ovarian suppression by treatment with goserelin had been shown to reduce the risk of mortality in premenopausal breast cancer patients , but data on the long - term benefit of this treatment were lacking .
the analysis was based on a randomized trial with 2  2 factorial assignment of breast cancer patients younger than 50 years to no hormonal therapy or 2 years of treatment with tamoxifen alone , goserelin alone , or goserelin plus tamoxifen .
meier curves were constructed and hazard ratios and absolute risk reductions were calculated to compare treatment groups in terms of survival and recurrence outcomes .
this study quantified the absolute risk reduction of mortality and recurrence conferred by goserelin treatment among women who did and did not take tamoxifen based on long - term follow - up ( mean follow - up time = 11 years ) . for every 100 women younger than 50 years and
not treated with tamoxifen , 2 years of goserelin treatment would result in 8.5 fewer breast cancer deaths compared to those not given goserelin .
the benefit of goserelin treatment in women treated with tamoxifen , if any , would be smaller ( possibly 2.6 fewer deaths ) .
women in the trial were treated with tamoxifen for 2 years , which is currently not standard practice .
the trial did not address the question of the optimal frequency and duration of goserelin treatment .
ovarian suppression by treatment with goserelin had been shown to reduce the risk of mortality in premenopausal breast cancer patients , but data on the long - term benefit of this treatment were lacking .
the analysis was based on a randomized trial with 2  2 factorial assignment of breast cancer patients younger than 50 years to no hormonal therapy or 2 years of treatment with tamoxifen alone , goserelin alone , or goserelin plus tamoxifen .
meier curves were constructed and hazard ratios and absolute risk reductions were calculated to compare treatment groups in terms of survival and recurrence outcomes .
this study quantified the absolute risk reduction of mortality and recurrence conferred by goserelin treatment among women who did and did not take tamoxifen based on long - term follow - up ( mean follow - up time = 11 years ) .
for every 100 women younger than 50 years and not treated with tamoxifen , 2 years of goserelin treatment would result in 8.5 fewer breast cancer deaths compared to those not given goserelin .
the benefit of goserelin treatment in women treated with tamoxifen , if any , would be smaller ( possibly 2.6 fewer deaths ) .
women in the trial were treated with tamoxifen for 2 years , which is currently not standard practice .
the trial did not address the question of the optimal frequency and duration of goserelin treatment .
the zipp trial was conducted jointly by 4 breast cancer study groups from cancer research uk ( cruk , formerly cancer research campaign ) , gruppo interdisciplinare valutazione interventi in oncologia ( givio ) italy , south east sweden , and stockholm .
the aim was to determine whether the addition of goserelin ( zoladex ) to local treatment , with or without tamoxifen , provided a benefit in survival or recurrence among pre- or perimenopausal women with operable , early breast cancer .
the investigators in each location used the same protocol and worked together when setting up and conducting the trial .
the local ethics committee for each center taking part in the trial approved the protocol , and all patients provided informed consent .
a total of 2710 premenopausal women were recruited from august 27 , 1987 , to march 22 , 1999 , and randomly assigned to receive goserelin alone ( 3.6-mg subcutaneous depot injection into the abdominal wall every 4 weeks ) , tamoxifen alone ( 20 or 40 mg daily ) , both treatments , or no endocrine therapy ( figure 1 ) .
most women were younger than 50 years , with invasive , operable breast cancer confined to one breast without evidence of metastatic disease .
women received primary therapy : surgery with or without radiotherapy and adjuvant systemic chemotherapy , where appropriate .
chemotherapy was perioperative cyclophosphamide , or six cycles of cyclophosphamide , methotrexate , and 5-fluorouracil ( cmf ) or 5-fluorouracil , epirubicin , and cyclophosphamide ( fec ) .
the proportions of patients who received surgery , radiotherapy , or chemotherapy were evenly distributed between the goserelin groups ( supplementary table 1 , available online ) , so these treatments would not be expected to affect the results .
