Sexuality and Body Image After Uterine Artery Embolization and Hysterectomy in the Treatment of Uterine Fibroids : A Randomized Comparison In this paper the effect of uterine artery embolization -LRB- UAE -RRB- on sexual functioning and body image is investigated in a randomized comparison to hysterectomy for symptomatic uterine fibroids . The EMbolization versus hysterectoMY -LRB- EMMY -RRB- trial is a randomized controlled study , conducted at 28 Dutch hospitals . Patients were allocated hysterectomy -LRB- n = 89 -RRB- or UAE -LRB- n = 88 -RRB- . Two validated questionnaires -LRB- the Sexual Activity Questionnaire -LSB- SAQ -RSB- and the Body Image Scale -LSB- BIS -RSB- -RRB- were completed by all patients at baseline , 6 weeks , and 6 , 12 , 18 , and 24 months after treatment . Repeated measurements on SAQ scores revealed no differences between the groups . There was a trend toward improved sexual function in both groups at 2 years , although this failed to reach statistical significance except for the dimensions discomfort and habit in the UAE arm . Overall quality of sexual life deteriorated in a minority of cases at all time points , with no significant differences between the groups -LRB- at 24 months : UAE , 29.3 % , versus hysterectomy , 23.5 % ; p = 0.32 -RRB- . At 24 months the BIS score had improved in both groups compared to baseline , but the change was only significant in the UAE group -LRB- p = 0.009 -RRB- . In conclusion , at 24 months no differences in sexuality and body image were observed between the UAE and the hysterectomy group . On average , both after UAE and hysterectomy sexual functioning and body image scores improved , but significantly so only after UAE . Introduction When hysterectomy looms as a definite treatment for fibroid related menorrhagia , women and their sexual partners often express their concern about negative effects of the operation on their sexual wellbeing -LSB- 1 -- 4 -RSB- . Furthermore , the uterus is considered important for a woman 's self-image and sexual image and some women fear that they will be `` less of a woman '' to their sexual partners -LSB- 2 , 4 , 5 -RSB- . Therefore a hysterectomy may also interfere with the woman 's body image . These concerns may cause some women to choose alternative treatment options -LSB- 5 -RSB- . During the last decade , uterine artery embolization -LRB- UAE -RRB- has emerged as an alternative treatment for hysterectomy -LSB- 6 -RSB- . UAE has been investigated in several case series and three randomized controlled trials -LSB- 7 -- 13 -RSB- , but the advantage of UAE in terms of sexual wellbeing and body image in comparison to hysterectomy remains unknown , since randomized controlled trials on this subject are not available as yet . Randomized controlled data are preferential to nonrandomized data , since nonrandomized data tend to overestimate treatment effect and are prone to selection bias -LSB- 14 -RSB- . We initiated a randomized trial comparing UAE and hysterectomy and have published several short-term results previosly -LSB- 15 -- 17 -RSB- . In the present paper , we compare changes in sexuality and body image in patients with symptomatic uterine fibroids who were randomly assigned to either UAE or hysterectomy . Materials and Methods Study Design The details of our study design have been described elsewhere and are discussed here briefly -LSB- 15 -RSB- . The EMMY trial -LRB- EMbolization versus hysterectoMY -RRB- is a prospective randomized multicenter clinical trial with 28 participating hospitals in the Netherlands . Eligible patients met the following inclusion criteria : they were clinically diagnosed with uterine fibroids -LRB- confirmed by ultrasonography -RRB- , had menorrhagia as the major complaint , were premenopausal , and had no wish to conceive . All patients were candidates for undergoing a hysterectomy : other treatment options either had failed , were undesired , or had provided unsatisfactory results . Eligible patients were informed verbally and in writing about possible risks and benefits of both procedures , and were invited to participate in the trial . After written informed consent had been obtained , patients were randomly assigned -LRB- 1:1 -RRB- to UAE or hysterectomy by computerized randomization , stratified for hospital . The study was approved by the Dutch Central Committee Involving Human Subjects -LRB- www.ccmo.nl -RRB- and the local ethics committees of all participating hospitals . Pre-assessment All patients were assessed by the attending gynaecologist . Current symptoms and a complete medical and gynaecological history were recorded . All patients underwent a pelvic ultrasound to determine the number of fibroids and the size of the largest fibroid . Sociodemographic characteristics were assessed by means of a questionnaire . Procedures Uterine artery embolization UAE was performed by an interventional radiologist . A catheter was introduced into the femoral artery and advanced over the aortic bifurcation to the contralateral internal iliac artery , and digital subtraction angiography was performed to identify the origin of the uterine artery . When catheters were placed correctly , the UAE was carried out . Polyvinyl alcohol -LRB- PVA -RRB- particles of 355 -- 500 μm were used in all procedures . UAE patients were advised to refrain from sexual intercourse for at least 2 weeks and thereafter , depending on their complaints . Hysterectomy The type of hysterectomy and the route of access were determined by the gynecologist . The following procedures were allowed : abdominal hysterectomy , vaginal hysterectomy , laparoscopically assisted vaginal hysterectomy , and laparoscopic hysterectomy . Both supravaginal and total hysterectomies were allowed . After discharge hysterectomy patients were advised not to have sex until the first outpatient visit at 6 weeks . Questionnaires Sexual functioning and body image were assessed by means of patient questionnaires . At baseline , questionnaires were completed by all patients before randomization . Follow-up questionnaires were completed at 6 weeks and 6 , 12 , 18 , and 24 months after treatment . The questionnaire consisted of the Sexual Activity Questionnaire -LRB- SAQ -RRB- , the Body Image Scale -LRB- BIS -RRB- , and the Mental Component Summary -LRB- MCS ; as part of the Medical Outcome Study Short Form -LSB- MOS SF-36 -RSB- -RRB- . The SAQ , originally designed to investigate sexual functioning in women treated with tamoxifen because of a positive family history of breast cancer -LSB- 18 -RSB- , is also useful in women with nonmalignant gynecological disorders -LSB- 19 -RSB- . In Table 1 the SAQ is displayed . The questionnaire consists of three dimensions , and each dimension yields its own score : pleasure from sexual intercourse -LRB- desire , enjoyment , and satisfaction ; score range , 0 -- 18 -RRB- , discomfort during intercourse -LRB- score range , 0 -- 6 -RRB- , and habit -LRB- frequency ; score range , 0 -- 3 -RRB- . Pleasure and habit are good with higher scores , while discomfort is worse with higher scores . The SAQ was only filled out by patients who were sexually active during the month before receiving the questionnaire . Table 1The Sexual Activity Questionnaire -LRB- SAQ -RRB- and the Body Image Scale -LRB- BIS -RRB- SAQ Dimension pleasure 1 . Was having sex an important part of your life in the last month ? 