MASTALGIA- latest data Professor Robert Mansel CBE MS FRCS Cardiff University - Wales miami 2002 PREVALENCE OF MASTALGIA WORKING POPULATION % 66 G.P. POPULATION 50 SCREENING CLINIC BREAST CLINIC (UK NHS) 69 40 US DATA – ADER et al REFRACTORY BREAST PAIN miami 2002 CLASSIFICATION OF BREAST PAIN 70% CYCLICAL ( On history or pain chart) 30% NON-CYCLICAL (By exclusion of above) i) Chest Wall + Tietze’s Syndrome ii) True non-cyclical iii) Intra thoracic disease CYCLICAL MASTALGIA DRUGS FOR MASTALGIA UNPROVEN PROGESTOGENS DIURETICS PROVEN IN DOUBLE BLIND TRIALS BROMOCRIPTINE DANAZOL EVENING PRIMROSE OIL TAMOXIFEN GOSERELIN BREAST PAIN - DANAZOL Meta-analysis of danazol trials TREATMENT WITH ZOLADEX miami 2002 Mansel et al Am J O&G 2004 EVENING PRIMROSE OIL - RECENT MULTICENTRE TRIAL Large multicentre (primary and secondary care) trial Showed no differences between EPO and placebo but huge placebo effect and placebo contained large doses of antioxidants Therefore position is unclear as to the precise efficacy UK government has withdrawn licence for cost/efficacy reasons – the drug remains on sale for patients at health food outlets 25 20 GLA+Multivitamins GLA+Placebo Placebo+Multivitamins Placebo+Placebo 15 10 5 12 11 10 9 8 7 6 5 4 3 2 1 0 Baseline Mean breast pain score Evening primrose oil and mastalgia Goyal and Mansel. Breast J 2005;11:41-47 Menstrual cycle ESCALATION OF TREATMENTS REASSURANCE and analgesics DIETARY APPROACHES - reduce Caffeine/Fats Evening Primrose Oil BROMOCRIPTINE - Little used (Side effects high) DANAZOL (low dose 100 or 50mgs) TAMOXIFEN 10mgs ZOLADEX (short term - 3 months thenTamoxifen) UNLICENSED DRUGS IN BREAST PAIN PROVEN IN DOUBLE BLIND TRIALS Tamoxifen Goserelin Topical non-steroidal gel POTENTIAL NEW DRUGS/TREATMENTS Aromatase inhibitors Faslodex Topical tamoxifen gel GLA/iodine mixtures LACK PREMENOPAUSAL DATA TAMOXIFEN THERAPY 2 randomised trials from Guys Hospital showed efficacy in both cyclic, (90% reduction) and non cyclic pain, (56% reduction) 10mgs daily as effective as 20mgs but lower side effects However 15% dropout on therapy(Fentiman Lancet 1986) Also marked reduction in breast symptoms seen in tamoxifen prevention trials NEW APPROACHES Trans Cutaneous tamoxifen Nutritional supplementation Iodine/fatty acids/selenium 4-OHT GEL TRIAL Change from Baseline in Average VAS Scores (mm) for Placebo, 2-mg and 4-mg Afimoxifene After 4 Cycles of Daily Therapy: ITT Population Dose of N Afimoxifene Adjusted Difference‡ 95% Confidence Interval Upper Lower Mean Pvalue Reduction† 2 mg/day 40 -25.76 -6.42 5.34 -18.18 0.28 4 mg/day 40 -32.06 -12.71 -0.96 -24.47 0.034 Placebo § 36 -19.34 †Data reported as adjusted means for the analysis of covariance (ANCOVA) model. Terms were included for treatment group, country, and baseline VAS score. ‡ Difference refers to values from the 2-mg/day or 4-mg/day groups minus values from the placebo group. Effect of Afimoxifene on Physician Assessment of Pain† Comparison Treatment Period Cycle 2-mg Afimoxifene vs Cycle 2 Physician Assessment, Pain 0.26 (0.11-0.62); P = 0.002* PBO Cycle 4 0.49 (0.21-1.13); P = 0.092 4-mg Afimoxifene vs Cycle 2 0.28 (0.12-0.67); P = 0.004* PBO Cycle 4 0.32 (0.14-0.76); P = 0.010* † Data are