Conflicts-donations to Mayo. Pfizer -pregabalin to prevent paclitaxel-induced neuropathy Competitive Technologies- donated Scrambler machines

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1 Conflicts-donations to Mayo Pfizer -pregabalin to prevent paclitaxel-induced neuropathy Competitive Technologies- donated Scrambler machines

2 Symptom Management of Therapy-Related Toxicities Charles L Loprinzi MD Regis Professor of Breast Cancer Oncology Mayo Clinic Rochester, MN cloprinzi@mayo.edu

3 Issues Hot Flashes Vaginal Dryness AI arthralgias Paclitaxel neuropathy

4 Hot Flash Topics Overview of Mayo/NCCTG Randomized Hot Flash Studies Newer antidepressant meta-analysis CYP 2D6/Tamoxifen metabolism Gabapentin meta-analysis Gabapentin vs venlafaxine Stellate ganglion block Clinical hypnosis

5 Basic Study Design Double Blind Eligible Patients Stratify Randomize Agent Placebo

6 Mean Hot Flash Score Reduction Randomized Studies Placebo (n=420) Soy (n=78) Vitamin E (n=53) Clonidine (n=75) Fluoxetine (n=36) Venlafaxine (n=48) Megestrol (n=74) Week

7 Mean Hot Flash Score Reduction Randomized Studies Black Cohosh (n=58) Placebo (n=420) Soy (n=78) Vitamin E (n=53) Clonidine (n=75) Fluoxetine (n=36) Citalopram (n=57) Ven (vs MPA) (n=94) Venlafaxine (n=48) MPA 400 mg (n=94) Megestrol (n=74) Flaxseed (n=69) Pregabalin (n=63) Week

8 Mean Hot Flash Score Reduction Randomized Studies Black Cohosh (n=58) Placebo (n=420) Soy (n=78) Vitamin E (n=53) Clonidine (n=75) Fluoxetine (n=36) Citalopram (n=57) Ven (vs MPA) (n=94) Venlafaxine (n=48) MPA 400 mg (n=94) Megestrol (n=74) Flaxseed (n=69) Pregabalin (n=63) Week

9 Hot Flash Topics Overview of Mayo/NCCTG Randomized Hot Flash Studies Newer antidepressant meta-analysis CYP 2D6/Tamoxifen metabolism Gabapentin meta-analysis Gabapentin vs venlafaxine Stellate ganglion block Clinical hypnosis

10 Study Loprinzi, Fluoxetine 20 mg/g HR (fixed) 95% CI Stearns, Paroxetine 10 mg/d Stearns, Paroxetine 20 mg/d Stearns, Paroxetine 12.5 mg/d Stearns, Paroxetine 25 mg/d Paroxetine total Gordon, Sertraline 50 mg/d Kimmick, Sertraline 50 mg/d Grady, Sertraline 100 mg/d Sertraline total Loprinzi, Venlafaxine 37.5 mg/d Loprinzi, Venlafaxine 75 mg/d Loprinzi, Venlafaxine 150 mg/d Venlafaxine total Antidepressants total Favors antidepressant Loprinzi CL et al J Clin Oncol 2009, 27(17); Favors placebo CP B-23

11 Are there other placebo-controlled trials published after this metaanalysis?

12 Subsequent Placebocontrolled Hot Flash Antidepressant Studies with Similar Outcomes Desvenlafaxine Citalopram Escitalopram Barton DL, et al; J Clin Oncol Jul 10;28(20): Archer DF, et al; Am J Obstet Gynecol. 2009; 200(3):238 Freeman, et al; JAMA 2011; 305; Speroff L, et al; Obstet Gynecol. 2008;111(1):77-87.

13 FDA NEWS RELEASE: June 28, 2013 The U.S. Food and Drug Administration today approved Brisdelle (paroxetine) to treat moderate to severe hot flashes (vasomotor symptoms) associated with menopause.

14 Hot Flash Topics Overview of Mayo/NCCTG Randomized Hot Flash Studies Newer antidepressant meta-analysis CYP 2D6/Tamoxifen metabolism Gabapentin meta-analysis Gabapentin vs venlafaxine Stellate ganglion block Clinical hypnosis

15 JNCI 2003;95;

16 Hot Flash Topics Overview of Mayo/NCCTG Randomized Hot Flash Studies Newer antidepressant meta-analysis CYP 2D6/Tamoxifen metabolism Gabapentin meta-analysis Gabapentin vs venlafaxine Stellate ganglion block Clinical hypnosis

17 Study HR (fixed) 95% CI Pandya 300 mg/d Pandya 900 mg/d Guttuso 900 mg/d Reddy 2400 mg/d Total Favors gabapentin Favors placebo Loprinzi CL et al J Clin Oncol 2009, 27(17); CP B-22

18 Reduction from baseline (%) Pregabalin Median Hot Flash Score P= (75 bid) P= (150 bid) Placebo Pregabalin 75 mg bid Pregabalin 150 mg bid 0 Baseline Week Loprinzi CL, et al JCO (4):651-7.