distribution of patients in the zoladex in premenopausal patients ( zipp ) trial ( consort flow diagram ) .
all patients in the stockholm and givio trials were included in the 2  2 factorial random assignment .
patients in the cruk and south east sweden trials were initially randomly assigned into four arms , but with the publication of the data on tamoxifen in younger patients ( 6 ) , investigators were permitted to give tamoxifen electively , following random assignment to goserelin or no goserelin .
this did not affect the results because the numbers of women treated and not treated with tamoxifen were balanced between the trial arms : of those electively given tamoxifen , 432 were randomly assigned to goserelin and 428 to no goserelin , and of those electively not given tamoxifen , 25 were randomly assigned to goserelin and 25 to no goserelin .
four patients were subsequently found to have been ineligible at the time of random assignment ( two had contralateral breast cancer , one had metastatic disease , and one had recurrent disease ) and were excluded from this analysis .
the numbers of women analyzed in the control , tamoxifen - only , goserelin - only , and both therapies arms were 476 , 879 , 469 , and 882 , respectively ( 2706 in total ) .
the following four outcome measures were examined : ( 1 ) event - free survival ( efs ) , the main trial endpoint and defined as a recurrence , new tumor , or death .
( 2 ) overall survival ( os , death from any cause ) . ( 3 ) risk of recurrence [ recurrence could be local or distant and among 10 women who died from breast cancer with no previously recorded recurrence , it was assumed that they had a distant recurrence , assumed to occur on the date of death ; consistent with the assumptions of the ebctcg overview ( 3 ) ] .
there were also 110 whose cause of death was unknown , but these deaths also were assumed to be due to breast cancer because among those with a known cause of death , 90% were due to breast cancer .
in addition , there were 13 women who died from other known causes but in whom breast cancer was present at death ; these women were censored at the date of first recurrence because according to the ebctcg overview ( 3 ) , cause of death may not be reliably recorded after a recurrence .
the sample size target was set at 2700 women to detect an absolute difference in the 5-year efs rate of 5% ( 70% vs 75% in the control and treated group , respectively ) , with 83% power and alpha set at .05 .
simple randomization was used in each of the four trial groups to allocate patients to the trial arms with a block size of four .
meier survival curves and hazard ratios ( hrs ) were used to compare treatment groups based on intention - to - treat analyses .
we examined the interaction between goserelin and tamoxifen and whether the effect of goserelin differed between subgroups of patients for four prognostic factors : age ( < 40 or 40 years ) , nodal status ( positive or negative ) , er status ( positive , negative , or unknown ) , and previous adjuvant systemic chemotherapy ( yes or no ) .
although age was not prespecified in the original trial protocol , the intention was to include it in the long - term follow - up analysis , particularly because it was examined in detail in the recent lhrh overview ( 4 ) .
the assumption of proportional hazards was verified using a plot of the schoenfeld residuals ( 7 ) .
statistical analyses were performed using sas 9.1 ( 8) . because tamoxifen is the current standard of treatment
, most analyses were presented according to whether women received tamoxifen or not , allowing an examination of the effect of goserelin in addition to tamoxifen . relative or proportional risk reductions , based on hazard ratios , are indicated by percentages ( % ) , whereas absolute risk differences at specified time points are indicated by percentage points ( ie , the number of events prevented among every 100 treated women ) .
all statistical tests were two - sided , and p values less than .05 were considered statistically significant .
a total of 2710 premenopausal women were recruited from august 27 , 1987 , to march 22 , 1999 , and randomly assigned to receive goserelin alone ( 3.6-mg subcutaneous depot injection into the abdominal wall every 4 weeks ) , tamoxifen alone ( 20 or 40 mg daily ) , both treatments , or no endocrine therapy ( figure 1 ) .
most women were younger than 50 years , with invasive , operable breast cancer confined to one breast without evidence of metastatic disease .
women received primary therapy : surgery with or without radiotherapy and adjuvant systemic chemotherapy , where appropriate .
