Beth I. LaVasseur

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.

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.

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.

Phase III Double-Blind, Randomized, Placebo-Controlled Crossover Trial of Black Cohosh in the Management of Hot Flashes: NCCTG Trial N01CC1

PURPOSE Hot flashes can cause significant morbidity in postmenopausal women undergoing or finished with breast cancer treatment. Black cohosh has been used to treat hot flashes, but definitive clinical data about efficacy have been equivocal. METHODS A double-blind, randomized, cross-over clinical trial with two 4-week periods, was used to study the efficacy of black cohosh (1 capsule, Cimicifuga racemosa 20 mg BID) for the treatment of hot flashes in women. Participants kept a daily hot flash diary during a baseline week and then during two 4-week crossover treatment periods. Hot flash scores were measured by assigning points (1 to 4 for mild to very severe) to each hot flash based on severity and then adding the points for a given time period. RESULTS Between October 31, 2003, to March 4, 2004, 132 patients were randomly assigned. Toxicity was minimal and not different by treatment group. Patients receiving black cohosh reported a mean decrease in hot flash score of 20% (comparing the fourth treatment week to the baseline week) compared with a 27% decrease for patients on placebo (P = .53). Mean hot flash frequency was reduced 17% on black cohosh and 26% on placebo (P = .36). Patient treatment preferences were measured after completion of both treatment periods by ascertaining which treatment period, if any, the patient preferred. Thirty-four percent of patients preferred the black cohosh treatment, 38% preferred the placebo, and 28% did not prefer either treatment. CONCLUSION This trial failed to provide any evidence that black cohosh reduced hot flashes more than the placebo.

Phase III, Placebo-Controlled Trial of Three Doses of Citalopram for the Treatment of Hot Flashes: NCCTG Trial N05C9

PURPOSE Up to 75% of women experience hot flashes, which can negatively impact quality of life. As hot flash physiology is not definitively understood, it cannot be assumed that effective agents represent class effects. Therefore, there is a continued need for rigorous evaluation to identify effective nonhormonal options for hot flash relief. METHODS A randomized, double-blind trial evaluated citalopram at target doses of 10, 20, or 30 mg/d versus placebo for 6 weeks. Postmenopausal women with at least 14 bothersome hot flashes per week recorded hot flashes for 7 days before starting treatment and were then titrated to their target doses. The primary end point was the change from baseline to 6 weeks in hot flash score. RESULTS Two hundred fifty-four women were randomly assigned onto this study. Data for hot flash scores and frequencies showed significant improvement in hot flashes with citalopram over placebo, with no significant differences among doses. Reductions in mean hot flash scores were 2.0 (23%), 7.0 (49%), 7.7 (50%), and 10.7 (55%) for placebo and 10, 20, and 30 mg of citalopram, respectively (P <or= .002). Improvement in secondary outcomes, such as the Hot Flash Related Daily Interference Scale, was statistically superior in the 20-mg arm. Citalopram was well-tolerated, with no significant negative adverse effects. CONCLUSION Citalopram is an effective, well-tolerated agent in managing hot flashes. There does not appear to be a significant dose response above 10 mg/d, but broader helpful effects of the agent appear to be more evident at 20 mg/d.

The use of Valeriana officinalis (Valerian) in improving sleep in patients who are undergoing treatment for cancer: a phase III randomized, placebo-controlled, double-blind study (NCCTG Trial, N01C5).

Sleep disorders are a substantial problem for cancer survivors, with prevalence estimates ranging from 23% to 61%. Although numerous prescription hypnotics are available, few are approved for long-term use or have demonstrated benefit in this circumstance. Hypnotics may have unwanted side effects and are costly, and cancer survivors often wish to avoid prescription drugs. New options with limited side effects are needed. The purpose of this trial was to evaluate the efficacy of a Valerian officinalis supplement for sleep in people with cancer who were undergoing cancer treatment. Participants were randomized to receive 450 mg of valerian-or placebo orally 1 hour before bedtime for 8 weeks. The primary end point was area under the curve (AUC) of the overall Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes included the Functional Outcomes of Sleep Questionnaire, the Brief Fatigue Inventory (BFI), and the Profile of Mood States (POMS). Toxicity was evaluated with both self-reported numeric analogue scale questions and the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Questionnaires were completed at baseline and at 4 and 8 weeks. A total of 227 patients were randomized into this study between March 19, 2004, and March 9, 2007, with 119 being evaluable for the primary end point. The AUC over the 8 weeks for valerian was 51.4 (SD = 16), while that for placebo was 49.7 (SD = 15), with a P value of 0.6957. A supplemental, exploratory analysis revealed that several fatigue end points, as measured by the BFI and POMS, were significantly better for those taking valerian over placebo. Participants also reported less trouble with sleep and less drowsiness on valerian than placebo. There were no significant differences in toxicities as measured by self-report or the CTCAE except for mild alkaline phosphatase increases, which were slightly more common in the placebo group. This study failed to provide data to support the hypothesis that valerian, 450 mg, at bedtime could improve sleep as measured by the PSQI. However, exploratory analyses revealed improvement in some secondary outcomes, such as fatigue. Further research with valerian exploring physiologic effects in oncology symptom management may be warranted.