19 Study HR (fixed) 95% CI Pandya 300 mg/d Pandya 900 mg/d Guttuso 900 mg/d Reddy 2400 mg/d Pregabalin Total Favors gabapentin Favors placebo CP B-22

20 Hot Flash Topics Overview of Mayo/NCCTG Randomized Hot Flash Studies Newer antidepressant meta-analysis CYP 2D6/Tamoxifen metabolism Gabapentin meta-analysis Gabapentin vs venlafaxine Stellate ganglion block Clinical hypnosis

21 Which do patients prefer better, gabapentin or venlafaxine?

22 A randomized crossover trial of venlafaxine versus gabapentin for hot flashes in breast cancer survivors Louise Bordeleau Kathleen Pritchard David Warr Charles Loprinzi Olivera Jugovic Marguerite Ennis Rashida Haq Pamela Goodwin JCO 28; #9023; ASCO, 2010

23 Study schema: Crossover RCT Venlafaxine Venlafaxine Gabapentin Gabapentin 2 weeks 4 weeks 2 weeks 4 weeks Screening Randomization Venlafaxine: 37.5mg daily X 7d 75mg daily Gabapentin: 300mg daily X 3d 300 mg BID X 3d 300mg TID

24 Mean of daily hot flash scores Overall Efficacy G V GV G V G V GV GV GV V G Week

25 Patient Preference Number of preference forms completed: 58 - Did not prefer one drug over another: 2 - Expressed a preference: 56 Patients with a preference: 56 - Preferred venlafaxine: 38 (68%) - Preferred gabapentin: 18 (32%) P=0.01

26 Hot Flash Topics Overview of Mayo/NCCTG Randomized Hot Flash Studies Newer antidepressant meta-analysis CYP 2D6/Tamoxifen metabolism Gabapentin meta-analysis Gabapentin vs venlafaxine Stellate ganglion block Clinical hypnosis

27 Lipov EG et al Med Hypotheses 69:758-63, 2007 Lipov EG et al Med Hypotheses 72:657-61, 2009

28 Stellate ganglion blockade provides relief from menopausal hot flashes: a case report series. Lipov E, Lipov S, Stark JT J Womens Health 14:737-41, 2005

29 Effects of stellate-ganglion block on hot flushes and night awakenings in survivors of breast cancer: a pilot study. Lipov EG, Joshi JR, Sanders S, et al: Lancet Oncol 9:523-32, 2008

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31 Stellate-ganglion block: a new treatment for hot flushes? Loprinzi CL, Barton DL, Carns PE Lancet Oncol 9:506-7, 2008

32 MC08C8 Mayo Clinic Cancer Center Pilot Evaluation of a Stellate Ganglion Block for the Treatment of Hot Flashes

33 Mean Percent of Baseline Figure 1: Mean Percent of Baseline Score and Frequency Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Score Frequency

34 Percent of Baseline Figure 2: Percent of Baseline Score by Patient Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

35 DOES THE STELLATE GANGLION BLOCK REDUCE SEVERE HOT FLUSHES AND SLEEP DISTURBANCES IN BREAST CANCER PATIENTS? K. Haest, A. Kumar, K. Leunen, A. Smeets, F. Amant, P. Berteloot, H. Wildiers, R. Paridaens, E. Van Limbergen, W. Van den Bogaert, C. Weltens, H. Janssen, S Peeters, J. Menten, I. Vergote, B.Morlion, MR. Christiaens, P. Neven Leuven, Belgium SABCS, 2009

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38 Effects of Stellate Ganglion Block on Vasomotor Symptoms: Findings from a Randomized Clinical Trial in Postmenopausal Women Maki et al Abstract S-14 NAMS 2013

39 Randomized Sham controlled 40 patients total Balanced arms at baseline

40 Moderate-severe hot flashes Baseline to 4-6 months SGB-50% reduction Sham-0% reduction P < 0.001

41 Total number of objective hot flashes from baseline to 3 months Reduced more in the active versus sham arm RR 0.71 (CC ); p= 0.05

