The Breast 19 (2010) 7683

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The Breast
journal homepage: www.elsevier.com/brst

Review

Aromatase inhibitors versus tamoxifen as adjuvant hormonal therapy for oestrogen sensitive early breast cancer in post-menopausal women: Meta-analyses of monotherapy, sequenced therapy and extended therapy
Mette L. Josefsson*, Samuel J. Leinster
School of Medicine, Health Policy and Practice, University of East Anglia, Norwich NR4 7TJ, United Kingdom

a r t i c l e i n f o
Article history: Received 10 June 2009 Received in revised form 21 December 2009 Accepted 22 December 2009 Keywords: Adjuvant hormonal therapy Tamoxifen Aromatase inhibitor Breast cancer

a b s t r a c t
Adjuvant tamoxifen reduces relapses and prolongs survival in patients with oestrogen sensitive breast cancer. Development of resistance is however common. Tamoxifen can be given for a maximum of ve years; although the risk of recurrences remains high after this period. This review examines nine randomised controlled trials including 28 632 women, which studied aromatase inhibitors (AIs) as an alternative to tamoxifen in three treatment settings: monotherapy (instead of tamoxifen), sequenced therapy (tamoxifen is switched to an AI) and extended therapy (following adjuvant tamoxifen). Disease free survival was signicantly improved for monotherapy (HR 0.89, [95% CI 0.830.96] p 0.002) and sequenced therapy (HR 0.72, [0.630.83] p < 0.00001). There was no difference in overall survival for monotherapy (HR 0.94, [0.821.08] p 0.39) or extended therapy (HR 0.86 [0.791.16] p 0.67). Importantly, overall survival was prolonged for patients who switched from tamoxifen to AI therapy (HR 0.78 95%CI 0.680.91, p 0.001). 2009 Elsevier Ltd. All rights reserved.

Introduction Early breast cancer is dened as invasive cancer that has not spread beyond the breast or the axillary lymph nodes.1 It is thus potentially curable, as the tumour and any nodal metastases can be removed surgically. However, micro-metastasis may remain undetected and can cause relapse and death several years after the initial operation. Randomised controlled trials have shown that adjuvant hormonal therapy effectively reduces the risk of recurrences if the tumour is sensitive to oestrogen, which is the case in 75%.2 With a rise in the incidence of breast malignancy and more women being diagnosed at an early stage, adjuvant hormonal therapy is becoming increasingly important in the management of breast cancer.13 Tamoxifen (Nolvadex), the gold standard, is a selective oestrogen receptor modulator that prevents cell proliferation by acting as a competitive antagonist to oestrogen within breast tissue.4 Five years of tamoxifen has been shown to effectively prolong disease free survival (47% disease reduction), and prevent death (26% mortality reduction) and contra-lateral breast cancer (47%

* Corresponding author. Fax: 44 (0)1603 593752. E-mail addresses: m.josefsson@doctors.org.uk (M.L. Josefsson), s.leinster@uea. ac.uk (S.J. Leinster). 0960-9776/$ see front matter 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2009.12.010

reduction).4 Protective properties against osteopenia and hypercholesterolaemia have been shown.5,6 However, serious side effects include endometrial cancer and thromboembolic events.6,7 Development of resistance is also common.8 Tamoxifen is not effective for more than ve years, although the risk of recurrence remains high beyond this period and more than two thirds of all deaths occur after completed therapy.811 Low rates of compliance have been reported with no more than one third of patients adhering to ve years of treatment.12 Aromatase inhibitors (AIs) have been brought forward as a potential alternative. They act by preventing the enzyme aromatase to convert androgens into oestrogen, a process that produces most of the hormone in post-menopausal females. There are two types; nonsteroidal and steroidal. Nonsteroidal AIs bind reversibly and noncovalently to the aromatase enzyme, while steroidal AIs bind irreversibly and covalently.13 The clinical implications of these differences remain unknown.13 AIs have been shown to cause less gynaecological and menopausal symptoms compared with tamoxifen, while fractures and hypercholesterolaemia have been reported more frequently.14,15 Randomised controlled trials (RCTs) have studied AIs in three treatment settings; monotherapy (instead of tamoxifen), sequenced therapy (tamoxifen is switched to AI, or vice versa) and extended therapy (AI beyond ve years of tamoxifen). The results have shown AI to be at least as effective as tamoxifen in prolonging disease free survival;

