not reached in the apalutamide group; not reached-not reached in the placebo group). 25th percentiles for time to pain interference progression were 9·17 months (5·55-11·96) in the apalutamide group and 6·24 months (4·63-7·43) in the placebo group (HR 0·90 [95% CI 0·73-1·10]; p=0·29). FACT-P total scores and EQ-5D-5L data showed preservation of HRQOL in both groups. The median time to deterioration as determined by FACT-P total score was 8·87 months (95% CI 4·70-11·10) in the apalutamide group and 9·23 months (7·39-12·91) in the placebo group (HR 1·02 [95% CI 0·85-1·22]; p=0·85). INTERPRETATION: Apalutamide with ADT is a well-tolerated and effective option for men with metastatic castration-sensitive prostate cancer. The combination significantly improves survival outcomes compared with ADT alone while maintaining HRQOL despite additive androgen blockade. FUNDING: Janssen Research & Development.

Efficacy of Laparoscopic Nissen Fundoplication vs Transoral Incisionless Fundoplication or Proton Pump Inhibitors in Patients With Gastroesophageal Reflux Disease: A Systematic Review and Network Meta-analysis.

BACKGROUND & AIMS: The effects of transoral incisionless fundoplication (TIF) and laparoscopic Nissen fundoplication (LNF) have been compared with those of proton pump inhibitors (PPIs) or a sham procedure in patients with gastroesophageal reflux disease (GERD), but there has been no direct comparison of TIF vs LNF. We performed a systematic review and network meta-analysis of randomized controlled trials to compare the relative efficacies of TIF vs LNF in patients with GERD. METHODS: We searched publication databases and conference abstracts through May 10, 2017 for randomized controlled trials that compared the efficacy of TIF or LNF with that of a sham procedure or PPIs in patients with GERD. We performed a network meta-analysis using Bayesian methods under random-effects multiple treatment comparisons. We assessed ranking probability by surface under the cumulative ranking curve. RESULTS: Our search identified 7 trials comprising 1128 patients. Surface under the cumulative ranking curve ranking indicated TIF had highest probability of increasing patients' health-related quality of life (0.96), followed by LNF (0.66), a sham procedure (0.35), and PPIs (0.042). LNF had the highest probability of increasing percent time at pH <4 (0.99), followed by PPIs (0.64), TIF (0.32), and the sham procedure (0.05). LNF also had the highest probability of increasing LES pressure (0.78), followed by TIF (0.72) and PPIs (0.01). Patients who underwent the sham procedure had the highest probability for persistent esophagitis (0.74), followed by those receiving TIF (0.69), LNF (0.38), and PPIs (0.19). Meta-regression showed a shorter follow-up time as a significant confounder for the outcome of health-related quality of life in studies of TIF. CONCLUSIONS: In a systematic review and network meta-analysis of trials of patients with GERD, we found LNF to have the greatest ability to improve physiologic parameters of GERD, including increased LES pressure and decreased percent time pH <4. Although TIF produced the largest increase in health-related quality of life, this could be due to the shorter follow-up time of patients treated with TIF vs LNF or PPIs. TIF is a minimally invasive endoscopic procedure, yet based on evaluation of benefits vs risks, we do not recommend it as a long-term alternative to PPI or LNF treatment of GERD.

Bisphosphonates in multiple myeloma: an updated network meta-analysis.