42 SGB-Conclusions This looks like it actually works More data would be nice

43 Hot Flash Topics Overview of Mayo/NCCTG Randomized Hot Flash Studies Newer antidepressant meta-analysis CYP 2D6/Tamoxifen metabolism Gabapentin meta-analysis Gabapentin vs venlafaxine Stellate ganglion block Clinical hypnosis

44 Hypnosis for Hot Flashes 60 BCS with hot flashes Randomized to hypnosis intervention (5 weekly sessions) no treatment Elkins G, Marcus J, Stearns V, et al: JCO 26:5022-6, 2008

45 Hot flash scores pre- and post-test by treatment condition. Elkins G et al. JCO 2008;26: by American Society of Clinical Oncology

46 Clinical hypnosis in the treatment of postmenopausal hot flashes: a randomized controlled trial Elkins GR, Fisher WI, Johnson AK, et al:. Menopause 20:291-8, 2013

47 Methods Randomized, single-blind 187 postmenopausal women > 7 hot flashes/d 5 weekly sessions of Clinical hypnosis Structured-attention control Elkins GR, Fisher WI, Johnson AK, et al:. Menopause 20:291-8, 2013

48 Results from baseline to week 12 Hot flash frequency reduction 74 % for hypnosis 17 % for controls (P < 0.001) Hot flash score reduction 80 % for hypnosis 15 % for controls (P < 0.001) Physiologically monitored hot flashes reduction 57 % for hypnosis 10 % for controls (P < 0.001) Elkins GR, Fisher WI, Johnson AK, et al:. Menopause 20:291-8, 2013

49 Schema Randomize placebo pill + focused attn training/ practice 75 mg venlafaxine + focused attn training/ practice placebo pill + selfhypnosis training/ practice 75 mg venlafaxine + selfhypnosis training/ practice 7 weeks study duration

50 Issues Hot Flashes Vaginal Dryness AI arthralgias Paclitaxel neuropathy

51 Vaginal Dryness The reported incidence of vaginal dryness was 36-71% in two studies that looked at menopausal symptoms in breast cancer survivors. Ganz PA, et al: J Natl Cancer Inst 92: , Knobf MT: Cancer Nurs 24:201-10; quiz 210-1, 2001.

52 Vaginal Dryness Non-estrogenic vaginal lubricants Vaginal estrogen

53 Loprinzi et al JCO 15: , 1997

54 Vaginal Dryness Non-estrogenic vaginal lubricants Vaginal estrogen

55 Vaginal estrogen appears to work better than does Replens. Nachtigall LE: Comparative study: Replens versus local estrogen inmenopausal women. Fert Steril 61: , Bygdeman M, Swahn ML: Replens versus dienoestrol cream in the symptomatic treatment of vaginal atrophy in postmenopausal women. Maturitas 23: , 1996.

56 Is there concern regarding vaginal estrogen use with AIs?

57 The Effects of Vaginal Estrogens (VE) on Serum Estradiol Levels Breast Cancer Survivors Receiving an Aromatase Inhibitor (AI) or a Selective Estrogen Receptor Modulator (SERM) S Wills, A Ravipati P Venuturumilli, C Kresge, E Folkerd, M Dowsett, D Hayes, D Decker SABCS; 2009

58 Controls on AI Only

59 Cases Using E2 Ring: AI or SERM

60 Cases Using E2 Tablet: AI or SERM

61 Issues Hot Flashes Vaginal Dryness AI arthralgias Paclitaxel neuropathy

62 What is the natural history of AI arthralgias?

63 Aromatase Inhibitor Arthralgias Large early trials Incidence ~5-20% Patients report : I feel like an old lady True incidence is probably ~50% ~10-20% discontinue therapy because of toxic effects Usually with symptom resolution Crew Hershman, JCO 2007

64 Prevalence of joint symptoms in women on AI s for early stage BC Cross-sectional survey of 200 consecutive pts receiving adjuvant AI therapy Self-administered 25-item survey Crew Hershman, JCO 2007

65 % of Patients With AI-Related Joint Symptoms Location of Joint Symptoms Pain Stiffness Crew Hershman, JCO 2007 Hands Knees Back

66 % of Patients With AI-Related Joint Symptoms Severity of Joint Symptoms Pain Stiffness Mild (1-4) Moderate (5-7) Severe (6-10) Crew Hershman, JCO 2007

67 Are there any promising appearing therapies for AI arthralgias?

68 Promising-Appearing Study Ideas Acupuncture Testosterone Omega 3 FA Duloxetine Vitamin D

69 Randomized Placebo-Controlled Trial of Acupuncture for AI-related Joint Symptoms Eligibility: Postmenopausal Adjuvant AI for > 6 mo Worst joint pain score 3 N=40 R A N D O M I Z E Acupuncture twice weekly x 6wks Sham Acupuncture twice weekly x 6wks Primary Outcome: Change in joint pain score (BPI-SF) Crew Hershman et al. JCO MAR 1, 2010:1154