2 . Did you enjoy sexual activity in the last month ? 3 . Did you desire to have sex with your partner in the last month ? 4 . In general were you satisfied after sexual activity in the last month ? 5 . How often did you engage in sexual activity in the last month ? 6 . Were you satisfied with the frequency of sex in the last month ? Dimension discomfort 1 . Did you notice dryness of your vagina in the last month ? 2 . Did you feel pain or discomfort in the last month ? Dimension habit 1 . How did the frequency of sexual behavior in the last month compare with what is usual for you?BIS In the last month 1 . Have you been feeling self-conscious about your appearance ? 2 . Have you felt less physically attractive as a result of your menstrual bleeding problem ? 3 . Have you been dissatisfied with your appearance when dressed ? 4 . Have you been feeling less feminine as a result of your menstrual bleeding problem ? 5 . Did you find it difficult to look at yourself naked ? 6 . Have you been feeling less sexually attractive as a result of your menstrual bleeding problem ? 7 . Did you avoid people because of the way you felt about your appearance ? 8 . Have you been feeling the treatment has left your body less whole ? 9 . Have you felt dissatisfied with your body ? 10 . Have you been dissatisfied with the appearance of your scar ? Questions on the BIS shown in italics have been omitted Furthermore , participating patients were asked to judge their current sexual life in two questions : `` How would you describe the quality of your current sexual life ? '' and `` How well can you live with your current sexual life ? '' One of the following responses could be ticked : `` very good , '' `` good , '' `` moderately good , '' `` neither good nor bad , '' `` moderately bad , '' `` bad , '' and `` very bad . '' The BIS was designed in order to asses changes in body image among cancer patients -LSB- 20 -RSB- . The questionnaire was also found reliable and valid in women with benign gynecological conditions -LSB- 21 -RSB- . Table 1 displays the questions of which the BIS consists . Unfortunately , questions 2 , 4 , and 6 were not represented correctly in the questionnaire due to a translation error . Therefore we decided to omit these questions in order to attain a comparable outcome between groups . The BIS score ranges from 0 to 30 . A higher BIS score indicates a worse body image . In order to assess mental health before treatment as a predictor of worse sexual function after treatment , the MCS score of the 36-item MOS SF-36 was used -LSB- 22 -RSB- . This was done because bad preoperative mental health is associated with bad sexual life outcome -LSB- 23 -RSB- . Sample Size and Endpoints of the Present Study The sample size was based on the primary endpoint of the clinical study , published elsewhere -LSB- 24 -RSB- : the elimination of menorrhagia in such way that hysterectomy could be avoided in the UAE group in at least 75 % of patients within 2 years after the primary interventions . The objective of the present study was to compare the following endpoints between both interventions : the number of sexually active patients , the scores yielded by the SAQ and the BIS , the subjective quality of sexual life . For this analysis , no separate power calculation was made . Statistical Analysis Data entry was performed using SPSS data entry for Windows 3.0 . A random sample of 10 % of the questionnaires was visually double checked by an independent second investigator , revealing a false entry level of 0.3 % . All false data entries were corrected . All analyses were performed using SPSS -LRB- release 11.5.1 -RRB- statistical software . Missing items in the questionnaire were treated as follows . For the SAQ no advice is available on scoring missing items . If one item was missing , we regarded the dimension score -LRB- which the item was part of -RRB- as being missing completely , according to earlier research -LSB- 25 -RSB- . For the BIS no missing values were allowed since three questions were omitted already . In these cases , the entire score was omitted . For the three omitted questions , the individual mean score of the remaining seven questions was imputed . First , we determined how many patients in both treatment groups were sexually active before and after treatment . An overall percentage per treatment group was calculated , after which sexual activity in subgroups was assessed : those being sexually active and those not being sexually active before treatment . Second , the mean of the dimension scores were plotted for the hysterectomy and UAE group . Third , the mean differences between all follow-up SAQ dimension scores and baseline were compared between treatment groups . This was only possible for patients who were sexually active both before and after treatment . Within group changes were analyzed as well . Similar analyses were performed for the BIS . Differences in pleasure , discomfort , habit -LRB- SAQ -RRB- , and body image -LRB- BIS -RRB- between groups over time were tested with repeated measurement analysis , excluding the 6-week measurement for the SAQ , since a high proportion of patients was expected not to be sexually active at that time and therefore not to yield a score . Differences in continuous variables were tested with Student 's t test . Differences in data with skewed distributions were tested with the nonparametric Mann-Whitney U test . The two added questions on the quality of current sexual life were compared between the groups using the chi-square test -LRB- or Fishers ' exact test when appropriate -RRB- . Furthermore , the quality of sex life and the additional questions at the various follow-up moments were compared to baseline , yielding two different options : `` worse , '' `` the same , '' or `` better '' compared to baseline . Differences between the groups were compared with the chi-square test -LRB- or Fishers ' exact test when appropriate -RRB- . Logistic regression analysis was performed to investigate variables associated with a worse sexual life quality at 24 months after treatment compared to baseline versus unchanged or improved quality of sexual life . First , univariate analysis was performed with the following baseline characteristics : intended treatment , age , BMI , parity , ethnicity , having a partner , employment status , smoking status , number of fibroids , uterine volume measured by ultrasound , dominant fibroid volume measured by ultrasound , existence of any comorbid disease , and mental health status -LRB- MCS-MOS-SF36 -RRB- at baseline . Second , covariates with p values < 0.1 in the univariate analysis were selected for multivariate analysis . All analyses were two-tailed and carried out based on the intention-to-treat principle . A p value < 0.05 -LRB- two-tailed -RRB- was considered statistically significant . Results Patients were enrolled between March 2002 and February 2004 . Of 349 eligible patients , 177 were randomized : 89 were allocated hysterectomy and 88 were allocated UAE . In the hysterectomy group 14 patients refused the allocated treatment , compared to 7 patients in the UAE group , and these patients withdrew from participation . In 4 UAE patients embolization failed bilaterally . These patients subsequently had a hysterectomy but were analyzed in the UAE group according to the intention-to-treat