BACKGROUND: Bisphosphonates are specific inhibitors of osteoclastic activity and are used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to be effective in reducing vertebral fractures and pain, their role in improving overall survival (OS) remains unclear. This is an update of a Cochrane review first published in 2002 and previously updated in 2010 and 2012. OBJECTIVES: To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus non-aminobisphosphonates) in the management of patients with MM. Our primary objective was to determine whether adding bisphosphonates to standard therapy in MM improves OS and progression-free survival (PFS), and decreases skeletal-related morbidity. Our secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw (ONJ) and hypocalcemia. SEARCH METHODS: We searched MEDLINE, Embase (September 2011 to July 2017) and the CENTRAL (2017, Issue 7) to identify all randomized controlled trial (RCT) in MM up to July 2017 using a combination of text and MeSH terms. SELECTION CRITERIA: Any randomized controlled trial (RCT) comparing bisphosphonates versus placebo/no treatment/bisphosphonates and observational studies or case reports examining bisphosphonate-related ONJ in patients with MM were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors extracted the data. Data were pooled and reported as hazard ratio (HR) or risk ratio (RR) using a random-effects model. We used meta-regression to explore statistical heterogeneity. Network meta-analysis using Bayesian approach was conducted. MAIN RESULTS: In this update, we included four new studies (601 participants), resulting in a total of 24 included studies.Twenty RCTs compared bisphosphonates with either placebo or no treatment and four RCTs involved another bisphosphonate as a comparator. The 24 included RCTs enrolled 7293 participants. Pooled results showed that there was moderate-quality evidence of a reduction in mortality with on OS from 41% to 31%, but the confidence interval is consistent with a larger reduction and small increase in mortality compared with placebo or no treatment (HR 0.90, 95% CI 0.76 to 1.07; 14 studies; 2706 participants). There was substantial heterogeneity among the included RCTs (I2 = 65%) for OS. To explain this heterogeneity we performed a meta-regression assessing the relationship between bisphosphonate potency and improvement in OS, which found an OS benefit with zoledronate but limited evidence of an effect on PFS. This provided a further rationale for performing a network meta-analyses of the various types of bisphosphonates that were not compared head-to-head in RCTs. Results from network meta-analyses showed evidence of a benefit for OS with zoledronate compared with etidronate (HR 0.56, 95% CI 0.29 to 0.87) and placebo (HR 0.67, 95% CI 0.46 to 0.91). However, there was no evidence for a difference between zoledronate and other bisphosphonates.The effect of bisphosphonates on disease progression (PFS) is uncertain. Based on the HR of 0.75 (95% CI 0.57 to 1.00; seven studies; 908 participants), 47% participants would experience disease progression without treatment compared with between 30% and 47% with bisphosphonates (low-quality evidence). There is probably a similar risk of non-vertebral fractures between treatment groups (RR 1.03, 95% CI 0.68 to 1.56; six studies; 1389 participants; moderate-quality evidence). Pooled analysis demonstrated evidence for a difference favoring bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; seven studies; 1116 participants; moderate-quality evidence) and skeletal-related events (SREs) (RR 0.74, 95% CI 0.63 to 0.88; 10 studies; 2141 participants; moderate-quality evidence). The evidence for less pain with bisphosphonates was of very low quality (RR 0.75, 95% CI 0.60 to 0.95; eight studies; 1281 participants).Bisphosphonates may increase ONJ compared with placebo but the confidence interval is very wide (RR 4.61, 95% CI 0.99 to 21.35; P = 0.05; six studies; 1284 participants; low-quality evidence). The results from the network meta-analysis did not show any evidence for a difference in the incidence of ONJ (eight RCTs, 3746 participants) between bisphosphonates. Data from nine observational studies (1400 participants) reported an incidence of 5% to 51% with combination of pamidronate and zoledronate, 3% to 11% with zoledronate alone, and 0% to 18% with pamidronate alone.The pooled results showed no evidence for a difference in increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.59; seven studies; 1829 participants; low-quality evidence).The pooled results showed no evidence for a difference in increase in frequency of hypocalcemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74; three studies; 1090 participants; low-quality evidence). The results from network meta-analysis did not show any evidence for differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used. AUTHORS' CONCLUSIONS: Use of bisphosphonates in participants with MM reduces pathological vertebral fractures, SREs and pain. Bisphosphonates were associated with an increased risk of developing ONJ. For every 1000 participants treated with bisphosphonates, about one patient will suffer from the ONJ. We found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or non-aminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate was found to be better than placebo and first-generation bisposphonate (etidronate) in pooled direct and indirect analyses for improving OS and other outcomes such as vertebral fractures. Direct head-to-head trials of the second-generation bisphosphonates are needed to settle the issue if zoledronate is truly the most efficacious bisphosphonate currently used in practice.

Nonfluorodeoxyglucose-Avid Persistent Splenomegaly at Time of Transplantation Delays Neutrophil and Platelets Engraftment without Affecting Survival in Patients with Lymphomas Undergoing Allogeneic Hematopoietic Cell Transplantation.

It is unclear if persistent splenomegaly in the presence of a negative positron emission tomography (PET) scan before allogeneic hematopoietic cell transplantation (HCT) influences post-transplantation outcomes in patients with lymphoma. We retrospectively reviewed records of 152 patients who underwent allogeneic HCT for various lymphomas. Centralized review of pretransplantation computed tomography (CT) and PET images was performed. Spleen volume (SV) was measured using the freehand volume segmentation tool in AW Workstation software (General Electric, Waukesha, WI). Splenic index (SI) was calculated as a product of width, thickness, and length of the spleen. Normal SV was defined as SV < 314.5 cm3 and normal SI was defined as SI ≤ 480 cm3, as described in the literature. Among the study population, 42.8% received an allogeneic HCT from an HLA-matched related donor, 36.2% from a matched unrelated donor, 12.5% from a mismatched unrelated donor, and 8.6% received a double umbilical cord blood transplantation. Most (61.8%) received myeloablative conditioning. Median age at transplantation was 52 (range, 21 to 68) years. Pre-allogeneic HCT spleen CT and PET images were available on 88% and 70.3% patients, respectively. SV ranged from 90 cm3 to 4684 cm3 with a median of 290.5 cm3 and a mean of 400.3 cm3. SI calculation showed a range from 50.3 cm3 to 8276.4 cm3 with a median of 582.1 cm3 and a mean of 771.2 cm3. The majority of patients (83.1%) had PET-negative spleen before allogeneic transplantation. Engraftment was delayed in PET-negative patients with persistent splenomegaly, with median days to neutrophil engraftment of 17 versus 16 (P = .03) and median days to platelet engraftment of 16 versus 14 (P = .04) when using SV. However, persistent splenomegaly did not appear to impact progression-free survival (P = .11) or overall survival (P = .37). Splenomegaly in the setting of a PET-negative study before allogeneic HCT delays neutrophil and platelet engraftment but does not appear to affect survival. Future studies using registry data or larger multicenter studies would be required to evaluate the impact of splenomegaly and its fluorodeoxyglucose avidity on allogeneic HCT outcomes in specific subtypes of lymphomas.

