Paul J. Novotny

Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial

BACKGROUND Hot flashes can be troublesome, especially when hormonal therapy is contraindicated. Preliminary data have suggested that newer antidepressants, such as venlafaxine, can diminish hot flashes. We undertook a double-blind, placebo-controlled, randomised trial to assess the efficacy of venlafaxine in women with a history of breast cancer or reluctance to take hormonal treatment because of fear of breast cancer. METHODS Participants were assigned placebo (n=56) or venlafaxine 37.5 mg daily (n=56), 75 mg daily (n=55), or 150 mg daily (n=54). After a baseline assessment week, patients took the study medication for 4 weeks. All venlafaxine treatment started at 37.5 mg daily and gradually increased in the 75 mg and 150 mg groups. Patients completed daily hot-flash questionnaire diaries. The primary endpoint was average daily hot-flash activity (number of flashes and a score combining number and severity). Analyses were based on the women who provided data throughout the baseline and study weeks. FINDINGS 191 patients had evaluable data for the whole study period (50 placebo, 49 venlafaxine 37.5 mg, 43 venlafaxine 75 mg, 49 venlafaxine 150 mg). After week 4 of treatment, median hot flash scores were reduced from baseline by 27% (95% CI 11-34), 37% (26-54), 61% (50-68), and 61% (48-75) in the four groups. Frequencies of some side-effects (mouth dryness, decreased appetite, nausea, and constipation) were significantly higher in the venlafaxine 75 mg and 150 mg groups than in the placebo group. INTERPRETATION Venlafaxine is an effective non-hormonal treatment for hot flashes, though the efficacy must be balanced against the drugs side-effects. Confirmation of the results of this 4-week study awaits the completion of three ongoing randomised studies to assess the effects of other related antidepressants for the treatment of hot flashes.

Burnout and medical errors among American surgeons.

Objective:To evaluate the relationship between burnout and perceived major medical errors among American surgeons. Background:Despite efforts to improve patient safety, medical errors by physicians remain a common cause of morbidity and mortality. Methods:Members of the American College of Surgeons were sent an anonymous, cross-sectional survey in June 2008. The survey included self-assessment of major medical errors, a validated depression screening tool, and standardized assessments of burnout and quality of life (QOL). Results:Of 7905 participating surgeons, 700 (8.9%) reported concern they had made a major medical error in the last 3 months. Over 70% of surgeons attributed the error to individual rather than system level factors. Reporting an error during the last 3 months had a large, statistically significant adverse relationship with mental QOL, all 3 domains of burnout (emotional exhaustion, depersonalization, and personal accomplishment) and symptoms of depression. Each one point increase in depersonalization (scale range, 0–33) was associated with an 11% increase in the likelihood of reporting an error while each one point increase in emotional exhaustion (scale range, 0–54) was associated with a 5% increase. Burnout and depression remained independent predictors of reporting a recent major medical error on multivariate analysis that controlled for other personal and professional factors. The frequency of overnight call, practice setting, method of compensation, and number of hours worked were not associated with errors on multivariate analysis. Conclusions:Major medical errors reported by surgeons are strongly related to a surgeons degree of burnout and their mental QOL. Studies are needed to determine how to reduce surgeon distress and how to support surgeons when medical errors occur.