principle -LRB- Fig. 1 -RRB- -LSB- 15 -RSB- . The baseline characteristics of all randomized patients are reported in Table 2 . No differences between the groups are apparent , as expected considering the randomized design . Fig. 1FlowchartTable 2Baseline characteristicsUAE -LRB- N = 88 -RRB- Hysterectomy -LRB- N = 89 -RRB- Age -LRB- yr -RRB- , mean -LRB- SD -RRB- 44.6 -LRB- 4.8 -RRB- 45.4 -LRB- 4.2 -RRB- Body mass index -LRB- weight -LSB- kg -RSB- / length -LSB- m -RSB- 2 -RRB- , mean -LRB- SD -RRB- 26.7 -LRB- 5.6 -RRB- 25.4 -LRB- 4.0 -RRB- Parity -LRB- n -RRB- 030 -LRB- 34.1 % -RRB- 20 -LRB- 22.5 % -RRB- ≥ 158 -LRB- 65.9 % -RRB- 69 -LRB- 77.5 % -RRB- Ethnicity -LRB- n -RRB- Black24 -LRB- 27.3 % -RRB- 20 -LRB- 22.5 % -RRB- White54 -LRB- 61.4 % -RRB- 57 -LRB- 64.0 % -RRB- Other10 -LRB- 11.4 % -RRB- 12 -LRB- 13.5 % -RRB- Marital statusa -LRB- n -RRB- Single16 -LRB- 18.2 % -RRB- 13 -LRB- 14.8 % -RRB- Married55 -LRB- 62.5 % -RRB- 54 -LRB- 61.4 % -RRB- Living apart together5 -LRB- 5.7 % -RRB- 4 -LRB- 4.5 % -RRB- Divorced12 -LRB- 13.6 % -RRB- 15 -LRB- 17.0 % -RRB- Widow0 -LRB- 0 % -RRB- 2 -LRB- 2.3 % -RRB- Partner relationshipa -LRB- n -RRB- No partner13 -LRB- 15.3 % -RRB- 19 -LRB- 22.4 % -RRB- Partner72 -LRB- 84.7 % -RRB- 66 -LRB- 77.6 % -RRB- Employment statusa -LRB- n -RRB- Employed68 -LRB- 77.3 % -RRB- 69 -LRB- 78.4 % -RRB- Unemployed20 -LRB- 22.7 % -RRB- 19 -LRB- 21.6 % -RRB- Smoking status -LRB- n -RRB- Current smoker21 -LRB- 23.9 % -RRB- 23 -LRB- 25.8 % -RRB- Former smoker11 -LRB- 12.5 % -RRB- 14 -LRB- 15.7 % -RRB- Nonsmoker56 -LRB- 63.6 % -RRB- 52 -LRB- 58.4 % -RRB- Comorbid diseaseb Any comorbid disease24 -LRB- 27.3 % -RRB- 22 -LRB- 24.7 % -RRB- Number of fibroids , median -LRB- range -RRB- 2 -LRB- 1 -- 20 -RRB- 2 -LRB- 1 -- 9 -RRB- Uterine volume -LRB- cm3 -RRB- , median -LRB- range -RRB- 321 -LRB- 31 -- 3005 -RRB- 313 -LRB- 58 -- 3617 -RRB- Fibroid volume -LRB- dominant fibroid ; cm3 -RRB- , median -LRB- range -RRB- 59 -LRB- 1 -- 673 -RRB- 87 -LRB- 4 -- 1641 -RRB- Mental Component Summary -LRB- SF-36 -RRB- , mean -LRB- SD -RRB- 40.9 -LRB- 10.7 -RRB- 41.5 -LRB- 11.0 -RRB- aSome values are missingbAny of the following : hypertension , diabetes , astma , clotting disease , system disease , or other The proportion of questionnaires available for analysis ranged from 96.0 % -LRB- baseline -RRB- to 98.7 % -LRB- 6 weeks , 24 months -RRB- . Before treatment 54 of 81 -LRB- 67 % -RRB- and 46 of 75 -LRB- 61 % -RRB- of the participating patients were sexually active in the UAE and hysterectomy groups , respectively -LRB- Fig. 2A -RRB- . Six weeks after treatment , sexual activity had decreased in both groups , with significantly more patients showing sexual activity in the UAE group compared to hysterectomy -LRB- 53 % versus 29 % ; p = 0.004 -RRB- . Hereafter sexual activity was restored in both groups , with no significant differences between the groups at 24 months -LRB- p = 0.07 -RRB- . Fig. 2Proportion of sexually active women , by treatment strategy , over time . -LRB- A -RRB- The weighted average of women who were not sexually active at baseline -LRB- B -RRB- and those who were sexually active at baseline -LRB- C -RRB- Patients who were not sexually active before treatment gradually resumed sexual activity after both UAE and hysterectomy -LRB- Fig. 2B -RRB- . After 24 months 31 % -LRB- hysterectomy -RRB- and 52 % -LRB- UAE -RRB- were sexually active -LRB- p = 0.118 -RRB- . No significant differences were observed between the groups . Among those patients who were sexually active before treatment , there was a major drop in activity at 6 weeks after treatment , which was partially restored . After 2 years , 86 % -LRB- UAE -RRB- and 90 % -LRB- hysterectomy -RRB- of these patients had resumed their sexual activities -LRB- Fig. 2C -RRB- . Only at 6 weeks had significantly more UAE patients resumed sexual activity -LRB- p = 0.01 -RRB- . Figure 3 shows the course of the SAQ dimensions pleasure , discomfort , and habit and the BIS scores over time . There were no differences between the groups at baseline -LRB- pleasure , p = 0.76 ; discomfort , p = 0.44 ; habit , p = 0.77 ; body image , : p = 0.60 -RRB- . Repeated measurements revealed no differences between the groups for the SAQ dimensions pleasure -LRB- p = 0.343 -RRB- , discomfort -LRB- p = 0.246 -RRB- , and habit -LRB- p = 0.453 -RRB- or for body image scores -LRB- p = 0.359 -RRB- . Table 3 shows the changes in dimension scores per treatment group for patients who were sexually active at baseline . Positive numbers for pleasure and habit and negative numbers for discomfort and body image are indicative for improvement compared to baseline . No significant differences were found between the two treatment groups at all time points , except for body image at 6 months after treatment : body image had improved significantly more in UAE patients than in hysterectomy patients -LRB- UAE , -- 1.34 , versus hysterectomy , no change ; difference , -- 1.34 ; 95 % CI , -- 2.50 to -- 0.18 ; p = 0.02 -RRB- . Within the groups , however , a significant improvement of various dimension scores was noted -LRB- indicated in boldface -RRB- : at 24 months UAE patients reported significantly less discomfort , a higher frequency of intercourse , and a better body image compared to baseline -LRB- p = 0.022 , p = 0.022 , and p = 0.009 respectively -RRB- . At 24 months hysterectomy patients improved on all dimensions compared to baseline , but differences were not statistically significant . Fig. 3Pleasure , discomfort , habit , and body image , by treatment strategy , over timeTable 3Mean differences in pleasure , discomfort , habit , and body image compared to baseline , by treatment strategy , over timeUAEHysterectomyp valueSAQ : pleasure -LRB- 0 -- 18 -RRB- a 6 wk0 .29 − 0.500.47 6 mo1 .631.230.61 12 mo0 .951.490.50 18 mo1 .860.680.13 24 mo0 .891.180.74 SAQ : discomfort -LRB- 0 -- 6 -RRB- b 6 wk − 0.25 − 0.210.96 6 mo − 0.58 − 0.320.41 12 mo − 0.47 − 0.470.98 18 mo − 0.51 − 0.290.51 24 mo − 0.43 − 0.490.88 SAQ : habit -LRB- 0 -- 3 -RRB- a 6 wk − 0.030.000.92 6 mo0 .480.280.30 12 mo0 .180.420.24 18 mo0 .270.190.70 24 mo0 .280.220.74 BIS -LRB- 0 -- 30 -RRB- b 6 wk − 1.27 − 0.280.10 6 mo − 1.340.000.02 12 mo − 0.240.080.64 18 mo − 1.24 -- 0.280.15 24 mo − 1.06 -- 0.500.36 Note . SAQ , Sexual Activity Questionnaire ; BIS , Body Image Scale . Boldface numbers indicate a significant difference from baseline within group -LRB- p < 0.05 -RRB- aA higher score represents more favorable sexual functioning -LRB- pleasure , habit -RRB- bA lower score represents more favorable sexual functioning -LRB- discomfort -RRB- or body image Table 4 reports the patients ' experienced quality of their sexual life at 6 weeks and 12 and 24 months . No differences between groups were observed . Table 5 presents the proportion of patients who judged the quality of sexual life as better , comparable to , or worse compared to baseline based on the question : `` How is the quality of your current sexual life ? '' A minority of patients reported worsened sexual life quality compared to baseline at all time points . At 24 months the proportion of patients reporting a worse sexual life compared to baseline was slightly higher in the UAE than in the hysterectomy group , but the difference was not statistically significant -LRB- 29.3 % versus 23.5 % ; p = 0.43 -RRB- . Table 4Satisfaction