Estimated levator ani subtended volume: a novel assay for predicting surgical failure after uterosacral ligament suspension.

BACKGROUND: Levator ani muscle complex plays an important role in pelvic support and defects or laxity in this muscle complex contributes to pelvic organ prolapse and recurrence after surgical repair. OBJECTIVE: The purpose of this study was to determine whether estimated levator ani subtended volume can predict surgical outcomes for laparoscopic bilateral uterosacral ligament suspension. STUDY DESIGN: A retrospective cohort study was performed in patients who underwent laparoscopic uterosacral ligament suspension from 2010-2012. Only patients with a preoperative pelvic magnetic resonance image were included. Surgical failure was defined as a composite score that included the presence of anatomic bulge beyond the hymen with sensation of vaginal bulge or repeat treatment for prolapse via pessary or surgery by 1-year follow-up evaluation. Standard protocol pelvic magnetic resonance imaging measurements pubococcygeal line, H-line, and M-line were collected along with the calculation of the width of the levator ani hiatus. Estimated levator ani subtended volume was calculated for each subject. An optimal cutoff point was calculated and compared against categoric values of surgical success/failure. A Fisher exact test, an area under receiver operating characteristics curve, and logistic regression analysis were performed. A probability value of <.05 was considered statistically significant. RESULTS: Ninety-three women underwent laparoscopic bilateral uterosacral ligament suspension during study period. Of these, 66 women had a standardized preoperative pelvic magnetic resonance image per institutional protocol. Thirteen patients (19.6%) met the criteria for surgical failure by 1 year. An optimal cutoff point of 38.5 was calculated by Liu's method for optimization. Among the patients with defined surgical failures, 84.6% (11/13) had an estimated levator ani subtended volume above cutoff point of 38.5. Among the patients with defined surgical success, 39.6% (21/53) had an estimated levator ani subtended volume above the cutoff point (84.6% vs 39.6%; P = .0048) with a significant odds ratio of 8.38 (95% confidence interval, 1.69-41.68; P = .009). An area under receiver operating characteristics curve of 0.725 (95% confidence interval, 0.603-0.847), sensitivity of 84.6% (95% confidence interval, 54.6%-98.1%), and specificity of 60.4% (95% confidence interval, 46%-73.5%) at 38.5 were predictors of surgical success/failure by 1 year. Logistic regression analysis demonstrated no significant confounders among age, body mass index, stage, or parity. CONCLUSIONS: Estimated levator ani subtended volume may predict surgical failure for laparoscopic bilateral uterosacral ligament suspension. Patients with a calculated estimated levator ani subtended volume above 38.5 on a preoperative pelvic magnetic resonance imaging were associated with an increased risk for surgical failure by 1 year, regardless of age, body mass index, stage, or parity. Future investigation that will include repeatability, reliability analysis, and a prospective study is warranted.

Safety of Gastrointestinal Endoscopy With Conscious Sedation in Patients With and Without Obstructive Sleep Apnea.

BACKGROUND AND STUDY AIMS: Patients with obstructive sleep apnea (OSA) undergoing endoscopy with sedation are considered by practitioners to be at a higher risk for cardiopulmonary complications. The aim of the present study was to evaluate the safety of conscious sedation in patients with OSA undergoing gastrointestinal endoscopy. PATIENTS AND METHODS: This is an IRB-approved prospective cohort study performed at the James A. Haley VA. A total of 248 patients with confirmed moderate or severe OSA by polysomnography and 252 patients without OSA were enrolled. Cardiopulmonary variables such as heart rate, blood pressure, and level of blood oxygen saturation were recorded at 3-minute intervals throughout the endoscopic procedure. RESULTS: In total, 302 colonoscopies, 119 esophagogastroduodenoscopies, 6 flexible sigmoidoscopies, and 60 esophagogastroduodenoscopy/colonoscopies were performed. None of the patients in the study required endotracheal intubation, pharmacologic reversal, or experienced an adverse outcome as a result of changes in blood pressure, heart rate, or blood oxygen saturation. There were no significant differences in the rate of tachycardia (P=0.749), bradycardia (P=0.438), hypotension (systolic/diastolic, P=0.460; mean arterial pressure, P=0.571), or hypoxia (P=0.787) between groups. The average length of time spent in each procedure and the average dose of sedation administered also did not differ significantly between the groups. CONCLUSIONS: Despite the presumed increased risk of cardiopulmonary complications, patients with OSA who undergo endoscopy with conscious sedation have clinically insignificant variations in cardiopulmonary parameters that do not differ from those without OSA. Costly preventative measures in patients with OSA are not warranted.