expressed as odds ratios (95% confidence intervals). PBO = placebo Effect of Afimoxifene After 4 Cycles of Therapy on Physician Assessment of Tenderness and Nodularity, and Patient Assessment of Pain Physician Assessment Tenderness Nodularity 2-mg 0.55 (0.23-1.30) 0.55 (0.21-1.43) Patient Global Assessment of Pain 0.58 (0.25-1.36) Afimoxifene P = 0.173 P = 0.221 P = 0.21 4-mg 0.33 (0.14-0.78) 0.30 (0.11-0.81) 0.36 (0.15-0.87) Afimoxifene P = 0.012* P = 0.017* P = 0.022* Comparison vs PBO vs PBO Data are expressed as odds ratios (95% confidence intervals). Tamoxifen gel trial results 4-OHT plasma levels (pg/ml) Top and bottom of each box represent 75th and 25th percentiles. Green line represents 50th percentile (median) and the end of each ‘whisker’ the 10th and 90th percentiles. 2000 1500 1000 500 o Oral Tam 0.5 mg/d 4-OHT gel o 1.0 mg/d 4-OHT gel 2.0 mg/d 4-OHT gel NEW STUDIES IN MASTALGIA Iogen study published 2004 Centchroman published 2007 GLA/Iodine mixture US multicenter study completed 2005 Efficacy Trials based on Iodine Eight different efficacy trials have been conducted on a total of more than 3,000 patients. The baseline level of pain and tenderness used for inclusion in these trials has varied dramatically. The response rate with I2 is a function of the baseline symptoms. Molecular Iodine Iogen trial Kessler – The Breast 2004 Molecular iodine (iodide + iodate) 1.5,3 and 6 mgs VLA pain scales & physician exam 111 women with cyclic mastalgia 30-50% reduction in pain scale by 5 months Higher dropout rate in active therapy group Efficacy in Iodine-based Clinical Trials Study Number Vishnyakova (n=176) MX02-CLN-01 (n=233) MX02-CLN-02 (n=588) Design Outcomes Single-center uncontrolled Single-center uncontrolled Single-center uncontrolled Reduction/elimination of pain in about 75% of patients 70% clinical improvement MX02-CLN-04 (n=92) Single-center uncontrolled Multi-center, controlled MX02-CLN-07 (n=389) Multi-center, controlled MX02-CLN-09 (n=136) Multi-center, controlled SYM-CL-02 (n=111) Multi-center, controlled MX02-CLN-03 (n=1388) Conducted with I2 (aqueous 93% improvement objective (fibrosis) and subjective (pain) evaluations 51% resolution of fibrosis; 67% resolution pain 31% improvement Statistically significant reduction in fibrosis (p<0.001) and pain (p=0.035) Significant pain reduction in 9 mg dose group No significant reductions Statistically significant reductions in pain amylose-I2 IoGen ) CENTCHROMAN IN MASTALGIA New antioestrogen (Ormeloxifine) synthesised in India non progestational/androgenic Pilot study (World J Surg 2007 June) 42 patients took 30mgs on alternate days for 3/12 VAS assessed pain showed reduction from 9 cms to 0 cms at 3 months (but non randomised) RCT in progress. FBD nutritional trial GLA/iodine/selenium mixture Daily use of Nutritional mixture with added iodine and essential fatty acids (GLA) and selenium FBD medical food - versus placebo drink- 4oz/day Demonstrated excellent tolerability/compliance Lower analgesic use (recorded daily) Lower nodularity as assessed by physician MASTALGIA – THE FUTURE Current treatments not satisfactory High level of patient demand for therapy New therapeutic approaches needed Huge potential for effective therapy