with sexual life and ability to cope with sexual life , by treatment strategy , over timeBaseline6 weeks12 months24 monthsUAE -LRB- N = 81 -RRB- Hyst . -LRB- N = 75 -RRB- p valueUAE -LRB- N = 81 -RRB- Hyst . -LRB- N = 75 -RRB- p valueUAE -LRB- N = 81 -RRB- Hyst . -LRB- N = 75 -RRB- p valueUAE -LRB- N = 81 -RRB- Hyst . -LRB- N = 75 -RRB- p valueHow is the quality of your current sex life ? Very good1580 .84710.487110.358110.54 Good2227252231182921 Somewhat good15131213911812 Neither good nor bad1212231915211615 Somewhat bad66445388 Bad43583444 Very bad33214251How well can you live with your current sex life ? Very good930 .771160.3318170.9320170.78 Good2021373035303431 Somewhat good1012151611131011 Neither good nor bad201710564106 Somewhat bad89251325 Bad44252222 Very bad65011100Table 5Changes in sexual wellbeing compared to baseline , by treatment strategy , over timeUAE -LRB- n = 81 -RRB- Hysterectomy -LRB- n = 75 -RRB- p value6 months Worse16130 .68 The same2527 Improved322512 months Worse17140 .81 The same2926 Improved252724 months Worse22160 .32 The same2720 Improved2632 Univariate logistic regression analysis revealed BMI , number of fibroids , and presence of comorbid disease to be associated with a worsened quality of sexual life at 24 months compared to baseline -LRB- p < 0.1 -RRB- . Allocated treatment and mental health at baseline were not associated with worse outcome . BMI was not significant in the multivariate analysis -LRB- p = 0.163 -RRB- . The other two parameters remained significantly associated with worse outcome : a higher number of fibroids -LRB- OR , 0.69 ; 95 % CI , 0.51 -- 0.94 ; p = 0.018 -RRB- predicted a decreased risk of a worsening sexual life at 24 months compared to baseline , while the presence of comorbid disease -LRB- OR , 3.20 ; 95 % CI , 1.38 -- 7.41 ; p = 0.007 -RRB- was associated with an increased risk of a worse sexual life quality at 24 months after treatment compared to baseline . Discussion In our trial no differences , on average , in sexual function at 24 months were observed between UAE and hysterectomy . After both treatments the dimensions `` pleasure '' and `` habit '' improved , while the dimension `` discomfort '' decreased at 24 months compared to baseline , although only the UAE group showed significant improvement in discomfort and frequency of intercourse . Sexuality and body image after UAE have never been evaluated in a randomized controlled trial before . However , some nonrandomized series have addressed this subject . The improvement of sexual functioning after UAE was in accordance with the limited number of earlier studies on this subject -LSB- 26 -- 28 -RSB- , which reported a significant improvement in sexual functioning as well . Sexual functioning after hysterectomy has received much attention in the literature . Improvement in sexual functioning after hysterectomy might indirectly be associated with the consequences of surgery , such as less worry about unwanted pregnancy , absence of vaginal bleeding , and more time for sexual activities by the cessation of monthly periods -LSB- 29 -RSB- . Most reports on sexual functioning after hysterectomy found significant benefits in various aspects of sexual functioning -LSB- 25 , 30 -- 35 -RSB- . In contrast , the improvement in sexual functioning within our hysterectomy group at 24 months of follow-up was not statistically significant in our trial . This might be explained by insufficient power , which is partly due to the relatively small sample size for the SAQ scores in our population : change scores were only available from women who were sexually active at baseline and at follow-up . Furthermore , the studies on sexuality after hysterectomy used varying follow-up intervals , ranging from 6 months to 2 years . In our series , hysterectomy patients experienced significantly improved pleasure and habit scores at 12 months of follow-up . These results might indicate that improvement in sexual functioning after hysterectomy could be temporary . On the other hand , a review article recently suggested that there is no scientific proof for either improvement or deterioration of sexual functioning after hysterectomy , unless hysterectomy was performed based on a sound clinical indication -LSB- 29 -RSB- . In our patient group , however , there was no doubt about the indication : complaints were serious and lengthy enough to warrant a hysterectomy . Although , on average , SAQ scores for the group as a whole improved , there was a small group of women who reported a deterioration in self-reported quality of sexual life , consistent with other reports -LSB- 30 -- 32 , 34 , 36 -RSB- . For obvious reasons , the prospects of deterioration of sexual life might be of greater concern to patients than the improvement after treatment . Regression analysis of worsened sexual life revealed that women with a low number of fibroids -LRB- possibly representing a group of women with less severe complaints -RRB- and women with other concomitant chronic diseases might not benefit from fibroid treatment in terms of sexual life improvement . The improved body image after UAE in our series is in accordance with another study that reported higher self-consciousness after UAE -LSB- 26 -RSB- . After hysterectomy a period of temporary worsened body image following the operation has been described previously -LSB- 25 , 36 , 37 -RSB- . This was not confirmed by our results , but in accordance with these studies , a normal or even improved body image was found 1 year after hysterectomy . There are several limitations of our study that need to be addressed . First , the values of the SAQ dimensions were based on all sexual active women at the various points in time . Reported values may reflect an ever-changing group of sexually active women . At any stage , some women may cease while others may initiate sexual activity . Of all non-sexually active women before treatment , 50 % became active after treatment . When comparing pre - and posttreatment scores , these women can not be included , since their baseline scores were missing . Second , the significant difference between resumption of sexual activity between the groups at 6 weeks is probably explained by differences in counseling between both treatments as mentioned earlier : hysterectomy patients in our trial were told not to have sex until the first outpatient visit at 6 weeks , while UAE patients were advised to refrain from intercourse for at least 2 weeks and thereafter , depending on their complaints . Third , we allowed all kinds of hysterectomies , thereby possibly biasing the results in the hysterectomy group . However , various reports found no long-term differences in sexual functioning after various surgical routes of hysterectomy -LSB- 25 , 32 , 35 -RSB- . Finally , as described above , three questions on the BIS were omitted because of wrongly posed questions , thereby creating asymmetry in the treatment arms . Since the remaining questions in both groups were identical , the comparison between the groups is still valid but reduces the comparability with other series . In conclusion , at 24 months no differences in sexuality and body image were observed between the UAE and the hysterectomy groups . After both UAE and hysterectomy , on average , sexual functioning and body image scores improved , but significantly so only after UAE .