Burnout and Suicidal Ideation among U.S. Medical Students

Death by suicide is a major occupational hazard for physicians (1). The suicide rate among male physicians is more than 40% higher than among men in the general population, whereas that of female physicians is a staggering 130% higher than among women in the general population (1, 2). The increased risk for suicide among physicians may begin during medical school (3). Available studies suggest that the suicide rate among medical students is higher than in the age-matched population (35). Other small, single-institution studies (610) have reported that 3% to 15% of medical students have suicidal ideation during medical school training. Suicidal ideation is a well-established predictor of suicidal planning and attempts. The National Comorbidity Survey found that 34% of individuals in the general population with suicidal ideation develop a suicide plan and, of those who plan, more than 70% will attempt suicide (11). Notably, 26% of individuals with suicidal ideation progressed directly to an unplanned suicide attempt (11). Suicide is at the extreme end of the personal distress continuum, and it is critical for medical schools to identify students at greatest risk for suicide in the hope of intervening before a tragic outcome. Several multi-institutional studies (1214) reveal that medical students have a substantially lower mental quality of life than similarly aged individuals in the general population and that burnout affects up to 50% of U.S. medical students. We hypothesized that burnout would relate to suicidal ideation among medical students. We used a mixed longitudinal and cross-sectional study design to evaluate the prevalence of suicidal ideation among U.S. medical students and to evaluate the relationship between suicidal ideation and burnout, symptoms of depression, and quality of life. Our objective was to assess the frequency of suicidal ideation among medical students and explore its relationship with burnout. Methods Participants In the spring of 2006 (baseline) and 2007 (1-year follow-up), we invited all medical students at the Mayo Medical School, University of Washington School of Medicine, University of Chicago Pritzker School of Medicine, University of Minnesota Medical School, and University of Alabama School of Medicine to complete Web-based surveys. Students at the University of California San Diego School of Medicine and Uniformed Services University of the Health Sciences also participated in the 2007 survey. Participation was elective, and responses were anonymized. We included all students who responded to the 2007 survey in the cross-sectional analysis and those who responded in both 2006 and 2007 in the longitudinal analysis. Each institutions institutional review board approved the study before participation of their students. Data Collection Participants returned the surveys electronically. Preserving student confidentiality was an essential feature. We linked individual responses on the 2006 and 2007 surveys for longitudinal analysis by using unique identifiers and stripped all data of identifiers before forwarding them to study statisticians for analysis. Study Measures We used established instruments to measure burnout, symptoms of depression, and quality of life on both the 2006 and 2007 surveys. These surveys also included questions about demographic characteristics, and the 2007 survey included questions about suicidal ideation. Suicidal Ideation We assessed suicidal ideation by asking students: Have you ever had thoughts of taking your own life, even if you would not really do it?, During the past 12 months have you had thoughts of taking your own life?, and Have you ever made an attempt to take your own life? These questions, which originated from an inventory developed by Meehan and colleagues (15) that has been used to assess suicidal ideation among medical students (9), are similar to questions used in large U.S. epidemiologic studies intended to assess suicidality (11, 1618). Burnout, Symptoms of Depression, and Quality of Life The Maslach Burnout Inventory is a 22-item instrument that is considered the gold standard for measuring burnout (1921). This instrument has separate subscales to evaluate each domain of burnout: emotional exhaustion, depersonalization, and low personal accomplishment. Tests of discriminant and convergent validity have been acceptable, construct validity of the 3 dimensions has been demonstrated (22, 23), and predictive validity has been suggested by burnout score predicting risk for future sick leave absences (24). The Maslach Burnout Inventory has also been used extensively in studies of both physicians (20,21, 25) and medical students (13, 14, 2628). According to convention, a score of 27 or higher on the emotional exhaustion subscale or 10 or higher on the depersonalization subscale was considered an indicator of professional burnout for medical professionals (19). Health professionals are considered to have a low score on the personal accomplishment scale if their score is 33 or less. Normal scores for health care professionals, including physicians, are 22.19, 7.12, and 36.53 on the emotional exhaustion, depersonalization, and personal accomplishment subscales, respectively (19). We identified symptoms of depression by using the 2-item Primary Care Evaluation of Mental Disorders (29), a screening tool which performs as well as longer instruments (30). This instrument has a sensitivity of 86% to 96% and a specificity of 57% to 75% for major depressive disorder (29, 30). With a reported positive likelihood ratio of up to 3.42 for the diagnosis of major depression (30) and an estimated 25% prevalence of depression among medical students (12), a positive result implies a 50% probability of current major depression. We measured mental and physical quality of life by using the Medical Outcomes Study Short Form-8 (SF-8) (31, 32), an alternate version of the SF-36. Norm-based scoring methods of responses on this instrument are used to calculate mental and physical quality of life summary scores (31). The mean mental and physical quality of life summary scores for the U.S. population are 49.2 (SD, 9.46) and 49.2 (SD, 9.07), respectively (31). Previous research has demonstrated acceptable reliability and testretest reliability (31). Several studies (31) have demonstrated content, construct, and criterion-related validity for the SF-8, and other studies (33) have demonstrated high convergent validity and good discriminate validity. The SF-8 has also been used in samples of residents (32) and medical students (14, 27, 28). Statistical Analysis Our primary analysis involved descriptive summary statistics for estimating the prevalence of suicidal ideation, burnout, a positive depression screen, and mental and physical quality of life for medical students. We evaluated differences by reported suicidal ideation in the previous year by using the WilcoxonMannWhitney test (for continuous variables) and the Fisher exact test (for categorical variables). We used the Wilcoxon rank-sum test rather than parametric tests to account for the interval level nature of the psychological tests. All tests were 2-sided, with a type I error rate of 0.05. We performed collinearity testing to determine whether multiple-way collinearity existed among the independent variables (34). No variables had achieved a level of collinearity that would bias the modeling process. We performed forward stepwise logistic regression to evaluate independent associations of the independent variables with suicidal ideation. We used a saturated model and backward stepping to confirm results of the initial stepwise regression. In all cases, backward stepping produced the same model as the stepwise approach. All analyses were done by using SAS, version 9 (SAS Institute, Cary, North Carolina). Role of the Funding Source This work was supported by an Education Innovation award from the Mayo Clinic. The Mayo Clinic played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation of the manuscript or decision to publish the manuscript. Results Cross-Sectional Survey A total of 2248 (52.4%) of 4287 medical students responded to the 2007 survey. Responders were less likely than the overall population to be male (51.6% vs. 54.9%), between 25 and 30 years of age (55.4% vs. 62.4%), or nonwhite (25.8% vs. 31.0%) (all P< 0.02). Table 1 shows the demographic characteristics of cross-sectional survey respondents. Table 1. Participant Characteristics, 2007 Table 2 shows the percentage of responders reporting suicidal ideation, burnout, and symptoms of depression and the mean quality-of-life scores. Of the 2230 responders on the 2007 survey who responded to questions on suicidal ideation, 249 (11.2% [CI, 9.9% to 12.6%]) reported considering suicide in the previous year and 43 (1.9% [CI, 1.4% to 2.6%]) had made a suicide attempt at some point in the past. On sensitivity analysis, assuming that all nonresponders did not have suicidal ideation, the prevalence of suicidal ideation in the past 12 months would be 249 (5.8%) of 4287 students. Table 2. Burnout, Quality of Life, and Depression Symptoms, 2007 Overall, 1069 (49.6%, [CI, 47.5%51.8%]) of 2154 students met the criteria for burnout (94 students did not answer enough Maslach Burnout Inventory questions to be included in this analysis). Among these students, 860 (40.1%) of 2142 had high emotional exhaustion, 648 (31.8%) of 2037 had high depersonalization, and 595 of 1945 (30.6%) had a low sense of personal accomplishment. Compared with age-comparable individuals and the general U.S. population, medical students had lower mental quality-of-life scores (mean, 43.5 [SD, 11.0] vs. 47.2 [SD, 9.9] for age-comparable individuals [P< 0.001] and 49.2 [SD, 9.5] for the general U.S. population [P< 0.001]) but higher physical quality-of-life scores (mean, 52.2 [6.9] vs. 51.4 [SD, 7.9] for age-comparable