chemotherapy was perioperative cyclophosphamide , or six cycles of cyclophosphamide , methotrexate , and 5-fluorouracil ( cmf ) or 5-fluorouracil , epirubicin , and cyclophosphamide ( fec ) .
the proportions of patients who received surgery , radiotherapy , or chemotherapy were evenly distributed between the goserelin groups ( supplementary table 1 , available online ) , so these treatments would not be expected to affect the results .
distribution of patients in the zoladex in premenopausal patients ( zipp ) trial ( consort flow diagram ) .
all patients in the stockholm and givio trials were included in the 2  2 factorial random assignment .
patients in the cruk and south east sweden trials were initially randomly assigned into four arms , but with the publication of the data on tamoxifen in younger patients ( 6 ) , investigators were permitted to give tamoxifen electively , following random assignment to goserelin or no goserelin .
this did not affect the results because the numbers of women treated and not treated with tamoxifen were balanced between the trial arms : of those electively given tamoxifen , 432 were randomly assigned to goserelin and 428 to no goserelin , and of those electively not given tamoxifen , 25 were randomly assigned to goserelin and 25 to no goserelin .
four patients were subsequently found to have been ineligible at the time of random assignment ( two had contralateral breast cancer , one had metastatic disease , and one had recurrent disease ) and were excluded from this analysis .
the numbers of women analyzed in the control , tamoxifen - only , goserelin - only , and both therapies arms were 476 , 879 , 469 , and 882 , respectively ( 2706 in total ) .
the following four outcome measures were examined : ( 1 ) event - free survival ( efs ) , the main trial endpoint and defined as a recurrence , new tumor , or death .
( 2 ) overall survival ( os , death from any cause ) . ( 3 ) risk of recurrence [ recurrence could be local or distant and among 10 women who died from breast cancer with no previously recorded recurrence , it was assumed that they had a distant recurrence , assumed to occur on the date of death ; consistent with the assumptions of the ebctcg overview ( 3 ) ] .
there were also 110 whose cause of death was unknown , but these deaths also were assumed to be due to breast cancer because among those with a known cause of death , 90% were due to breast cancer .
in addition , there were 13 women who died from other known causes but in whom breast cancer was present at death ; these women were censored at the date of first recurrence because according to the ebctcg overview ( 3 ) , cause of death may not be reliably recorded after a recurrence .
the sample size target was set at 2700 women to detect an absolute difference in the 5-year efs rate of 5% ( 70% vs 75% in the control and treated group , respectively ) , with 83% power and alpha set at .05 .
simple randomization was used in each of the four trial groups to allocate patients to the trial arms with a block size of four .
meier survival curves and hazard ratios ( hrs ) were used to compare treatment groups based on intention - to - treat analyses .
we examined the interaction between goserelin and tamoxifen and whether the effect of goserelin differed between subgroups of patients for four prognostic factors : age ( < 40 or 40 years ) , nodal status ( positive or negative ) , er status ( positive , negative , or unknown ) , and previous adjuvant systemic chemotherapy ( yes or no ) .
although age was not prespecified in the original trial protocol , the intention was to include it in the long - term follow - up analysis , particularly because it was examined in detail in the recent lhrh overview ( 4 ) .
the assumption of proportional hazards was verified using a plot of the schoenfeld residuals ( 7 ) .
statistical analyses were performed using sas 9.1 ( 8) . because tamoxifen is the current standard of treatment
, most analyses were presented according to whether women received tamoxifen or not , allowing an examination of the effect of goserelin in addition to tamoxifen .
relative or proportional risk reductions , based on hazard ratios , are indicated by percentages ( % ) , whereas absolute risk differences at specified time points are indicated by percentage points ( ie , the number of events prevented among every 100 treated women ) .
all statistical tests were two - sided , and p values less than .05 were considered statistically significant .
the median length of follow - up was 12 years , with 26  545 person - years in total .