B O B I O B I I O B O O O O O O O O O O O O O O O O B I I O O O O O O O B I O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O B O O O O O O O O O B O O O B I O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O B O O B O O O O B O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B I O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O B O O O O O O B O O O O O O O B I O O O O O O O O O O

uterine artery embolization
hysterectomy
fibroid
sexuality
body image


Letrozole in advanced breast cancer : the PO25 trial Tamoxifen has been a standard first-line endocrine therapy for post-menopausal women with hormone-responsive advanced breast cancer , but more than half of patients fail to respond and time to progression is less than 12 months in responders . The third-generation aromatase inhibitors were developed to provide more effective alternatives to tamoxifen . In the Femara Study PO25 , post-menopausal women with advanced breast cancer were randomized to receive letrozole 2.5 mg -LRB- n = 453 -RRB- or tamoxifen 20 mg -LRB- n = 454 -RRB- given orally daily until progressive disease occurred . Patients were permitted to cross over to the other treatment at progression . In the primary efficacy analysis , median time to progression -LRB- TTP -RRB- was significantly longer with letrozole than with tamoxifen -LRB- 9.4 months vs. 6.0 months , respectively ; P < 0.0001 -RRB- . The objective response rate -LRB- ORR -RRB- was significantly higher for letrozole than for tamoxifen -LRB- 32 % vs. 21 % ; P = 0.0002 -RRB- . Prospectively planned analyses of the intent-to-treat population showed that letrozole significantly improved overall survival -LRB- OS -RRB- compared with tamoxifen over the first 24 months of the trial . An exploratory analysis of patients , who did not cross over , indicated a median OS benefit of 14 months for letrozole compared with tamoxifen . Letrozole is the only third-generation aromatase inhibitor that has demonstrated significant improvements in ORR , TTP , and early OS . Introduction and rationale The treatment goals for advanced or metastatic breast cancer -LRB- MBC -RRB- are to delay disease progression and to prolong survival -LSB- 1 , 2 -RSB- and to optimize patient care in terms of ameliorating symptoms , thereby improving or maintaining quality of life -LSB- 3 -- 5 -RSB- . Although treatment may include surgery and radiation therapy for the treatment of locally advanced tumors or isolated metastases , systemic therapies -LRB- endocrine , cytotoxic , biologic , and palliative -RRB- are the foundation of disease management -LSB- 6 , 7 -RSB- . Systemic therapy for patients with advanced breast cancer should be tailored according to specific tumor biology , particularly with respect to hormone receptor -LRB- HR -RRB- and human epidermal growth factor receptor 2 -LRB- HER2 -RRB- status , the growth rate of disease , presence of visceral metastases , history of prior therapy and response , susceptibility to treatment-related toxicity , and individual patient preference -LSB- 7 -- 14 -RSB- . Systemic therapy can prolong survival and enhance patient quality of life but is not curative -LSB- 1 -RSB- . Consequently , minimally toxic endocrine therapies are generally preferred to cytotoxic therapy as initial therapy for patients with hormone-responsive tumors -LSB- 6 , 15 -RSB- . Since the 1980s , endocrine therapy with tamoxifen was well established as a standard first-line treatment for post-menopausal women with advanced breast cancer , even though estrogen receptor -LRB- ER -RRB- expression was not always used routinely to select patients for endocrine therapy -LSB- 16 -- 18 -RSB- . The first-generation aromatase inhibitor aminoglutethimide or a progestin such as megestrol acetate has provided a reasonable second-line alternative -LSB- 19 -- 22 -RSB- . The objective response rate -LRB- ORR -RRB- to tamoxifen was shown to be in the range of 25 % -- 45 % -LSB- 16 , 17 , 19 , 21 , 23 -- 32 -RSB- , indicating that more than half of the patients with advanced breast cancer are intrinsically resistant to tamoxifen . Furthermore , the short median time to treatment failure -LRB- TTF -RRB- , in the range 6 -- 8 months , demonstrates a relatively rapid emergence of resistance in patients initially sensitive to tamoxifen -LSB- 19 , 27 -RSB- . Loss of ER expression appears to be the dominant mechanism of de novo resistance , and most ER/progesterone receptor negative -LRB- PgR − -RRB- tumors do not respond to tamoxifen -LSB- 18 , 33 -- 36 -RSB- . However , the majority of patients who develop acquired tamoxifen resistance still express ER at the time of progression -LSB- 37 , 38 -RSB- and may respond to alternative endocrine therapies -LSB- 39 -RSB- . The third-generation aromatase inhibitors letrozole , anastrozole , and exemestane were developed in the search for more effective therapeutic alternatives to tamoxifen . Aromatase inhibitors prevent estrogen synthesis by potently inhibiting the aromatase enzyme , which converts androgens to estrogen -LSB- 40 -RSB- . Unlike tamoxifen , the aromatase inhibitors do not have any partial estrogen-agonist activity -LSB- 41 -RSB- and are less susceptible to the emergence of resistance associated with long-term estrogen deprivation -LSB- 42 -RSB- . The development and mechanism of action of aromatase inhibitors is described in detail in the article by Dr. Bhatnagar in this supplement . Studies of aromatase inhibitors in the second-line setting The initial randomized controlled trials of third-generation aromatase inhibitors were conducted in patients with advanced breast cancer in whom tamoxifen had failed -LRB- i.e. , second-line setting -RRB- . Letrozole , anastrozole , and exemestane all demonstrated evidence of clinical superiority to megestrol acetate in the second-line setting -LSB- 43 -- 47 -RSB- . Thus , the individual trials demonstrate a trend or even a significant difference in favor of the third-generation aromatase inhibitors in one or more efficacy end points ; in addition , the aromatase inhibitors were shown to be associated with improved tolerability versus comparator endocrine therapy in these randomized trials . One trial demonstrated a significantly higher ORR for letrozole -LRB- 2.5 mg dose -RRB- compared with megestrol acetate -LRB- 24 % vs. 16 % , respectively ; P = 0.04 -RRB- and a trend toward longer time to progression -LRB- 5.6 vs. 5.1 months , P = 0.07 -RRB- -LSB- 45 -RSB- . In this trial , low-dose letrozole -LRB- 0.5 mg -RRB- was associated with similar efficacy outcomes compared with megestrol acetate . However , in another similarly designed trial with letrozole versus megestrol acetate , overall response rates with the two doses of letrozole -LRB- 0.5 and 2.5 mg -RRB- and with the comparator were similar -LRB- 21 % , 16 % , and 15 % , respectively -RRB- . In this trial , low-dose letrozole was superior to megestrol acetate in terms of time to progression -LRB- TTP -RRB- -LRB- P = 0.044 -RRB- and survival -LRB- P = 0.053 -RRB- . Differences in the distribution of baseline variables may explain the different outcomes in the two trials in terms of the superiority of letrozole over megestrol acetate according to dose -LSB- 48 -RSB- . Letrozole was significantly better tolerated than megestrol acetate , specifically in terms of serious adverse experiences , discontinuation due to poor tolerability , cardiovascular side effects , and weight gain -LSB- 45 -RSB- . Third-generation aromatase inhibitors have demonstrated greater potency and selectivity than the first-generation compound aminoglutethimide -LSB- 49 -RSB- . Two doses of the most potent aromatase inhibitor letrozole -LRB- 2.5 mg and 0.5 mg -RRB- -LSB- 49 -RSB- were compared with aminoglutethimide in a randomized controlled trial in the second-line setting and demonstrated superior efficacy and improved safety -LSB- 50 -RSB- . The higher dose of letrozole showed a trend -LRB- P = 0.06 -RRB- toward superior ORR -LRB- 19.5 % -RRB- compared with aminoglutethimide -LRB- 12.4 % -RRB- . Letrozole 2.5 mg was also significantly superior in TTP , TTF , and overall survival -LRB- OS -RRB- . Fewer patients taking letrozole experienced adverse events than those taking aminoglutethimide -LRB- 33 % vs. 46 % -RRB- -LSB- 50 -RSB- . Letrozole has also been compared with anastrozole