The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis-stimulating agents.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are commonly used to treat chemotherapy-induced anemia (CIA). However, about half of patients do not benefit. OBJECTIVES: To evaluate the benefits and harms related to the use of iron as a supplement to ESA and iron alone compared with ESA alone in the management of CIA. SEARCH METHODS: We searched for relevant trials from the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 1 January 2016), MEDLINE (1950 to February 2016), and www.clinicaltrials.gov without using any language limits. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing 'iron plus ESA' or 'iron alone' versus 'ESA alone' in people with CIA were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included eight RCTs (12 comparisons) comparing ESA plus iron versus ESA alone enrolling 2087 participants. We did not find any trial comparing iron alone versus ESAs alone in people with CIA. None of the included RCTs reported overall survival. There was a beneficial effect of iron supplementation to ESAs compared with ESAs alone on hematopoietic response (risk ratio (RR) 1.17, 95% confidence interval (CI) 1.09 to 1.26; P < 0.0001; 1712 participants; 11 comparisons; high-quality evidence). Assuming a baseline risk of 35% to 80% for hematopoietic response without iron supplementation, between seven and 16 patients should be treated to achieve hematopoietic response in one patient. In subgroup analyses, RCTs that used intravenous (IV) iron favored ESAs and iron (RR 1.20 (95% CI 1.10 to 1.31); P < 0.00001; 1321 participants; eight comparisons), whereas we found no evidence for a difference in hematopoietic response in RCTs using oral iron (RR 1.04 (95% CI 0.87 to 1.24); P = 0.68; 391 participants; three comparisons). There was no evidence for a difference between the subgroups of IV and oral iron (P = 0.16). There was no evidence for a difference between the subgroups of types of iron (P = 0.31) and types of ESAs (P = 0.16) for hematopoietic response.The iron supplementation to ESAs might be beneficial as fewer participants treated with iron supplementation required red blood cell (RBC) transfusions compared to the number of participants treated with ESAs alone (RR 0.74 (95% CI 0.60 to 0.92); P = 0.007; 1719 participants; 11 comparisons; moderate-quality evidence). Assuming a baseline risk of 7% to 40% for RBC transfusion without iron supplementation, between 10 and 57 patients should be treated to avoid RBC transfusion in one patient.We found no evidence for a difference in the median time to hematopoietic response with addition of iron to ESAs (hazard ratio (HR) 0.93 (95% CI 0.67 to 1.28); P = 0.65; 1042 participants; seven comparisons; low-quality evidence). In subgroup analyses, RCTs in which dextran (HR 0.95 (95% CI 0.36 to 2.52); P = 0.92; 340 participants; three comparisons), sucrose iron (HR 1.15 (95% CI 0.60 to 2.21); P = 0.67; 102 participants; one comparison) and sulfate iron (HR 1.24 (95% CI 0.99 to 1.56); P = 0.06; 55 participants; one comparison) were used showed no evidence for difference between iron supplementation versus ESAs alone compared with RCTs in which gluconate (HR 0.78 (95% CI 0.65 to 0.94); P = 0.01; 464 participants; two comparisons) was used for median time to hematopoietic response (P = 0.02). There was no evidence for a difference between the subgroups of route of iron administration (P = 0.13) and types of ESAs (P = 0.46) for median time to hematopoietic response.Our results indicated that there could be improvement in the hemoglobin (Hb) levels with addition of iron to ESAs (mean difference (MD) 0.48 (95% CI 0.10 to 0.86); P = 0.01; 827 participants; seven comparisons; low-quality evidence). In RCTs in which IV iron was used there was evidence for a difference (MD 0.84 (95% CI 0.21 to 1.46); P = 0.009; 436 participants; four comparisons) compared with oral iron (MD 0.07 (95% CI -0.19 to 0.34); P = 0.59; 391 participants; three comparisons) for mean change in Hb level (P = 0.03). RCTs in which dextran (MD 1.55 (95% CI 0.62 to 2.47); P = 0.001; 102 participants; two comparisons) was used showed evidence for a difference with iron supplementation versus ESAs alone compared with RCTs in which gluconate (MD 0.54 (95% CI -0.15 to 1.22); P = 0.12; 334 participants; two comparisons) and sulfate iron (MD 0.07 (95% CI -0.19 to 0.34); P = 0.59; 391 participants; three comparisons) were used for mean change in Hb level (P = 0.007). RCTs in which epoetin was used showed evidence for a difference with iron supplementation versus ESAs alone (MD 0.77 (95% CI 0.25 to 1.29); P = 0.004; 337 participants; five comparisons) compared with darbepoetin use (MD 0.10 (95% CI -0.13 to 0.33); P = 0.38; 490 participants; two comparisons) for mean change in Hb level (P = 0.02).We found no evidence for a difference in quality of life with addition of iron to ESAs (standardized mean difference 0.01 (95% CI -0.10 to 0.12); P = 0.88; 1124 participants; three RCTs; high-quality evidence).We found no evidence for a difference in risk of grade III-IV thromboembolic events (RR 0.95 (95% CI 0.54 to 1.65); P = 0.85; 783 participants; three RCTs; moderate-quality evidence). The incidence of treatment-related mortality (TRM) was 0% (997 participants; four comparisons; high-quality evidence).Other common adverse events included vomiting, asthenia, and leukopenia, and were similar in both arms.Overall the risk of bias across outcomes was high to low. Since the included RCTs had shorter follow-up duration (up to 20 weeks), the long-term effects of iron supplementation are unknown. Our main reasons for downgrading the quality of evidence were inconsistency across the included studies and imprecision of results. AUTHORS' CONCLUSIONS: Our systematic review shows that addition of iron to ESAs offers superior hematopoietic response, reduces the risk of RBC transfusions, and improves Hb levels, and appears to be well tolerated. None of the included RCTs reported overall survival. We found no evidence for a difference in quality of life with iron supplementation.

