1. A randomized crossover trial of venlafaxine (V) versus gabapentin (G) for hot flashes in breast cancer survivors Louise J Bordeleau 1, Olivera Jugovic 2, Marguerite Ennis 3, Kathleen Pritchard 4, David Warr 5, Rashida Haq 6, Charles Loprinzi 7, Pamela Goodwin 2,5 1 Juravinski Cancer Centre, Hamilton, ON, CA; 2 Mount Sinai Hospital, Toronto ON, CA; 3 Applied Statistician, Markham, ON, CA; 4 Sunnybrook Odette Regional Cancer, Toronto, ON,CA; 5 Princess Margaret Hospital, Toronto, ON,CA; 6 St. Michaels Hospital, Toronto,ON,CA; 7 Mayo Clinic, Rochester, MN, USA Background: Non-hormonal pharmacologic interventions are recommended for the treatment of hot flashes (HF) in breast cancer survivors. Antidepressants (SSRI/SNRI) and G have been shown to be effective, however, it is still unclear which agent is best. Methods: A randomized crossover trial compared 4 weeks of V (37.5mg x 7days followed by 75mg/day) and G (300mg daily x 3days, 300mg BID x 3 days then 300 mg TID). Eligibility included postmenopausal women with at least 14 bothersome HF per week for the prior month. A 2 week baseline period was followed by the first treatment period. Crossover to the alternative treatment occurred following a 2 week dose tapering/wash out period. The primary endpoint was patient preference. Secondary endpoints included change from baseline in HF score (frequency x severity) per a prospective daily HF diary, change in HF frequency, QOL, and toxicity. Toxicities were evaluated with a self-report questionnaire and NCI common terminology criteria. A two-stage group sequential design was used with the first analysis pre-planned at 66 patients and the second (if needed) at 131, allowing for drop out/indecision rate of 25%. The design had 80% power to detect a shift from equal preference of ≥ 15 % (2 sided type 1 error at 5%). Results: Data analysis after 66 patients showed the pre-defined stopping rule was satisfied. The study arms were well balanced. Of 56 patients with a preference (8 dropped out and 2 had no preference), 18 preferred G and 38 preferred V (32% and 68% respectively; p=0.01). Both V and G reduced HF scores (66% reduction) and frequency (55% reduction) similarly and significantly. Satisfaction with the preferred treatment was high. V was associated with more appetite loss, nausea and constipation, and less sleeplessness, nervousness, and negative mood changes than at baseline (all p ≤ 0.03) whereas G was associated with more dizziness and increased appetite, and less sleeplessness (all p ≤ 0.004). Conclusions: Breast cancer survivors prefer V over G for the treatment of HF. Both agents are effective in the management of HF based on recorded diary experience. Preference appears to be driven by the balance between effectiveness and tolerance. PARTICIPATING CENTRES Mount Sinai Hospital, Toronto, ON, CANADA Princess Margaret Hospital, Toronto, ON, CANADA St. Michael’s Hospital, Toronto, ON, CANADA STRAFICATION 1) centre of enrolment 2) concurrent use of tamoxifen or Aromatase inhibitor ASSESSMENTS Hot flash diary completed throughout the study Symptom experience diary completed at baseline and at the end of each study period MOS-SF36 completed at baseline and at the end of each study period SYMPTOM EXPERIENCE DIARY: Appetite, fatigue, mouth dryness, abnormal sweating, constipation, swelling, undesirable weight gain, trouble sleeping, nervousness, negative mood changes, interest in sexual relations, difficulty achieving an orgasm, rash, heart palpitation TREATMENT PREFERENCE collected at time of study completion STATISTICAL CONSIDERATIONS Two-stage group sequential design First analysis pre-planned at 66 patients Second (if needed) at 131 patients Allow drop out/indecision rate of 25% 80% power to detect a shift from equal preference of > 15% (2 sided type 1 error at 5%) Abstract Conclusions Study Schema Methods. PRIMARY OBJECTIVE To compare patient preference for venlafaxine versus gabapentin SECONDARY OBJECTIVES To compare hot flash frequency, severity and composite score To compare QOL (MOS-SF36) To compare toxicities To correlate patient preferences with standard outcome measurements Results #9023 Objectives VENLAFAXINE Off Therapy 4 weeks 2- 4 weeks4 weeks2 weeks GABAPENTIN VENLAFAXINE GABAPENTIN Randomization Screening Study period 1 Study period 2 Arm 1 Arm 2 Eligibility Criteria INCLUSION:  Women with a history of breast cancer (disease free) with at least 14 hot flashes per week  Normal creatinine clearance EXCLUSION:  Previous use of any antidepressants within a year  Previous use of a calcium channel antagonist or gabapentin within 2 weeks  Current (< 2 weeks) or planned use of other agents for HF  Tam/AI/GHRH analog allowed unless  Started within 4 weeks of study entry  Planning to discontinue during study period Results 66 patients enrolled (May 2007- Jan 2009) Pre-defined stopping rule satisfied Study arms were well balanced 66 patients enrolled (May 2007- Jan 2009); pre-defined stopping rule satisfied Study arms were well balanced Table1. Patient Preference (Primary Outcome) Prefer gabapentin N=18 Prefer venlafaxine N=38 Total N=56 Strength of Preference Much better Little better 12(66.7%) 6(33.3%) 22(57.9%) 16(42.1%) 34(60.7%) 22(39.3%) Reasons for Preference  Severity of hot flashes  Frequency of hot flashes Fewer side effects 17 (94.4%) 11 (61.1%) 36 (94.7%) 32 (84.2%) 22 (57.9%) 53 (94.6%) 49 (87.5%) 33 (58.9%) Figure 1. Mean daily hot flash scores plotted by study week for patients randomized to venlafaxine (V) followed by gabapentin (G) versus the alternative, using all available data. Dotted lines (weeks 1-2 and 7-8) represent baseline and tapering/washout periods; solid lines (weeks 3-6 and 9-12) the first and second treatment periods. Figure 2. Mean symptoms scores at baseline (dot) and on treatment with venlafaxine (V) and gabapentin (G). Line segments indicate cases where the mean symptom scores of the two drugs were significantly different at the 5% level. The number of patients that answered each question is given on the left side of each panel. QUALITY OF LIFE (MOS SF-36 normed) Baseline mean physical component summary score: 44.4+ 9.8 Baseline mean mental component summary score: 48.2 + 11.7 Difference between groups was not statistically significant Venlafaxine associated with:  nausea  appetite loss  constipation  negative mood changes Gabapentin associated with:  Dizziness  Increased appetite Analysis by preference:  Prefer venlafaxine HF scores 41% lower on V than G  Prefer gabapentin HF scores 47% lower on G than V  Breast cancer survivors prefer venlafaxine over gabapentin for the treatment of hot flashes  Individual experience with each treatment was a key determinant of preference  Both venlafaxine and gabapentin are effective in the management of hot flashes