in a randomized , unblinded trial in the second-line setting in patients with MBC . The trial showed that letrozole was associated with a statistically higher ORR than anastrozole -LRB- 19.1 % vs. 12.3 % , respectively ; P = 0.013 -RRB- , whereas TTP -LRB- the major end point -RRB- , TTF , and clinical benefit and duration of response were similar between the two agents -LSB- 51 -RSB- . Both letrozole and anastrozole were well tolerated , and a similar incidence of adverse events was observed in the two groups . These studies generated the hypothesis that letrozole might have superior efficacy to tamoxifen as first-line therapy for advanced breast cancer . A large clinical trial -LRB- Femara Study PO25 -RRB- was therefore conducted to compare the efficacy and tolerability of letrozole with those of tamoxifen as first-line therapy in post-menopausal women with advanced breast cancer -LSB- 52 -RSB- . This review will describe the results of the PO25 trial , highlighting the evidence for the superiority of letrozole over tamoxifen as first-line endocrine therapy in this setting . Trial design and patients The Femara Study PO25 was the largest phase 3 trial conducted in the advanced breast cancer setting -LSB- 52 , 53 -RSB- . This randomized , double-blind , double-dummy trial was powered for superiority and needed to enroll approximately 900 patients to demonstrate a 20 % reduction in the risk of progression with the more effective treatment . To achieve the recruitment target , the trial was conducted in 201 centers in 29 countries . Local ethics review boards approved the protocol , and all patients gave written informed consent before study enrollment . Randomized trial design Patients were randomized to receive letrozole 2.5 mg or tamoxifen 20 mg given orally daily until progressive disease occurred . Patients were permitted to cross over from 1 treatment arm to the other in a double-blind fashion if their first-line treatment was discontinued because of progressive disease or for any other reason -LRB- Fig. 1 -RRB- . Patients in whom endocrine therapy was discontinued were subsequently treated as clinically indicated , using chemotherapy , trastuzumab , and bisphosphonates . The crossover design was an integral part of the study , and it probably affected the assessment of OS . Fig. 1Study design Patient population Post-menopausal women with advanced breast cancer , defined as stage IIIB locally advanced disease , locoregionally recurrent disease that was not amenable to surgery or radiotherapy , or metastatic disease , were eligible for inclusion in the trial . All patients presented with measurable or assessable tumors and were candidates for endocrine therapy . Patients had estrogen receptor-positive -LRB- ER + -RRB- and/or progesterone receptor-positive -LRB- PgR + -RRB- tumors or unknown HR status . One prior chemotherapy regimen for the treatment of metastatic disease was permitted , but recurrence during or within 12 months of adjuvant antiestrogen therapy and any prior endocrine therapy for advanced breast cancer precluded enrollment . End points The primary end point was TTP , defined as the interval between date of randomization and the earliest date of disease progression . Disease progression was determined on the basis of tumor progression -LRB- an increase of 25 % or more in measurable lesions , an estimated increase of the same magnitude of nonmeasurable lesions , or the appearance of new lesions -RRB- , treatment discontinuation with evidence of clinical deterioration due to breast cancer , death due to breast cancer , or death of unknown cause -LRB- with documented evidence of clinical deterioration due to breast cancer -RRB- while receiving treatment or within 6 weeks of discontinuation of treatment . The secondary end points were ORR , duration of overall response , rate and duration of clinical benefit , TTF , time to response -LRB- TTR -RRB- , time to chemotherapy -LRB- TTC -RRB- , safety , and OS . ORR was defined as the proportion of patients who achieved a complete response -LRB- CR -RRB- or a partial response -LRB- PR -RRB- , confirmed by a second evaluation 1 -- 3 months later . The duration of overall response was defined for patients with CR or PR , as the interval between date of randomization and the earliest date of disease progression . The rate of clinical benefit was defined as proportion of patients who achieved CR or PR or who stabilized -LRB- NC -RRB- for at least 24 weeks ; the duration of clinical benefit was defined for patients who achieved CR or PR or NC as the interval between date of randomization and the earliest date of disease progression . TTF was defined as the interval between date of randomization and the earliest date of disease progression , withdrawal , lost to follow-up , or death . TTR was defined for CR or PR patients as the interval between randomization and the earliest documentation of response , and TTC was defined as the total duration of endocrine therapy . The duration of OS was defined as the interval between randomization and death for any reason . Exploratory analyses of OS were performed . The first analysis included all patients with censoring at crossover , whereas the second included only patients with no crossover . The latter group predominantly comprised of patients with `` nonresponsive '' disease -LRB- patients who responded to first-line therapy are more likely to be crossed over later at progression -RRB- , whereas the former included `` nonresponsive '' as well as `` responsive '' patients . Efficacy The characteristics of the 907 patients included in the intent-to-treat -LRB- ITT -RRB- population were well balanced between the letrozole and tamoxifen arms . The median age of the patients was 65 years -LRB- range 31 -- 96 years -RRB- in the letrozole arm and 64 years -LRB- range 31 -- 93 years -RRB- in the tamoxifen arm . Patients were predominantly white -LRB- 86 % -RRB- , and 92 % had Karnofsky performance status -LRB- KPS -RRB- scores of 80 -- 100 . The majority -LRB- 93 % -RRB- of the study population had metastatic disease . Soft tissue lesions were the dominant metastatic site in one quarter of patients and were present in 63 % and 61 % of patients in the letrozole and tamoxifen arms , respectively . Bone metastases were the dominant metastatic site in approximately 30 % of patients and were present in 54 % and 50 % , respectively . Visceral metastases were the dominant site in 43 % of patients in the letrozole arm and 46 % of the patients in the tamoxifen arm . Most patients -LRB- 71 % in the letrozole arm and 66 % in the tamoxifen arm -RRB- had not received any prior chemotherapy , and few had received chemotherapy for advanced disease -LRB- 9 % and 11 % , respectively -RRB- . The majority of patients -LRB- 109 of 167 -RRB- treated with adjuvant tamoxifen received at least 2 years of therapy , and the treatment-free interval between stopping adjuvant therapy and entering the study was more than 2 years in 126 of 167 patients . Of the 907 patients included in the ITT efficacy population , 467 crossed over to the other treatment arm , 75 continued on first-line therapy without progression , and the remainder terminated first-line treatment without crossover -LRB- Fig. 2 -RRB- . Fig. 2Patient disposition Letrozole was superior to tamoxifen for all primary and secondary efficacy end points , including a prospectively planned survival analysis at 1 - and 2-year follow-up -LSB- 53 -RSB- . Time to progression In the primary efficacy analysis , the median TTP was significantly longer with letrozole than with tamoxifen -LRB- 9.4 months vs. 6.0 months , respectively ; P < 0.0001 -RRB- -LRB- Fig. 3 -RRB- -LSB- 53 -RSB- . Of patients in the letrozole arm , 359 -LRB- 79 % -RRB- progressed , compared with 387 -LRB- 85 % -RRB- in the tamoxifen arm . The hazard ratio of 0.72 represents a 28 % reduction in the risk of disease progression with letrozole -LRB- P = 0.0001 -RRB- . Fig. 3Time to progression at median follow-up of 32 months for patients on first-line letrozole versus tamoxifen . Reprinted from ref . -LSB- 53 -RSB- with permission from the American Society of Clinical Oncology The significant improvement in TTP with letrozole was confirmed in supportive multivariate analysis of prospectively defined baseline covariates , including