Outpatient Management of Neonatal Abstinence Syndrome: A Quality Improvement Project.

BACKGROUND: An increasing number of infants are diagnosed with neonatal abstinence syndrome (NAS). The study's primary objectives were to describe an academic medical center's level IV neonatal ICU's (NICU's) comprehensive outpatient NAS management effort, measure guideline compliance, and assess its safety. Secondary objectives were to describe the duration and cumulative methadone exposure, and to improve parent and provider knowledge of NAS. METHODS: The study included 22 infants having a gestational age of 35-41 weeks, diagnosed with NAS, and discharged for outpatient methadone management. Discharges spanned 10 months and included 3 improvement periods. The outpatient program includes comprehensive discharge planning, a focused electronic health record (EHR) template, management guidelines, and parent and provider education. RESULTS: Providers complied with using the outpatient management guideline and EHR template, and assessed weight, NAS symptoms, and methadone dose during appointments. Two infants required NAS-related hospital readmission in the study period. From improvement period 1 to period 3 there was no difference in total outpatient days on methadone (58, 53, 74 days, respectively) or cumulative methadone dose (2.7, 2.6, 3.1mg/kg, respectively). A downward trend pattern in cumulative methadone exposure was noted in improvement period 2. Pre- and postimplementation surveys revealed that after implementation, parents had better understanding of NAS before delivery (71% vs. 100%, p = 0.009), while providers had increased comfort with outpatient management (24% vs. 67%, p < 0.001) and educating parents (48% vs. 82%, p = 0.001). CONCLUSION: This preliminary study suggests that outpatient NAS management can be safe when a comprehensive management program is implemented and can result in provider compliance with the program.

Defining optimum treatment of patients with pancreatic adenocarcinoma using regret-based decision curve analysis.

OBJECTIVE: To use regret decision theory methodology to assess three treatment strategies in pancreatic adenocarcinoma. BACKGROUND: Pancreatic adenocarcinoma is uniformly fatal without operative intervention. Resection can prolong survival in some patients; however, it is associated with significant morbidity and mortality. Regret theory serves as a novel framework linking both rationality and intuition to determine the optimal course for physicians facing difficult decisions related to treatment. METHODS: We used the Cox proportional hazards model to predict survival of patients with pancreatic adenocarcinoma and generated a decision model using regret-based decision curve analysis, which integrates both the patient's prognosis and the physician's preferences expressed in terms of regret associated with a certain action. A physician's treatment preferences are indicated by a threshold probability, which is the probability of death/survival at which the physician is uncertain whether or not to perform surgery. The analysis modeled 3 possible choices: perform surgery on all patients; never perform surgery; and act according to the prediction model. RESULTS: The records of 156 consecutive patients with pancreatic adenocarcinoma were retrospectively evaluated by a single surgeon at a tertiary referral center. Significant independent predictors of overall survival included preoperative stage [P = 0.005; 95% confidence interval (CI), 1.19-2.27], vitality (P < 0.001; 95% CI, 0.96-0.98), daily physical function (P < 0.001; 95% CI, 0.97-0.99), and pathological stage (P < 0.001; 95% CI, 3.06-16.05). Compared with the "always aggressive" or "always passive" surgical treatment strategies, the survival model was associated with the least amount of regret for a wide range of threshold probabilities. CONCLUSIONS: Regret-based decision curve analysis provides a novel perspective for making treatment-related decisions by incorporating the decision maker's preferences expressed as his or her estimates of benefits and harms associated with the treatment considered.

A single-institution experience: the integrated vascular surgery residency's effect on fellowship and general surgery resident case volume and diversity.

BACKGROUND: To determine whether the formation of an integrated vascular surgery residency (0 + 5) has negatively impacted the case volume and diversity of the vascular surgery fellows (5 + 2) and chief general surgeons at the same institution. METHODS: Operative data from the vascular integrated (0 + 5), independent (5 + 2), and general surgery residencies at a single institution were retrospectively reviewed and analyzed to determine vascular surgery case volumes from 2006-2012. National operative data (Residency Review Committee) were used for comparison of diversity and volume. Standard statistical methods were applied. RESULTS: During this period, the 5 + 2 fellows at our institution performed on average 741 (range, 554-1002) primary cases and 1091 (range, 844-1479) combined primary and secondary cases for the 2-year fellowship. Our integrated residency began in July 2007. Our fellows' primary case volumes remained relatively stable between 2006 and 2011, with a 4% increase in the number of cases, although their total (primary and secondary) case volumes fell 15%; by comparison, the equivalent national 50th percentile rates rose 16% during this time frame. Our institution's general surgery residents performed an average of 116 (range, 56-221) vascular cases individually during their 5-year residency from 2005-2011. From 2006-2011, the total case volume fell only 5%, while the national 50th percentile rate fell 24%. Across all years, however, resident and fellow volumes both continue to be above Accreditation Council for Graduate Medical Education minimum requirements, and the major vascular case volume at our institution in all groups studied remained statistically greater than or equal to the national 50th percentile of cases. Our first integrated resident to graduate finished in June 2012 with 931 total vascular cases and 249 general surgery cases for a total operative experience of 1180 cases during the 5-year residency. Finally, after an 8-year period (2003-2010) in which none of our general surgery residents pursued vascular training, 1 resident in each of the 2011, 2012, and 2013 graduating years has now done so. CONCLUSIONS: At our institution, the introduction of a 0 + 5 vascular residency has correlated with a modest drop (15%) in overall case volume for the 5 + 2 fellows, but the number of primary cases have actually increased slightly and they continue to meet or exceed Accreditation Council for Graduate Medical Education requirements and national 50th percentile rates. General surgery residents' vascular volumes, by contrast, have remained stable, and interest in vascular surgery by residents has increased. Our integrated vascular residents are projected to exceed the fellows' 50th percentile case volume and diversity targets during their residency experience.