the numbers of efs events ( recurrence , second primary tumor , or death ) , deaths , breast cancer recurrences , and breast cancer deaths were 1148 , 690 , 941 , and 630 , respectively ( supplementary table 2 , available online ) .
hrs associated with goserelin treatment according to trial group and overall for the four outcome measures are shown in ( supplementary table 3 , available online .
goserelin was associated with a risk reduction in all four endpoints : the risk of having an efs event ( hr  =  0.82 , 95% confidence interval [ ci ] 0.73 to 0.92 , p  =  .001 ) , overall mortality ( hr  =  0.83 , 95% ci 0.71 to 0.96 , p  =  .013 ) , the risk of recurrence ( hr  =  0.81 , 95% ci 0.71 to 0.92 , p  =  .001 ) , and breast cancer mortality ( hr  =  0.82 , 95% ci 0.70 to 0.96 , p  =  0.03 ) . although the point estimates of hr for efs , os , recurrence , and breast cancer mortality in the givio trial appeared to differ from those of the other trials , the confidence intervals contained the overall estimate for each outcome , suggesting that the differences may have been due to chance .
there was a clear benefit on survival and recurrence 10 or 15 years after randomization ( figure 2 ) .
a ) the percentages ( 95% confidence interval [ ci ] ) of women treated with goserelin who experienced death , had recurrence , or had a new tumor at 5 , 10 , and 15 years were 25 ( 23 to 27 ) , 38 ( 35 to 41 ) , and 47 ( 43 to 51 ) , respectively ; corresponding percentages in control women were 32 ( 29 to 35 ) , 43 ( 40 to 46 ) , and 52 ( 48 to 55 ) .
b ) the percentages ( 95% ci ) of women treated with goserelin who died at 5 , 10 , and 15 years were 12 ( 10 to 14 ) , 21 ( 19 to 23 ) , and 29 ( 26 to 32 ) , respectively ; the corresponding percentages in control women were 15 ( 13 to 17 ) , 26 ( 23 to 28 ) , and 33 ( 30 to 36 ) .
c ) the percentages ( 95% ci ) of women treated with goserelin who had a recurrence at 5 , 10 , and 15 years were 22 ( 20 to 24 ) , 31 ( 28 to 34 ) , and 36 ( 33 to 39 ) , respectively ; the corresponding percentages in control women were 27 ( 24 to 29 ) , 37 ( 34 to 40 ) , and 42 ( 39 to 45 ) .
d ) the percentages ( 95% ci ) of women treated with goserelin who died from breast cancer at 5 , 10 , and 15 years were 11 ( 9 to 13 ) , 20 ( 18 to 22 ) , and 26 ( 23 to 29 ) , respectively ; the corresponding percentages in control women were 14 ( 12 to 16 ) , 24 ( 22 to 26 ) , and 30 ( 27 to 33 ) .
two - sided p values from log - rank tests are shown . the effect of goserelin depended on whether women received tamoxifen ( table 1 ) .
the test for interaction was statistically significant for efs and recurrence , and although the p values were greater than .05 for os and breast cancer mortality , the hrs were in a direction similar to the other endpoints , that is , women who did not receive tamoxifen experienced a greater benefit from goserelin than those who received tamoxifen .
thus , in women who did not receive tamoxifen , goserelin was associated with a 33% reduction in the risk of having an efs event , a 29% reduction in risk of overall mortality , a 34% reduction in risk of recurrence , and a 29% reduction in risk of breast cancer mortality . in women who received tamoxifen , there was a much smaller benefit due to goserelin : 8% reduction in risk of efs events , 10% reduction in risk of overall mortality , 9% reduction in risk of recurrence , and 11% reduction in risk of breast cancer mortality .
table 1 also shows that goserelin was as effective as tamoxifen ; the hazard ratios for each treatment on its own were similar , when compared with the control group .
examination of the interaction between goserelin and tamoxifen the hazard ratios can be converted to percentage reduction or increase in risk by subtracting 1 and multiplying by 100 .