receptor status , prior adjuvant tamoxifen therapy , and dominant site of metastatic disease -LSB- 52 , 54 -RSB- . The analysis showed that the risk of progression was increased by the presence of either visceral or bone metastases as the dominant site of metastatic disease compared with soft tissue as dominant site . In the multivariate analysis , the significant improvement in TTP with letrozole over tamoxifen -LRB- hazard ratio 0.70 ; 95 % confidence intervals -LSB- CI -RSB- 0.60 , 0.81 ; P = 0.0001 -RRB- was similar to the benefit observed in unadjusted analysis and was significant for each individual covariate -LRB- P = 0.0001 -RRB- -LSB- 53 -RSB- . Median TTP values for letrozole and tamoxifen in the different subgroups are shown in Table 1 . In patients with nonvisceral metastases , the risk for progression was 25 % lower with letrozole than with tamoxifen , whereas in patients with visceral metastases , excluding the liver , the risk for progression was 34 % lower and the median TTP was almost twice as long with letrozole than with tamoxifen -LSB- 54 -RSB- . Although TTP was shortest for patients with liver lesions , the risk for progression was still 36 % lower with letrozole than with tamoxifen in this subgroup -LSB- 54 -RSB- . Table 1Time to progression in different patient subgroups -LSB- 57 -RSB- SubgroupLetrozoleTamoxifenDominant disease site : soft tissuen113115Median TTP12 .1 months6 .4 monthsDominant disease site : bonen145131Median TTP9 .5 months6 .3 monthsDominant disease site : visceran195208Median TTP8 .3 months4 .6 monthsPatients who had n9483 received priorMedian TTP8 .9 months5 .9 months antiestrogenHazard ratio -LRB- 95 % CI -RRB- a0 .60 -LRB- 0.43 , 0.84 -RRB- HR-positiven294305Median TTP9 .4 months6 .0 monthsHazard ratio -LRB- 95 % CI -RRB- a0 .69 -LRB- 0.58 , 0.83 -RRB- HR-unknownn159149Median TTP9 .2 months6 .0 monthsHazard ratio -LRB- 95 % CI -RRB- a0 .77 -LRB- 0.60 , 0.99 -RRB- TTP , time to progression ; CI , confidence interval ; HR , hormone receptoraHazard ratios < 1.0 indicate superiority for letrozole relative to tamoxifen Patients with prior adjuvant antiestrogen therapy benefited from letrozole in line with the total group , as did patients irrespective of positive or unknown receptor status of the primary tumor . A prospectively planned analysis by patient age -LRB- < 70 years and ≥ 70 years -RRB- also demonstrated that median TTP was significantly longer for letrozole than for tamoxifen in both age groups -LRB- 8.8 months vs. 6.0 months , respectively , in the younger group and 12.2 months vs. 5.8 months in the older group -RRB- -LSB- 55 -RSB- . Response to therapy Letrozole was associated with a significantly better response to therapy compared with tamoxifen -LSB- 52 , 53 -RSB- . ORR was significantly higher for letrozole than for tamoxifen -LRB- 32 % vs. 21 % ; P = 0.0002 -RRB- , and the corresponding rate of CRs was also significantly higher for letrozole -LRB- 9 % vs. 3 % ; P = 0.0004 -RRB- . The rate of treatment failure was lower with letrozole -LRB- 75 % -RRB- than with tamoxifen -LRB- 85 % -RRB- , and median TTF was significantly prolonged -LRB- 9.0 months vs. 5.7 months , respectively ; P < 0.0001 -RRB- . A supportive multivariate analysis of ORR , adjusted for the same covariates as used for the TTP analysis , showed that prior adjuvant tamoxifen , as well as visceral or bone metastases as the dominant site of metastases , significantly decreased the probability of achieving a response . The analysis also confirmed that letrozole significantly increased the probability of achieving a CR or PR compared with tamoxifen -LRB- odds ratio 1.80 , 95 % CI 1.32 -- 2.47 ; P = 0.0002 -RRB- and that the superiority of letrozole remained statistically significant for each of covariates -LRB- P = 0.001 -RRB- -LSB- 52 -RSB- . ORRs achieved with letrozole and tamoxifen in the different subgroups are shown in Table 2 . Table 2Objective response rate in different patient subgroups -LSB- 57 -RSB- SubgroupLetrozoleTamoxifenDominant disease site : soft tissuen113115ORR50 % 34 % Dominant disease site : bonen145131ORR23 % 15 % Dominant disease site : visceran195208ORR28 % 17 % Patients who hadn8483 received priorORR26 % 8 % antiestrogenOdds ratio -LRB- 95 % CI -RRB- a3 .85 -LRB- 1.50 , 9.60 -RRB- HR-positiven294305ORR33 % 22 % Odds ratio -LRB- 95 % CI -RRB- a1 .78 -LRB- 1.20 , 2.60 -RRB- HR-unknownn159149ORR30 % 20 % Odds ratio -LRB- 95 % CI -RRB- a1 .79 -LRB- 1.10 , 3.00 -RRB- ORR , objective response rate ; CI , confidence interval ; HR , hormone receptoraOdds ratios > 1.0 indicate superiority for letrozole relative to tamoxifen Overall survival The median OS was 34 months for the letrozole group and 30 months for the tamoxifen group -LRB- P = 0.53 -RRB- . Prospectively planned analyses of the ITT population showed that letrozole significantly improved OS compared with tamoxifen over the first 24 months of the trial -LSB- 53 -RSB- . A Kolmogorov-Smirnov analysis to compare the survival distributions in the 2 arms -LSB- 56 -RSB- demonstrated a significant difference in favor of letrozole between 6 and 20 months -LRB- P = 0.003 -RRB- and showed that the maximum difference in survival occurred at 14 months ; at this time point , there were 85 deaths -LRB- 19 % -RRB- in the letrozole arm compared with 132 deaths -LRB- 29 % -RRB- in the tamoxifen arm . In addition , repeated log-rank tests performed at 6-month intervals indicated that survival was significantly greater with letrozole between 6 and 24 months -LRB- 6 months : P = 0.0167 ; 12 months : P = 0.0038 ; 18 months : P = 0.0010 ; 24 months : P = 0.0246 -RRB- -LRB- Fig. 4 -RRB- . The OS curves for the letrozole and tamoxifen groups crossed at around 36 months , at which time point most patients had either crossed over to the other study drug or had switched to different second-line treatments -LSB- 53 -RSB- . Fig. 4Letrozole versus tamoxifen : patients alive at 6-month intervals . Reprinted from ref . -LSB- 48 -RSB- with permission from Elsevier Additional exploratory analyses were therefore performed to determine the influence of crossover on OS . The crossover design was an integral part of the trial and , as with all crossover designs , had a confounding influence on the assessment of OS . Second-line endocrine therapy is generally less effective than first-line treatment in patients responsive to first-line therapy -LSB- 16 -RSB- ; therefore , evaluation of OS may be impaired if the second-line treatment is actually more effective than the original first-line treatment . Furthermore , patients who are responsive to first-line therapy are more likely to cross over than are patients with nonresponsive disease who do not obtain benefit from first-line therapy . Approximately 50 % of patients crossed over to the other treatment arm -LRB- Fig. 2 -RRB- , and almost all of the crossovers had occurred by 36 months . The median time to crossover was longer for patients initially randomized to the letrozole arm -LRB- 17 months for letrozole to tamoxifen vs. 13 months for tamoxifen to letrozole -RRB- . The median OS from initial randomization , censoring time to death at crossover , was 42 months -LRB- 95 % CI 36 months to not estimable -RRB- for letrozole and 30 months -LRB- 95 % CI 27 to < 36 months -RRB- for tamoxifen -LSB- 53 -RSB- . The superior efficacy of letrozole compared with tamoxifen was also indicated by an analysis of mortality rates and OS following crossover to the alternate treatment . The analysis showed that the mortality rate was substantially reduced -LRB- 47 % vs. 63 % , respectively -RRB- , and OS improved in patients who crossed over to second-line letrozole compared with those who crossed over to second-line tamoxifen -LRB- 31 months ; 95 % CI 22 -- 40 months vs. 19 months ; 95 % CI 17 -- 24 months , respectively -RRB- -LSB- 53 -RSB- . This OS analysis included all patients censored at the time of crossover -LRB- i.e. , both `` nonresponsive '' and `` responsive '' patients -RRB- . A second exploratory efficacy analysis of OS included only patients who did not cross over to the other arm and thus predominantly comprised patients with nonresponsive disease . This second analysis , limited to the patients who did not cross over to the alternate drug at progression , indicated a median OS benefit of 14 months for