How do physicians decide to treat: an empirical evaluation of the threshold model.

BACKGROUND: According to the threshold model, when faced with a decision under diagnostic uncertainty, physicians should administer treatment if the probability of disease is above a specified threshold and withhold treatment otherwise. The objectives of the present study are to a) evaluate if physicians act according to a threshold model, b) examine which of the existing threshold models [expected utility theory model (EUT), regret-based threshold model, or dual-processing theory] explains the physicians' decision-making best. METHODS: A survey employing realistic clinical treatment vignettes for patients with pulmonary embolism and acute myeloid leukemia was administered to forty-one practicing physicians across different medical specialties. Participants were randomly assigned to the order of presentation of the case vignettes and re-randomized to the order of "high" versus "low" threshold case. The main outcome measure was the proportion of physicians who would or would not prescribe treatment in relation to perceived changes in threshold probability. RESULTS: Fewer physicians choose to treat as the benefit/harms ratio decreased (i.e. the threshold increased) and more physicians administered treatment as the benefit/harms ratio increased (and the threshold decreased). When compared to the actual treatment recommendations, we found that the regret model was marginally superior to the EUT model [Odds ratio (OR) = 1.49; 95% confidence interval (CI) 1.00 to 2.23; p = 0.056]. The dual-processing model was statistically significantly superior to both EUT model [OR = 1.75, 95% CI 1.67 to 4.08; p < 0.001] and regret model [OR = 2.61, 95% CI 1.11 to 2.77; p = 0.018]. CONCLUSIONS: We provide the first empirical evidence that physicians' decision-making can be explained by the threshold model. Of the threshold models tested, the dual-processing theory of decision-making provides the best explanation for the observed empirical results.

Challenges and Opportunities in Establishing Appropriate Intermediate Endpoints Reflecting Patient Benefit: A Roadmap for Research and Clinical Application in Nonmetastatic Prostate Cancer.

Defining meaningful endpoints for research of early-stage high-risk prostate cancer is challenging, with established measures such as overall survival and metastasis-free survival facing limitations related to feasibility and adequate reflection of patient relevance. Developing endpoints must cater to diverse perspectives across scientific, clinical, regulatory, and patient viewpoints. Endpoints such as pathological complete response, no evidence of disease, and prevention of prostate-specific antigen relapse may reflect patient benefit by accounting for diagnostic and treatment burdens.

External validation of a web-based prognostic tool for predicting survival for patients in hospice care.

Prognostat is an interactive Web-based prognostic tool for estimating hospice patient survival based on a patient's Palliative Performance Scale (PPS) score, age, gender, and cancer status. The tool was developed using data from 5,893 palliative care patients, which was collected at the Victoria Hospice in Victoria, British Columbia, Canada, beginning in 1994. This study externally validates Prognostat with a retrospective cohort of 590 hospice patients at LifePath Hospice and Palliative Care in Florida, USA. The criteria used to evaluate the prognostic performance were the Brier score, area under the receiver operating curve, discrimination slope, and Hosmer-Lemeshow goodness-of-fit test. Though the Kaplan-Meier curves show each PPS level to be distinct and significantly different, the findings reveal low agreement between observed survival in our cohort of patients and survival predicted by the prognostic tool. Before developing a new prognostic model, researchers are encouraged to update survival estimates obtained using Prognostat with the information from their cohort of patients. If it is to be useful to patients and clinicians, Prognostat needs to explicitly report patient risk scores and estimates of baseline survival.

Early Endpoints in High-risk Localized Prostate Cancer: Exploratory Analysis of Three Radiation Therapy Oncology Group Phase 3 Studies.