the p values for the test of interaction between goserelin and tamoxifen were .01 ( any event ) , .13 ( death from any cause ) , .016 ( breast cancer recurrence ) , and .17 ( death from breast cancer ) .
taking either tamoxifen or goserelin had similar and large effects , but using both was associated with a possible small additional benefit that was not statistically significant .
we calculated absolute risk differences associated with goserelin treatment at 5 , 10 , and 15 years after random assignment among women who did or did not take tamoxifen ( table 2 ) . among women who did not take tamoxifen
, there was a clear and substantial benefit associated with goserelin treatment for all four endpoints .
for example , the estimated efs absolute risk difference at 15 years indicates that for every 100 such women treated with goserelin , there could be 13.9 fewer with an event ( recurrence , new tumor or death ) , compared with those not given goserelin ( risk difference 13.9 percentage points , 95% ci 19.4 to 7.5 ) .
this corresponds to a number needed to treat of 7 . among women who took tamoxifen ,
the benefit was smaller and not statistically significant : for every 100 such women treated with goserelin , there could be 2.8 fewer with an event ( 95% ci 7.7 to 2.0 ) .
with regards to the effect on breast cancer mortality , 12 patients needed to be treated with goserelin ( and not tamoxifen ) to avoid one woman dying ( risk difference 8.5 percentage points , 95% ci 13.7 to 2.2 ) , compared with no goserelin , whereas 38 needed to be treated with both goserelin and tamoxifen to avoid one death ( risk difference 2.6 percentage points , 95% ci 6.6 to 2.1 ) .
risk differences and nnts are likely to be different in populations with much lower or higher baseline risks than in the zipp trial . estimated absolute risk difference ( percentage points ) between goserelin and no goserelin for four outcomes
if p is the event rate in the no goserelin arm ( eg , efs rate or risk of recurrence ) at a specified time point , then the absolute difference at this time is p  exp[hazard ratio  logep  ] .
the hazard ratios were taken from table 1 ( tamoxifen =  no  or  yes  ) .
number needed to treat = 100% ( absolute risk difference ) . the expected number of women who need to be treated with goserelin to avoid one event at the specified time point .
outcomes considered were death , recurrence , or new tumor ( a ) ; death from any cause ( b ) ; breast cancer recurrence ( c ) ; and death due to breast cancer ( d ) .
older women ( 40 years ) who did not take tamoxifen benefited the most : the absolute risk difference was 14.8 percentage points after 15 years . in younger women ( < 40 years ) , goserelin decreased the event rate by 45 percentage points at 15 years , but the confidence intervals were wide , which may partly reflect the smaller sample size in these subgroups .
the least benefit associated with goserelin treatment appeared to be among older women who took tamoxifen ( the absolute risk was 1.7 percentage points lower ) .
estimated absolute risk difference ( percentage points ) for any event ( recurrence , new tumour or death ) between women treated with goserelin and those not treated with goserelin , according to age and whether women took tamoxifen or not .
if p  =  the event rate in the  no goserelin arm at a specified time point , then the absolute risk difference at this time is p minus exp[hazard ratio x logep ] . among younger women who had prior chemotherapy
, the hazard ratio for goserelin treatment ( compared with those not given goserelin ) in relation to breast cancer mortality was 0.66 ( 95% ci 0.44 to 0.98 ) , and this reduction in risk did not seem to depend on whether they took tamoxifen or not ( hrs 0.66 and 0.63 , respectively ) .
the corresponding hazard ratio in younger women without prior chemotherapy was 0.86 ( 95% ci 0.55 to 1.34 ) .
these observations could be partly explained by the fact that younger women derive greater benefits from adjuvant chemotherapy . among older women who had prior chemotherapy , the hr was 0.87 ( 95% ci 0.68 to 1.13 ) ,
although the effect might be greater when they also took tamoxifen ( hrs of 0.80 and 0.93 , with and without tamoxifen , respectively ) . among older women who did not have prior chemotherapy ,
the effect of goserelin depended on whether they took tamoxifen ( hr for the effect of goserelin for older women who did or did not receive tamoxifen was 1.06 [ 95% ci = 0.75 to 1.52 ] and 0.60 [ 95% ci = 0.39 to 0.93 ] , respectively )
. we investigated interactions between goserelin and four prognostic factors ( supplementary table 4 , available online ) .