70 Percent change in the group mean Brief Pain Inventory Short Form (BPI-SF) scores from baseline to 3 and 6 weeks for the true and sham acupuncture groups Crew K D et al. JCO 2010;28: by American Society of Clinical Oncology

71 Acupuncture Multi-institutional confirmatory trial underway

72 Promising-Appearing Study Ideas Acupuncture Testosterone Omega 3 FA Duloxetine Vitamin D

73 Testosterone undecanoate treatment reduces joint morbidities induced by anastrazole therapy in postmenopausal women with breast cancer: results of a double-blind, randomized phase II trial Birrell SN and Tilley WD. Australia

74 Trial Design 90 women on adjuvant anastrozole1mg per day plus 3 months of placebo or testosterone undecoanate (TU) 30=placebo 30= 40mg TU 30= 80mg TU

75 Percentage of patients with a PAIN VAS >50mm 100% 80% 60% 40% Baseline 1 month 3 months 20% 0% P=0.04 Placebo 40 mg TU 80 mg TU

76 Randomized Placebo-Controlled Trial of Testosterone for AI-related Joint Symptoms Eligibility: Postmenopausal Adjuvant AI Worst joint pain score 50/100 R A N D O M I Z E Subcutaneous Testosterone Placebo Primary Outcome: Change in joint pain score at 3 mos N=226

77 Promising-Appearing Study Ideas Acupuncture Testosterone Omega 3 FA Duloxetine Vitamin D

78 S0927:Randomized Placebo-Controlled Trial of Omega-3-Fatty Acid for the control of Aromatase Inhibitor-Induced Musculoskeletal Pain in Women with Early Stage Breast Cancer Eligibility: Age > 21 years Postmenopausal Stage I-III ER+ and/or PR+ breast cancer Taking an AI for > 3 mo Worst joint pain score 5 N=~246 R A N D O M I Z E Omega 3 Fatty Acid x 24 wks Placebo x 24 wks Stratification: history osteoarthritis and prior taxane use Follow-up: 0, 6, 12, 24 weeks Primary Endpoint: Change in worst joint pain/stiffness at 12 weeks

79 Promising-Appearing Study Ideas Acupuncture Testosterone Omega 3 FA Duloxetine Vitamin D

80 Pilot study of duloxetine for treatment of aromatase inhibitorassociated musculoskeletal symptoms. 30 mg for 7 days, then 60 mg daily 29 evaluable patients 72 % achieved > 30% decrease in average pain 61% mean percentage reduction in average pain severity between baseline and 8 weeks Henry NL et al Cancer Dec 15;117(24):

81 Duloxetine for AIA Multi-institutional confirmatory trial underway

82 Promising-Appearing Study Ideas Acupuncture Testosterone Omega 3 FA Duloxetine Vitamin D

83 The VITAL trial Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms and fatigue in women with breast cancer starting adjuvant letrozole. Qamar J. Khan Bruce F. Kimler Pavan S. Reddy Priyanka Sharma Jennifer R. Klemp Carol J. Fabian ASCO 2012 Abstract # 9000 The University of Kansas Medical Center Cancer Center of Kansas, Wichita KS

84 Schema Postmenopausal stage I-III breast cancer starting adjuvant Letrozole 25OHD levels 40 ng/ml or less Vit D3 30,000 IU/wk RDA of Ca + D 24 weeks Matching placebo/wk RDA of Ca + D Randomized, double-blind, placebo-controlled

85 Frequency of MS event, % Primary Endpoint (protocol defined): Incidence of a MS Event using Simple Descriptive Pain Intensity Scale* P= % 37% *Worsening pain (Simple Descriptive Pain Intensity Scale), worsening disability (HAQ II), or discontinuation of letrozole due to musculoskeletal pain

86 Vitamin D Confirmatory phase III trial needed

87 What is the current recommended treatment for AI arthralgias?

88 Current Recommendations Try analgesics, exercise If the patient is having substantial trouble, stop the AI and give a few weeks to resolve Consider re-starting another AI Consider tamoxifen Re-consider magnitude of benefit of adjuvant hormonal therapy

89 Issues Hot Flashes Vaginal Dryness AI arthralgias Paclitaxel neuropathy

90 Topics Natural history investigation results Important clinical study results

91 Introduction Paclitaxel infusion commonly is followed, in 2-4 days, by an acute pain syndrome, with symptoms usually resolving in 3-7 days This pain has been called paclitaxelinduced arthralgia or myalgia CP

92 CP

93 The Paclitaxel Acute Pain Syndrome: Sensitization of Nociceptors as the Putative Mechanism Loprinzi et al: J Cancer 13(6):399, 2007 CP

94 Paclitaxel-Associated Acute Pain Syndrome: Natural History Study N08C1 Patients scheduled to receive IV paclitaxel at one of 2 dose/schedules 175+ mg/m 2 Q 3 wks mg/m 2 weekly Patient questionnaires looking at the incidence and severity of paclitaxelassociated acute pain and sensory neuropathy.