BACKGROUND: Early endpoints in clinical trials of high-risk localized prostate cancer (HRLPC) that resemble those monitored in real-world practice could expedite clinical development. OBJECTIVE: To assess the association of prostate-specific antigen (PSA) recurrence (PSA-R)-based early endpoints with metastasis-free survival (MFS), overall survival (OS), and prostate cancer (PC)-specific survival (PCSS), and to identify clinically undetectable disease. DESIGN, SETTING, AND PARTICIPANTS: A post hoc analysis of patients with HRLPC from Radiation Therapy Oncology Group studies 9202, 9902, and 0521 was performed. INTERVENTION: Long-term adjuvant androgen-deprivation therapy (ADT) and post-primary definitive radiotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Event-free survival (EFS; PSA-R, locoregional recurrence [LRR], distant metastasis [DM], or death), biochemical failure (PSA-R), general clinical failure (PSA-R, LRR, DM, ADT initiation, or death), and no evidence of disease (NED; alive patients without PSA-R, LRR, DM, and subsequent PC therapy, and with testosterone recovery) were assessed for association with MFS, OS, and PCSS using correlation and landmark analyses, Kaplan-Meier method, and Cox proportional-hazard model. PSA-R was defined as PSA nadir + 2 ng/ml; PSA nadir + 2 ng/ml and rising; PSA >5, 10, and 25 ng/ml; or PSA doubling time (PSADT) <6 mo. RESULTS AND LIMITATIONS: Among assessed early endpoints, EFS with PSA nadir + 2 ng/ml and rising, or with PSA >5 ng/ml was associated with MFS, OS, and PCSS. No development of EFS with PSADT <6 mo or ADT initiation event or achievement of NED at 3 yr was associated with prolonged OS, MFS, and PCSS (hazard ratio [95% confidence interval], 0.53 [0.45-0.64], 0.63 [0.52-0.76], and 0.26 [0.18-0.36], or 0.56 [0.48-0.66], 0.62 [0.52-0.74], and 0.26 [0.19-0.37]) after the landmark time. Older studies performed before the current guidance should be interpreted with caution. CONCLUSIONS: We identified EFS with PSA nadir + 2 ng/ml and rising, PSA >5 ng/ml, or PSADT <6 mo ± ADT initiation and NED as potentially promising early endpoints in HRLPC that should be validated further. PATIENT SUMMARY: We identified novel clinical measures that may expedite the development of new medicines for patients with localized prostate cancer at a high risk of progression. These measures, which took into account prostate-specific antigen assessments and other clinical characteristics, should be confirmed in future studies. We also defined a novel measure of no evidence of disease that can help treating physicians identify patients with clinically undetectable disease.

Bisphosphonates in multiple myeloma: a network meta-analysis.

BACKGROUND: Bisphosphonates are specific inhibitors of osteoclastic activity and used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to be effective in reducing vertebral fractures and pain, their role in improving overall survival (OS) remains unclear. This is an update of a Cochrane review first published in 2002 and previously updated in 2010. OBJECTIVES: To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus nonamino bisphosphonates) in the management of patients with MM. Our primary objective was to determine whether adding bisphosphonates to standard therapy in MM improves OS and progression-free survival (PFS), and decreases skeletal-related morbidity. Our secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw and hypocalcemia. SEARCH METHODS: We searched MEDLINE, LILACS, EMBASE (December 2009 to October 2011) and the Cochrane Controlled Trials Register (all years, latest Issue September 2011) to identify all randomized trials in MM up to October 2011 using a combination of text and MeSH terms. We also handsearched relevant meeting proceedings (December 2009 to October 2011). SELECTION CRITERIA: Any randomized controlled trial (RCT) assessing the role of bisphosphonates and observational studies or case reports examining bisphosphonate-related osteonecrosis of the jaw in patients with MM were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors extracted the data. Data were pooled and reported as hazard ratio (HR) or risk ratio (RR) under a random-effects model. Statistical heterogeneity was explored using metaregression. MAIN RESULTS: In this update, we included 2 studies (2464 patients) that were not part of our last Cochrane review published in 2010. In this review we included 16 RCTs comparing bisphosphonates with either placebo or no treatment and 4 RCTs with a different bisphosphonate as a comparator. The 20 included RCTs enrolled 6692 patients. Overall methodological quality of reporting was moderate. Thirty per cent (6/20) of trials reported the method of generating the randomization sequence. Forty per cent (8/20) of trials had adequate allocation concealment. Withdrawals and dropouts were described in 60% (12/20) of trials. Pooled results showed no direct effect of bisphosphonates on OS compared with placebo or no treatment (HR 0.96, 95% CI 0.82 to 1.13; P = 0.64). However, there was a statistically significant heterogeneity among the included RCTs (I(2) = 55%, P = 0.01) for OS. To explain this heterogeneity we performed a metaregression assessing the relationship between bisphosphonate potency and improvement in OS, which found indicating an OS benefit with zoledronate (P = 0.058). This provided a further rationale for performing network meta-analyses of the various types of bisphosphonates that were not compared head to head in RCTs. Results from network meta-analyses showed superior OS with zoledronate compared with etidronate (HR 0.43, 95% CI 0.16 to 0.86) and placebo (HR 0.61, 95% CI 0.28 to 0.98). However, there was no difference between zoledronate and other bisphosphonates. Pooled analysis did not demonstrate a beneficial effect of bisphosphonates compared with placebo or no treatment in improving PFS (HR 0.70, 95% CI 0.41 to 1.19; P = 0.18) There was no heterogeneity among trials reporting PFS estimates (I(2) = 35%, P = 0.20).Pooled analysis demonstrated a beneficial effect of bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; I(2) = 7%), skeletal-related events (SRE) (RR 0.80, 95% CI 0.72 to 0.89; I(2) = 2%) and amelioration of pain (RR 0.75, 95% CI 0.60 to 0.95; I(2) = 63%). The network meta-analysis did not show any difference in the incidence of osteonecrosis of the jaw (5 RCTs, 3198 patients) between bisphosphonates. Rates of osteonecrosis of the jaw in observational studies (9 studies, 1400 patients) ranged from 0% to 51%. The pooled results (6 RCTs, 1689 patients) showed no statistically significant increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.60; P = 0.11).The pooled results (3 RCTs, 1002 patients) showed no statistically significant increase in frequency of hypocalcemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74). The network meta-analysis did not show any differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used. AUTHORS' CONCLUSIONS: Use of bisphosphonates in patients with MM reduces pathological vertebral fractures, SREs and pain. Assuming a baseline risk of 20% to 50% for vertebral fracture without treatment, between 8 and 20 MM patients should be treated to prevent vertebral fracture(s) in one patient. Assuming a baseline risk of 31% to 76% for pain amelioration without treatment, between 5 and 13 MM patients should be treated to reduce pain in one patient. With a baseline risk of 35% to 86% for SREs without treatment, between 6 and 15 MM patients should be treated to prevent SRE(s) in one patient. Overall, there were no significant adverse effects associated with the administration of bisphosphonates identified in the included RCTs. We found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or nonaminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate appears to be superior to placebo and etidronate in improving OS.