the effect of goserelin was greatest among women who were node negative , those with er - positive tumors , and those who had received no prior chemotherapy ( although age and tamoxifen use influenced this ) .
similar to other studies , a benefit of goserelin in women with er - positive tumors was observed , whether they took tamoxifen or not .
it is possible that the interaction between goserelin and nodal status might have been influenced by prior chemotherapy because women with node - positive tumors were more likely to receive chemotherapy .
however , when patients were stratified by nodal status and prior chemotherapy , there was still a tendency for the effect of goserelin to be greater among node - negative women , although those who were node positive who had prior chemotherapy did not appear to benefit from goserelin ( supplementary table 5 , available online ) .
to our knowledge , the zipp trial is the largest that has investigated an lhrh agonist ( 2706 women ) and the only factorial study that has evaluated goserelin and tamoxifen simultaneously with a control group of women who received no endocrine therapy .
recurrence and breast cancer mortality rates in both the tamoxifen and control arms were similar to those from the ebctcg overview ( 3 ) .
the overview of lhrh agonists ( 4 ) , based on an average follow - up of 6.8 years , reported data on recurrence , death from any cause , and death after recurrence .
the main conclusions were that lhrh agonists had an effect on reducing the risk of these events similar to that for chemotherapy ( such as fec or cmf ) , and could be used as an effective treatment in women with er - positive tumors , either alone or in combination with chemotherapy or tamoxifen .
furthermore , there seemed to be a particular benefit among younger women ( < 40 years ) who had received chemotherapy .
although our earlier data were included in the overview ( 4 ) , our results from the long - term follow - up ( average follow - up is 12 years ) add further information on the effect of lhrh agonists and allow estimates of the absolute risk difference at 10 and 15 years after the start of treatment .
in addition to information on recurrence and death from any cause , we analyzed the effect of goserelin on the chance of dying from breast cancer and the chance of having any event ( recurrence , new tumor , or death ) .
our analysis also quantified the long - term effect of goserelin separately among women who did or did not have tamoxifen . because tamoxifen is now offered routinely to many women , it is important to know what the additional benefit of goserelin is 10 and 15 years after the initiation of treatment . among women who did not receive tamoxifen ,
goserelin was associated with large reductions in the event rate , the chance of dying from any cause or from breast cancer , and the risk of having a recurrence ; the effect remained substantial 15 years later .
although the effect of goserelin was smaller ( and not statistically significant ) among women who took tamoxifen , a difference in risk of 23 percentage points in absolute risk at 15 years might be important , given the high incidence of early breast cancer
. this would correspond to treating 3350 women with tamoxifen and goserelin to avoid one woman having a recurrence , new tumor , or death .
indeed , the number needed to treat at 15 years was 18 in women younger than 40 years who also took tamoxifen ( table 3 ) .
the effect of goserelin was greatest in women who were node negative and in those with er - positive tumors .
our results were also consistent with the observation that the effect of goserelin may be greater in younger women who had prior chemotherapy ( 4 ) .
a limitation of our trial is that it was based on 2 years of tamoxifen treatment , like many other studies at the time , though it is now standard practice to treat women for 5 years .
data from the int 0101 trial , in which all women received chemotherapy , showed that the combination of 5 years of goserelin and tamoxifen was associated with a 9-year disease - free rate that was 9 and 7 percentage points higher among younger ( < 40 years ) and older ( 40 ) women , respectively , compared with those treated with goserelin alone ( 9 ) .
furthermore , there is evidence that a large proportion of women discontinue tamoxifen before 5 years . in a cohort of 2816 women in ireland , 20%
therefore , the effect of 2 years of goserelin or tamoxifen therapy might still be relevant in these women .