Percutaneous Image-Guided Radiofrequency Ablation of Painful Metastases Involving Bone: A Multicenter Study

PURPOSE Few options are available for pain relief in patients with bone metastases who fail standard treatments. We sought to determine the benefit of radiofrequency ablation (RFA) in providing pain relief for patients with refractory pain secondary to metastases involving bone. PATIENTS AND METHODS Thirty-one US and 12 European patients with painful osteolytic metastases involving bone were treated with image-guided RFA using a multitip needle. Treated patients had > or = 4/10 pain and had either failed or were poor candidates for standard treatments such as radiation or opioid analgesics. Using the Brief Pain Inventory-Short Form, worst pain intensity was the primary end point, with a 2-unit drop considered clinically significant. RESULTS Forty-three patients were treated (median follow-up, 16 weeks). Before RFA, the mean score for worst pain was 7.9 (range, 4/10 to 10/10). Four, 12, and 24 weeks following treatment, worst pain decreased to 4.5 (P <.0001), 3.0 (P <.0001), and 1.4 (P =.0005), respectively. Ninety-five percent (41 of 43 patients) experienced a decrease in pain that was considered clinically significant. Opioid usage significantly decreased at weeks 8 and 12. Adverse events were seen in 3 patients and included (1) a second-degree skin burn at the grounding pad site, (2) transient bowel and bladder incontinence following treatment of a metastasis involving the sacrum, and (3) a fracture of the acetabulum following RFA of an acetabular lesion. CONCLUSION RFA of painful osteolytic metastases provides significant pain relief for cancer patients who have failed standard treatments.