95 P-APS Data

96 Worst Pain Score (mean) Worst P-APS Scores for Cycle 1 (Weekly) Time (Days) n=

97 Mean P-APS Pain Worst P-APS Scores Per Cycle (Q 3 Weeks) Day Day Day Day Cycle 1 Cycle 2 Cycle 3 Cycle 4

98 Mean P-APS Pain Daily Mean Pain Scores (Q 3 Week) * Day Day Day Cycle 1 Cycle 2 Cycle 3 *Cycle 4, day 2

99 Patients (%) 70 Analgesic Use (Q 3 Weeks) OTC meds Opioids Cycles

100 CIPN Data

101 Baseline values (%) EORTC CIPN-20 Data (Weekly) Autonomic Motor Sensory P< Cycles n= n= n=

102 Individual questions from the CIPN20 sensory subscale used for this analysis Did you have tingling fingers or hands? Did you have tingling toes or feet? Did you have numbness in your fingers or hands? Did you have numbness in your feet or toes? Did you have shooting or burning pain in your fingers or hands? Did you have shooting or burning pain in your toes or feet?

103 CIPN-20 Scores EORTC CIPN-20 Tingling, Numbness and Pain Scores Hands (Weekly) Tingling Pain Numbness Cycles n= n= n=

104 CIPN-20 Pain Scores CIPN-20 Burning/Shooting Pain Scores Segregated by Cycle-1 P-APS Scores Feet 100 (Weekly) P-APS score P-APS score Cycles

105 Topics Natural history investigation results Important clinical study results

106 Selected CIPN Clinical Trials Gabapentin Duloxetine CP

107 Efficacy of Gabapentin in the Management of Chemotherapy-Induced Peripheral Neuropathy: A Phase 3 Randomized, Double-Blind, Placebo- Controlled, Crossover Trial (N00C3) Rao R, Michalak J, Sloan J, Loprinzi C, Soori G, Nikcevich D, Warner D, Novotny P, Kutteh L, Wong G Cancer 110(9):2110, 2007 CP

108 Study Schema Chemotherapy-induced neuropathy R 6 wk Gabapentin 2700 mg/day Placebo 2 wk Washout 6 wk Placebo Gabapentin 2700 mg/day Cancer 110(9):2110, 2007 CP

109 Mean Pain Intensity 10 Mean pain intensity P=0.21 Placebo Gabapentin First period Cancer 110(9):2110, 2007 Washout Gabapentin Placebo Week P=0.37 Second period CP

110 Pregabalin to Prevent the Paclitaxel Associated Acute Pain Syndrome and CIPN Patients receiving paclitaxel chemotherapy S R Pregabalin Placebo

111 Selected CIPN Clinical Trials Gabapentin Duloxetine CP

112 CALGB A Phase III Double Blind Trial of Oral Duloxetine for Treatment of Pain Associated with Chemotherapy-Induced Peripheral Neuropathy (CIPN) Principal Investigator: Ellen Lavoie Smith, PhD, APRN, AOCN Co-Investigators: Herbert Pang, PhD; Constance Cirrincione, MS; Stewart Fleishman, MD; Electra D. Paskett, PhD; Tim Ahles, PhD; Camilo Fadul, MD; Chetaye Knox; Charles L. Shapiro, MD

113 Study Objectives Primary Objective: To assess whether duloxetine 60mg daily decreases CIPN-related neuropathic pain caused by paclitaxel or oxaliplatin

114 Pain Reduction

115 Most Common AEs Initial Rx %

116 Take-Home Points Newer antidepressants, gabapentin, and progestational agents decrease hot flashes Don t mix tamoxifen and paroxetine Patients prefer venlafaxine over gabapentin Vaginal dryness: Vaginal estrogen works, but doesn t make sense, to me, to use with AIs

117 Take-Home Points AI arthralgias: acupuncture, vitamin D, an omega 3 F. A., and a testosterone preparation look promising P-APS appears to be of neurologic origin Pregabalin is being studied for prevention of the P-APS Duloxetine of some help for CIPN

118 CP