data on the tolerability of goserelin were presented in our first report ( 5 ) .
the most common side effect was hot flashes : this was experienced by none of the control patients , 26% of patients treated with goserelin , 17% of those treated with tamoxifen , and 44% of those who received goserelin plus tamoxifen . in a trial of 874 women with lymph node  negative breast cancer randomly assigned to receive six courses of cmf chemotherapy , goserelin for 2 years , or cmf followed by 18 months of goserelin , a greater proportion of women who received goserelin alone had hot flashes compared with those treated with cmf alone ( 11 ) .
however , in the goserelin group , the incidence 3 years later was similar to that in baseline , but not in those who received cmf .
this effect is expected , given that amenorrhea can be induced by either chemotherapy or goserelin , but is reversible after stopping goserelin but permanent after chemotherapy .
goserelin was also associated with an improvement in quality - of - life measures such as mood , coping effort , tiredness , nausea and/or vomiting , and overall subjective assessment of health , compared with cmf alone ( 11 ) .
treatment - induced bone loss is a side effect of ovarian ablation or aromatase inhibitor therapy , which increases the risk of fractures or spinal cord compression ( 12 ) . in a subgroup of patients randomly assigned to receive goserelin ( n = 53 ) for 2 years or cmf chemotherapy for 6 months ( n = 43 ) , loss of bone mineral density ( bmd ) was greater in the goserelin group ( 13 ) .
although there was partial recovery 1 year after stopping goserelin , the bone loss in the cmf group persisted .
although the combination of goserelin and tamoxifen may have a small additional benefit compared with either alone , there may be a further case for recommending both therapies because of the possible mitigating effect of tamoxifen on bmd .
markers of bone health were not measured in all women in the zipp trial , but the effects of 2 years of treatment with goserelin and tamoxifen on bmd were examined in a subgroup ( n = 89 ) of patients in the stockholm group ( 14 ) .
the reduction in bmd was 5% in the patients treated with goserelin ( with partial recovery 1 year after stopping therapy ) and 1.4% in the patients treated with tamoxifen and goserelin .
there is accumulating evidence that zoledronic acid combined with endocrine therapy can also help prevent bmd loss . in a trial of 401 patients treated with goserelin
, women were randomly assigned to receive 3 years of either tamoxifen or anastrazole , each with or without zoledronic acid ( 15 ) .
there were reductions in lumbar spine and trochanter bmd when tamoxifen or anastrazole was used alone , but no material reduction when zoledronic acid was added .
a combined interim analysis of two recent randomized trials , z - fast and zo - fast ( total from both trials , n = 1667 ) , in which all women received adjuvant letrozole , compared giving zoledronic acid either at the time of random assignment or only if their bone density fell below a prespecified cutoff or they suffered a nontraumatic fracture ( 16 ) .
after 1 year , the score for lumbar spine bmd was 5.2% higher in the patients given zoledronic acid at the time of random assignment , and the total hip score was 3.5% higher .
the effect of zoledronic acid on survival and recurrence has been confirmed in a large trial of 1801 premenopausal women randomly assigned to receive endocrine therapy ( tamoxifen or anastrozole ) , with or without zoledronic acid , with all women receiving goserelin ( 17 ) .
the risk of death or recurrence was reduced by 35% ( 95% ci = 8% to 54% ) among women who were given zoledronic acid . given its benefits in terms of both bone health and clinical outcome , zoledronic acid could be considered as an additional treatment to goserelin .
the optimal frequency and duration of treatment with lhrh agonists are unknown . in the zipp trial ,
evidence from a randomized trial of 599 women with node - positive breast cancer indicated that a less frequent schedule ( 3-monthly depot of the lhrh agonist leuprorelin acetate , 11.25 mg ) may be as beneficial as cmf chemotherapy in terms of the effect5-year recurrence - free survival ( hr 0.97 ) and after 2 years os was better in patients given leuprorelin acetate ( hr 0.64 , 95% ci 0.46 to 0.90 ) ( 18 ) . nevertheless , no trial has specifically addressed the question of the optimal frequency and duration of goserelin treatment . in summary ,
long - term follow - up of our large trial showed that goserelin had a demonstrable effect on survival and recurrence 15 years after starting treatment and is as effective as tamoxifen when each are given for 2 years .