Phase III Evaluation of Fluoxetine for Treatment of Hot Flashes

PURPOSE Hot flashes can be a prominent problem in women with a history of breast cancer. Given concerns regarding the use of hormonal therapies in such patients, other nonhormonal means for treating hot flashes are required. Based on anecdotal information regarding the efficacy of fluoxetine and other newer antidepressants for treating hot flashes, the present trial was developed. PATIENTS AND METHODS This trial used a double-blinded, randomized, two-period (4 weeks per period), cross-over methodology to study the efficacy of fluoxetine (20 mg/d) for treating hot flashes in women with a history of breast cancer or a concern regarding the use of estrogen (because of breast cancer risk). Eligible patients had to have reported that they averaged at least 14 hot flashes per week; they could have received tamoxifen or raloxifene as long as they were on a stable dose. The major outcome measure was a bivariate construct representing hot flash frequency and hot flash score, analyzed by a classic sums and differences cross-over analysis. RESULTS Eighty-one randomized women began protocol therapy. By the end of the first treatment period, hot flash scores (frequency x average severity) decreased 50% in the fluoxetine arm versus 36% in the placebo arm. Cross-over analysis demonstrated a significantly greater marked hot flash score improvement with fluoxetine than placebo (P =.02). The results were not adjusted for potential confounding influences, including age and tamoxifen use. The fluoxetine was well tolerated. CONCLUSION This dose of fluoxetine resulted in a modest improvement in hot flashes.

Methodologic lessons learned from hot flash studies

PURPOSE In the course of conducting a series of prospective clinical trials devoted to defining new treatment opportunities for hot flashes in cancer survivors, considerable experience has been acquired with related methodologic issues. This article has been written in response to many queries regarding this methodology. PATIENTS AND METHODS A series of seven different clinical trials that involved 968 patients was used for this work. Reliable and valid definitions of hot flash intensity were developed from patient-reported descriptions. Concomitant validity and reliability assessment of patient-completed diaries was undertaken to compare hot flash data with toxicity and quality-of-life (QOL) end points and to examine consistency across patient groups using variability analysis and correlation procedures. Parametric data from this meta-analysis was used to examine relative power considerations for the design of phase II and phase III clinical trials. RESULTS Daily diaries used in these studies exhibited consistency and reliability and had few missing data. Hot flash frequency and hot flash score (frequency multiplied by average severity) variables produced almost identical end point results. For phase III placebo-controlled studies, 50 patients per treatment arm seem appropriate to provide sufficient power specifications to detect a clinically meaningful change in hot flash activity. For phase II trials, 25 patients per trial seem to provide reasonable estimates of eventual hot flash efficacy to screen potential agents for more definitive testing. CONCLUSION Given the data gained from these experiences, we can plan and carry out more efficient trials to identify efficacious agents for the reduction of hot flash activity.

Burnout and career satisfaction among American surgeons.

Objective:To determine the incidence of burnout among American surgeons and evaluate personal and professional characteristics associated with surgeon burnout. Background:Burnout is a syndrome of emotional exhaustion and depersonalization that leads to decreased effectiveness at work. A limited amount of information exists about the relationship between specific demographic and practice characteristics with burnout among American surgeons. Methods:Members of the American College of Surgeons (ACS) were sent an anonymous, cross-sectional survey in June 2008. The survey evaluated demographic variables, practice characteristics, career satisfaction, burnout, and quality of life (QOL). Burnout and QOL were measured using validated instruments. Results:Of the approximately 24,922 surgeons sampled, 7905 (32%) returned surveys. Responders had been in practice 18 years, worked 60 hours per week, and were on call 2 nights/wk (median values). Overall, 40% of responding surgeons were burned out, 30% screened positive for symptoms of depression, and 28% had a mental QOL score >1/2 standard deviation below the population norm. Factors independently associated with burnout included younger age, having children, area of specialization, number of nights on call per week, hours worked per week, and having compensation determined entirely based on billing. Only 36% of surgeons felt their work schedule left enough time for personal/family life and only 51% would recommend their children pursue a career as a physician/surgeon. Conclusion:Burnout is common among American surgeons and is the single greatest predictor of surgeons’ satisfaction with career and specialty choice. Additional research is needed to identify individual, organizational, and societal interventions that preserve and promote the mental health of American surgeons.