letrozole -LRB- 35 months ; 95 % CI 29 -- 43 months -RRB- compared with tamoxifen -LRB- 20 months ; 95 % CI 16 -- 26 months -RRB- -LSB- 57 -RSB- . Time to chemotherapy Hormone therapy is the preferred treatment strategy for patients with hormone-responsive advanced breast cancer , except for those individuals with rapidly progressive disease for whom initial chemotherapy is indicated -LSB- 15 -RSB- . Extending the TTC is thus an important goal with hormone therapy and can maintain quality of life without having a detrimental effect on outcome . In the PO25 trial , TTC was significantly longer for patients whose initial treatment was letrozole compared with those initially randomized to receive tamoxifen -LRB- 16.3 vs. 9.3 months ; P = 0.005 -RRB- . Safety Both letrozole and tamoxifen were well tolerated -LSB- 52 , 53 -RSB- . The incidence of adverse effects related to study drug during first-line treatment was similar for letrozole -LRB- 38 % -RRB- and tamoxifen -LRB- 37 % -RRB- . Hot flushes -LRB- 16 % and 13 % , respectively -RRB- , nausea -LRB- 6 % and 6 % , respectively -RRB- , and hair thinning -LRB- 5 % and 3 % , respectively -RRB- were the most common treatment-related adverse events reported . Bone fractures of any etiology occurred in 5.3 % of patients in the letrozole group , compared with 4.2 % in the tamoxifen arm , resulting in fracture rates per patient-year of treatment of 0.0427 and 0.0451 , respectively -LSB- 52 -RSB- . A quality-adjusted time without symptoms or toxicity -LRB- Q-TWiST -RRB- follow-up study assessed the trade-offs between progression-free survival and toxicity in the ITT population from the PO25 trial -LSB- 58 -RSB- . The Q-TWiST approach quantitatively adjusts periods in which treatment toxicities or symptoms of disease progression are present to reflect the potentially reduced value for the patient ; this methodology divides the survival time of the patient into various health states , assigns utility states to each , and compares treatments based on OS experience -LSB- 59 -RSB- . The Q-TWiST analysis of the clinical trial data from the PO25 trial showed that the longer TTP with letrozole compared with tamoxifen is achieved without increased time with adverse events -LRB- 2.2 vs. 2 months , respectively -RRB- , resulting in a significantly greater quality-adjusted survival for patients on letrozole -LRB- 2.5-month advantage ; P < 0.0001 -RRB- -LSB- 58 -RSB- . Time to worsening of KPS -LRB- decrease of ≥ 20 points -RRB- was significantly delayed for first-line letrozole compared with first-line tamoxifen -LRB- hazard ratio 0.62 ; P = 0.001 -RRB- -LSB- 54 -RSB- . A subset analysis according to sites of metastases demonstrated that in patients with visceral metastases without liver involvement -LRB- mostly lung metastases -RRB- , significantly fewer letrozole patients -LRB- 14 % -RRB- than tamoxifen patients -LRB- 30 % -RRB- experienced deteriorations in their KPS scores by ≥ 20 points -LSB- 54 -RSB- . However , KPS was relatively insensitive to change in these first-line patients . Cost-effectiveness In addition to its clinical superiority over tamoxifen , economic analyses have also shown that letrozole is highly cost-effective as first-line endocrine therapy in post-menopausal women with advanced breast cancer -LSB- 60 -- 62 -RSB- . A follow-up analysis of patient data from the PO25 trial calculated the cost-effectiveness of first-line letrozole and tamoxifen by determining the ratio : difference in costs of breast cancer care to the difference in life years -LRB- LYs -RRB- between the two treatments -LSB- 60 -RSB- . The mean costs of care were $ 7323 and $ 5468 for letrozole and tamoxifen , respectively , representing $ 1855 in incremental costs with first-line letrozole . Mean LYs to death or to the end of first - or second-line hormonal therapy were 1.54 and 1.29 for patients randomized to first-line letrozole or tamoxifen , respectively . Thus , the incremental cost per LY saved with first-line letrozole vs. tamoxifen was $ 7420 -LRB- 1855/0 .25 = 7420 -RRB- -LRB- 2.5 -- 97.5 percentiles $ 6470 -- $ 14,865 -RRB- . In another economic analysis conducted in the United Kingdom , data from the PO25 trial were used to estimate the effectiveness of treatment -LSB- 61 -RSB- . The analysis showed that the mean cost of providing first - and second-line hormonal therapy was GBP4765 for first-line letrozole and GBP3418 for first-line tamoxifen -LRB- a difference of GBP1347 -RRB- . Since patients receiving first-line letrozole gain an additional 0.228 LYs , or 0.158 quality-adjusted life years -LRB- QALYs -RRB- , the cost-effectiveness analysis showed that first-line hormonal therapy with letrozole gains additional LYs at a cost of GBP5917 , whereas the cost per additional QALY gained is GBP8514 , which is well within the accepted cost range . The PO25 trial data were also used in a Canadian analysis that compared the cost-effectiveness of letrozole , anastrozole , and tamoxifen -LSB- 62 -RSB- . The analysis showed an incremental cost per quality-adjusted progression-free year of CAN$ 12,500 and CAN$ 19,600 for letrozole and anastrozole , respectively , relative to tamoxifen . The authors concluded that both letrozole and anastrozole are economically acceptable alternatives to tamoxifen . Conclusions The Femara Study PO25 has provided evidence from a well-powered , randomized , controlled trial to show that letrozole provides a significant advantage in OS compared with tamoxifen as first-line treatment of patients with advanced breast cancer -LSB- 53 -RSB- . Letrozole is the only aromatase inhibitor to demonstrate consistent superiority over tamoxifen in this setting -LSB- 53 , 54 -RSB- . Randomized first-line therapy trials of anastrozole , as part of the TARGET study -LSB- 63 -- 66 -RSB- , and exemestane in the EORTC study -LSB- 67 , 68 -RSB- have provided evidence of clinical equivalence or superiority to tamoxifen in post-menopausal women with advanced breast cancer . However , none of these trials demonstrated statistically significant improvements in all three end points -LRB- ORR , TTP , and OS -RRB- for the aromatase inhibitor compared with tamoxifen . The PO25 study was the largest of these randomized trials in the first-line setting and demonstrated extremely strong clinical benefits , evidenced by significant superiority in TTP and ORR , with letrozole compared with tamoxifen as first-line hormone therapy . The benefits of letrozole were observed in all patient subgroups , defined by prior antiestrogen therapy , dominant site of metastatic disease , HR status -LRB- positive or unknown -RRB- , and age -LSB- 52 -- 55 -RSB- . Furthermore , letrozole is the only aromatase inhibitor associated with an OS advantage for the first-line setting indication at 1-year and 2-year follow-up -LSB- 53 -RSB- . As demonstrated in the exploratory analysis of patients who did not cross over to the alternative treatment arm , letrozole prolonged OS by 14 months compared with tamoxifen . Thus , for every 100 patients treated with hormone therapy , eight more will be alive at 1 year if they receive letrozole instead of tamoxifen . In conclusion , third-generation aromatase inhibitors are effective and well tolerated . Letrozole should be considered as the first-line endocrine treatment in post-menopausal women with hormone-sensitive advanced or MBC . Of the available agents , only letrozole has demonstrated significant improvements in ORR , TTP , and early OS .

B O B I I O O O O B O O O O O O O O B O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B O O O O O O O B O O B I I O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B I B O O O O O O O O O O O O O O O O B O B I O O O O O O O O O O O O O O O O O O O O B O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B I O O O O O B I I O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O B I I O O O O O O O O O O O O O O O O O O O O B O O O B O O O O B O O B I I O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O B O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O B O O B I I O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O B I I O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O B I O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O

advanced breast cancer
aromatase inhibitors
letrozole
postmenopausal
tamoxifen