Partnering With Payers for Success: Quality Oncology Practice Initiative, Blue Cross Blue Shield of Michigan, and the Michigan Oncology Quality Consortium

More than 16% of the total sites participating nationally in the QOPI survey are in Michigan. A significant component of the growth in QOPI participation in Michigan can be attributed to the involvement and quality improvement efforts of Blue Cross Blue Shield of Michigan.

Potential mediators of improvement in painful chemotherapy-induced peripheral neuropathy via a web-based cognitive behavioural intervention

Purpose Preliminary evidence suggests that a self-guided cognitive and behaviourally-based pain management intervention (PROSPECT) is effective for chronic painful chemotherapy-induced peripheral neuropathy (CIPN), but its mechanism of action is unknown. The purpose of this secondary analysis was to explore if changes in anxiety, depression, sleep-related impairment, or fatigue mediated improvements in worst pain following PROSPECT in individuals with chronic painful CIPN. Methods Sixty participants were randomized to receive self-guided cognitive behavioural pain management (access for eight weeks) or treatment as usual. A seven-day worst CIPN pain diary and the PROMIS measures of anxiety, depression, fatigue, and sleep-related impairment were administered pre/posttest (eight-weeks). Causal mediation analysis was used to quantify mediators of worst pain improvement. Results None of the hypothesized mediators had a statistically significant effect on worst pain (n=38). Implications Further research is needed to identify potential mediators of pain intensity that can be targeted by specific cognitive behavioural strategies to improve painful CIPN severity.

Factors associated with toxicity-related service use among community oncology patients.

133 Background: Chemotherapy-associated toxicities occur often, yet sparse data are available to correlate toxicities with related service use. Toxicities may disrupt treatment, impair quality of life, and induce unplanned service use. We sought to understand the frequency and correlates of unplanned service use among patients receiving first-cycle chemotherapy at 5 community-based ambulatory oncology practices in southeast Michigan. METHODS A prospective survey examined the dichotomous outcome of toxicity-related unplanned service use. Newly-diagnosed patients were recruited before the first chemotherapy cycle. At the second cycle visit, patients completed a questionnaire that measured severity of nausea, vomiting, diarrhea, constipation, mouth sores, IV catheter problems, pain, fever/chills, extremity edema, and dyspnea on a 5-point scale (1 = did not experience to 5 = disabling). They also rated distress on a 10-point scale (0 = none, 10 = worst). Patients reported unplanned oncologist visits, emergency department visits, and unplanned hospitalizations, all of which were treated as unplanned service use. Mixed-effects logistic regression was used to identify factors associated with unplanned service use, with random effects for each clinic. RESULTS Among 106 patients (98% white, 74.5% women, mean age 60+11), common diagnoses were breast, lung, and colorectal cancer and non-Hodgkin lymphoma. Frequent toxicities were pain, nausea, diarrhea, and constipation. Thirty-six patients (34%) reported unplanned service use: 29% reported oncologist visits, 14% reported ED visits, and 8% reported hospitalizations. 45% of the total sample and 89% of patients with unplanned service use reported at least one toxicity that was severe or disabling. Factors associated with unplanned service use were high patient-reported distress and receipt of colony-stimulating factor. CONCLUSIONS Toxicity-related service use was common in this community oncology population. Proactive symptom assessment tools may help clinicians manage toxicities between visits. A deeper understanding of toxicity patterns and correlates can inform clinical practice guidelines in community oncology practices.

Frequency and burden of patient-reported chemotherapy toxicities in community-based oncology practices.

178 Background: Patient-reported outcomes measurement is recommended to improve care delivery. Toxicities are important to study given their impacts on treatment completion. We captured patient-reported toxicities in community-based oncology practices and identified toxicities associated with excess health care service use. METHODS We surveyed newly-diagnosed patients who completed their first chemotherapy cycle at 5 community practices. Exclusion criteria were prior cancer history, non-English speakers, psychiatric diagnosis, and clinical trial participation. At the second cycle return visit, patients completed a questionnaire that measured the severity of nausea, vomiting, diarrhea, constipation, mouth sores, intravenous catheter problem, pain, fever/chills, extremity edema, and dyspnea. These were rated on a 5-point scale (1= did not experience to 5 = very severe). Patients also reported unscheduled oncologist visits, emergency department visits, or inpatient hospitalization. RESULTS Of 117 eligible patients, 106 (91%) participated. Most patients (98%) were white, 25.5% were male, and the mean(SD) age was 60 (11) years. The most frequent diagnoses were breast (43%), lung (21%), colorectal cancer (13%), and non-Hodgkin lymphoma (13%). Between cycle 1 and 2, frequent severe or very severe toxicities were nausea (30%), pain (18%), diarrhea (9%), and mouth sores (9%). 15% of patients had an unscheduled oncologist visit, 18% had an emergency department visit, and 9% of patients were admitted. Nausea (11.3%) and diarrhea (6.6%) were frequent reasons for unscheduled oncology visits; nausea and pain (both 5%) for emergency department visits, and; pain and dyspnea (both 2%) for hospitalization. CONCLUSIONS Patient-reported toxicity monitoring is feasible and informative in community-based oncology practices. Despite widespread antiemetic use, nausea is a pervasive problem for newly-treated patients and drives excess service use. Pain assessment and management strategies are needed to reduce emergency department visits and hospitalizations.