the benefit was greatest among women who did not receive tamoxifen ( among every 100 women treated with goserelin , there could be 8.5 fewer breast cancer deaths ) , and there was a possible gain in those who did receive tamoxifen ( among every 100 women treated with goserelin , there could be 2.6 fewer breast cancer deaths )
. it may be that women who are unlikely to complete 5 years of tamoxifen tablets may prefer 2 years of goserelin injections .
it may also be reasonable to recommend both therapies to minimize the reduction in bmd associated with endocrine treatment .
free drug was supplied by ici ( now astrazeneca ) ( givio ) for the uk and gruppo interdisciplinare valutazione interventi in oncologia trials .
the uk trial was supported by a grant from cancer research uk ( formerly cancer research campaign ) . in italy ,
the coordination of the trial was supported by an educational grant from astrazeneca ( the manufacturer of goserelin ) .
the stockholm trial had received funding from the king gustaf v jubilee fund and an unrestricted research grant from astrazeneca . in 2007 , astrazeneca provided a grant to collect and collate the long - term follow - up data from the four study groups , and the statistical analysis was performed in the cancer research uk & ucl cancer trials centre .
( grant number 45034 ) m. baum has been a principal investigator for other trials sponsored by astrazeneca and spoken at events funded by the company .
astrazeneca was not involved in either the analysis or the writing of the paper , or the decision to publish .
 backgroundsystematic reviews have found that luteinizing hormone  releasing hormone ( lhrh ) agonists are effective in treating premenopausal women with early breast cancer.methodswe conducted long - term follow - up ( median 12 years ) of 2706 women in the zoladex in premenopausal patients ( zipp ) , which evaluated the lhrh agonist goserelin ( 3.6 mg injection every 4 weeks ) and tamoxifen ( 20 or 40 mg daily ) , given for 2 years . 
 women were randomly assigned to receive each therapy alone , both , or neither , after primary therapy ( surgery with or without radiotherapy / chemotherapy ) . 
 hazard ratios and absolute risk differences were used to assess the effect of goserelin treatment on event - free survival ( breast cancer recurrence , new tumor or death ) , overall survival , risk of recurrence of breast cancer , and risk of dying from breast cancer , in the presence or absence of tamoxifen.resultsfifteen years after the initiation of treatment , for every 100 women not given tamoxifen , there were 13.9 ( 95% confidence interval [ ci ] = 17.5 to 19.4 ) fewer events among those who were treated with goserelin compared with those who were not treated with goserelin . however , among women who did take tamoxifen , there were 2.8 fewer events ( 95% ci =  7.7 fewer to 2.0 more ) per 100 women treated with goserelin compared with those not treated with goserelin . 
 the risk of dying from breast cancer was also reduced at 15 years : for every 100 women given goserelin , the number of breast cancer deaths was lower by 2.6 ( 95% ci = 6.6 fewer to 2.1 more ) and 8.5 ( 95% ci = 2.2 to 13.7 ) in those who did and did not take tamoxifen , respectively , although in the former group the difference was not statistically significant.conclusionstwo years of goserelin treatment was as effective as 2 years of tamoxifen treatment 15 years after starting therapy . in women who did not take tamoxifen , there was a large benefit of goserelin treatment on survival and recurrence , and in women who did take tamoxifen , there was a marginal potential benefit on these outcomes when goserelin was added . 
Context and Caveats
Prior knowledge
Study design
Contribution
Implications
Limitations
Methods
Trial Design and Subsequent Modifications
Outcomes
Statistical Analysis
Results
Discussion
Funding
Supplementary Material