Evaluation of Soy Phytoestrogens for the Treatment of Hot Flashes in Breast Cancer Survivors: A North Central Cancer Treatment Group Trial

PURPOSE Hot flashes represent a significant clinical problem for some breast cancer survivors. Safe, effective treatment is needed for this prominent clinical problem. Although it has been shown that estrogen or progesterone replacement therapy can alleviate this problem, there are continued safety concerns regarding the use of hormonal therapies in these women. Based on anecdotal information, we hypothesized that soy-derived phytoestrogens, weak estrogen-like substances in the soybean that demonstrate estrogen agonist and/or antagonist effects when they bind to estrogen receptors, could alleviate hot flashes. This current trial was designed to investigate this hypothesis. PATIENTS AND METHODS This double-blind clinical trial involved breast cancer survivors with substantial hot flashes. After randomization, patients underwent a 1-week baseline period with no therapy. This was followed by 4 weeks of either soy tablets or placebo. The patients then crossed over to the opposite arm in a double-blind manner for the last 4 weeks. Patients completed a daily questionnaire documenting hot flash frequency, intensity, and perceived side effects. RESULTS Of the 177 women who were randomized and started the study substance, 155 (88%) provided useable data over the first 5 weeks; 149 provided usable data over the entire 9 weeks. There was no suggestion that the soy product was more effective in reducing hot flashes than the placebo. At study completion, patients preferred the soy product 33% of the time, the placebo 37% of the time, and neither substance 31% of the time. No toxicity was observed. CONCLUSION The soy product did not alleviate hot flashes in breast cancer survivors.

Prospective evaluation of vitamin E for hot flashes in breast cancer survivors.

PURPOSE Hot flashes represent a substantial clinical problem for some breast cancer survivors. Although estrogen or progesterone preparations can alleviate these symptoms in many patients, concern remains regarding the use of hormonal preparations in such women. Thus, there is a perceived need for nonhormonal treatments for hot flashes for breast cancer survivors. Based on anecdotal evidence that vitamin E was helpful, we designed a trial to investigate this matter. METHODS We developed and conducted a placebo-controlled, randomized, crossover trial where, after a 1 week baseline period, patients received 4 weeks of vitamin E 800 IU daily, then 4 weeks of an identical-appearing placebo, or vice versa. Diaries were used to measure potential toxicities and hot flashes during the baseline week and the two subsequent 4-week treatment periods. RESULTS The 120 patients evaluated for toxicity failed to show any. The 105 patients who finished the first treatment period showed a similar reduction in hot flash frequencies (25% v 22%; P = .90) for the two study arms. A crossover analysis, however, showed that vitamin E was associated with a minimal decrease in hot flashes (one less hot flash per day than was seen with a placebo) (P < or = .05). At the study end, patients did not prefer vitamin E over the placebo (32% v 29%, respectively). CONCLUSION Although this trial was able to show a statistically significant hot flash reduction with vitamin E compared to a placebo, the clinical magnitude of this reduction was marginal.

Dronabinol Versus Megestrol Acetate Versus Combination Therapy for Cancer-Associated Anorexia: A North Central Cancer Treatment Group Study

PURPOSE To determine whether dronabinol administered alone or with megestrol acetate was more, less, or equal in efficacy to single-agent megestrol acetate for palliating cancer-associated anorexia. PATIENTS AND METHODS Four hundred sixty-nine assessable advanced cancer patients were randomized to (1) oral megestrol acetate 800 mg/d liquid suspension plus placebo, (2) oral dronabinol 2.5 mg twice a day plus placebo, or (3) both agents. Eligible patients acknowledged that loss of appetite or weight was a problem and reported the loss of 5 pounds or more during 2 months and/or a daily intake of less than 20 calories/kg of body weight. RESULTS Groups were comparable at baseline in age, sex, tumor type, weight loss, and performance status. A greater percentage of megestrol acetate-treated patients reported appetite improvement and weight gain compared with dronabinol-treated patients: 75% versus 49% (P =.0001) for appetite and 11% versus 3% (P =.02) for > or = 10% baseline weight gain. Combination treatment resulted in no significant differences in appetite or weight compared with megestrol acetate alone. The Functional Assessment of Anorexia/Cachexia Therapy questionnaire, which emphasizes anorexia-related questions, demonstrated an improvement in quality of life (QOL) among megestrol acetate-treated and combination-treated patients. The single-item Uniscale, a global QOL instrument, found comparable scores. Toxicity was also comparable, with the exception of an increased incidence of impotence among men who received megestrol acetate. CONCLUSION In the doses and schedules we studied, megestrol acetate provided superior anorexia palliation among advanced cancer patients compared with dronabinol alone. Combination therapy did not appear to confer additional benefit.