New treatments compared to established treatments in randomized trials.

BACKGROUND: The proportion of proposed new treatments that are 'successful' is of ethical, scientific, and public importance. We investigated how often new, experimental treatments evaluated in randomized controlled trials (RCTs) are superior to established treatments. OBJECTIVES: Our main question was: "On average how often are new treatments more effective, equally effective or less effective than established treatments?" Additionally, we wanted to explain the observed results, i.e. whether the observed distribution of outcomes is consistent with the 'uncertainty requirement' for enrollment in RCTs. We also investigated the effect of choice of comparator (active versus no treatment/placebo) on the observed results. SEARCH METHODS: We searched the Cochrane Methodology Register (CMR) 2010, Issue 1 in The Cochrane Library (searched 31 March 2010); MEDLINE Ovid 1950 to March Week 2 2010 (searched 24 March 2010); and EMBASE Ovid 1980 to 2010 Week 11 (searched 24 March 2010). SELECTION CRITERIA: Cohorts of studies were eligible for the analysis if they met all of the following criteria: (i) consecutive series of RCTs, (ii) registered at or before study onset, and (iii) compared new against established treatments in humans. DATA COLLECTION AND ANALYSIS: RCTs from four cohorts of RCTs met all inclusion criteria and provided data from 743 RCTs involving 297,744 patients. All four cohorts consisted of publicly funded trials. Two cohorts involved evaluations of new treatments in cancer, one in neurological disorders, and one for mixed types of diseases. We employed kernel density estimation, meta-analysis and meta-regression to assess the probability of new treatments being superior to established treatments in their effect on primary outcomes and overall survival. MAIN RESULTS: The distribution of effects seen was generally symmetrical in the size of difference between new versus established treatments. Meta-analytic pooling indicated that, on average, new treatments were slightly more favorable both in terms of their effect on reducing the primary outcomes (hazard ratio (HR)/odds ratio (OR) 0.91, 99% confidence interval (CI) 0.88 to 0.95) and improving overall survival (HR 0.95, 99% CI 0.92 to 0.98). No heterogeneity was observed in the analysis based on primary outcomes or overall survival (I(2) = 0%). Kernel density analysis was consistent with the meta-analysis, but showed a fairly symmetrical distribution of new versus established treatments indicating unpredictability in the results. This was consistent with the interpretation that new treatments are only slightly superior to established treatments when tested in RCTs. Additionally, meta-regression demonstrated that results have remained stable over time and that the success rate of new treatments has not changed over the last half century of clinical trials. The results were not significantly affected by the choice of comparator (active versus placebo/no therapy). AUTHORS' CONCLUSIONS: Society can expect that slightly more than half of new experimental treatments will prove to be better than established treatments when tested in RCTs, but few will be substantially better. This is an important finding for patients (as they contemplate participation in RCTs), researchers (as they plan design of the new trials), and funders (as they assess the 'return on investment'). Although we provide the current best evidence on the question of expected 'success rate' of new versus established treatments consistent with a priori theoretical predictions reflective of 'uncertainty or equipoise hypothesis', it should be noted that our sample represents less than 1% of all available randomized trials; therefore, one should exercise the appropriate caution in interpretation of our findings. In addition, our conclusion applies to publicly funded trials only, as we did not include studies funded by commercial sponsors in our analysis.

Factors that affect the postnatal increase in superior mesenteric artery blood flow velocity in very low birth weight preterm infants.

OBJECTIVE: To identify factors related to the postnatal increase in superior mesenteric artery blood flow velocity (SMA BFV). STUDY DESIGN: SMA BFV was measured in 35 infants (birth weight 1047±246 g) on day of life (DOL) 1, 3, 5, 7 10 and 14. Latent curve modeling (LCM) was used to measure the longitudinal change in BFV for each subject, and the correlation between changes in BFV and baseline values. Non-parametric correlations were calculated between BFV and variables previously reported to be related to SMA BFV. RESULTS: There was significant variability in SMA BFV on DOL 1, a significant increase from DOL 1-14, and significant variability in the postnatal increase. Infants with higher enteral feeding volumes had greater increases, while infants receiving positive pressure ventilation or hyperalimentation had lower increases. CONCLUSIONS: Several clinical factors affect the postnatal increase in SMA BFV. The use of LCM is useful in longitudinal studies of very low birth weight (VLBW) infants, who are clinically and demographically heterogeneous.