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however they have not been able to demonstrate an impact on overall survival.1620 A meta-analysis by Jonat and Gnant included three trials that compared sequenced therapy with anastrozole following two to three years of tamoxifen, versus tamoxifen on its own.21 Disease free survival was signicantly prolonged in favour of sequenced therapy (HR 0.59 [95% CI 0.480.78] p < 0.0001). There was evidence of prolonged overall survival (HR 0.71, [0.520.98] p 0.0377). Their methodology had some limitations; no more than two databases were searched (PubMedandClinicalTrials.gov) and no discussion of potential conict of interest despite funding from the pharmaceutical industry. The addition of new studies such as BIG 1-98 trial and ABCSG 8, and updates of previous trials, such as the IE study, adds to the call for a new review that includes the three types of AIs.16,18,22 This review will not only look at the role of AIs as sequenced therapy, but also as monotherapy and extended therapy. Patient groups have highlighted the importance of quality of life (QoL) in the choice of hormonal therapy.1 RCTs on QoL were therefore actively sought. The results from the RCTs have led to changes in the British and American guidelines, which now recommend clinicians to consider AIs in specic patients.1,23 However, many questions still remain on the optimal therapy regime. A review that studies all three treatments regimes and includes quality of life as an outcome measure is needed to provide clinicians and patients with more information when choosing adjuvant therapy. The aim was therefore to systematically review all currently available evidence from randomised controlled trials on the optimal hormonal adjuvant therapy regime for post-menopausal women with oestrogen sensitive early breast cancer. Materials and methods

investigator reviewed each title to identify clearly irrelevant studies. A pre-specied Inclusion/Exclusion form was used to identify eligible studies. The inclusion requirements were the following: RCT, female subjects, oestrogen sensitive tumours, conrmed post-menopausal status and early stage cancer. The full text was obtained if a paper could not be rejected by evaluation of the title or abstract alone. The computer software EndNote was used to manage references. Any duplicates were excluded by comparing authors, location, participants and dates. The latest report was used in case trials had been reported more than once. Quality assessment Internal validity was assessed by using a risk of biases table in the data extraction form. The questions were adopted from The Cochrane Collaborations tool for assessing risk of the following biases; selection, performance, detection, reporting and attrition.24 Data extraction Data extraction was carried out by MLJ using a standardised data extraction form, and validated by the second reviewer SJL. The data extraction form was piloted on a few studies and revised accordingly. Data from multiple papers of the same trial was recorded on a single data extraction sheet. Details of study design, risk of bias assessment, participants, and data on outcomes was collected. The author was contacted in case of missing information. No outcome was obtained by reading curves. Denitions of post-menopausal status were included as arbitrary use between trials has been reported.25 Data analysis

Study selection All RCTs that compare the following treatment regimes; direct comparison between tamoxifen versus an AI, sequenced therapy, and extended therapy (AI versus placebo or no treatment following adjuvant treatment), was searched for. Any types of AIs in standard dosages were accepted. Participants had to be post-menopausal and have undergone surgery for oestrogen sensitive early breast cancer. Outcomes Results The primary outcome measures were overall survival (OS) (including death from any cause), disease free survival (DFS) (dened as time to recurrence at any site, contra-lateral breast cancer or death from any cause) and QoL. Trials containing data on at least one of the primary outcomes were included. Secondary outcomes were event-free survival (dened as time to recurrence at any site), distant-recurrence-free survival, number of drop-outs, adverse events and other outcomes, which were not pre-specied but were considered important in the trial. Search methods The databases Cochrane Central Register of Controlled Trials (CENTER), MEDLINE(R) and EMBASE (via OVID), in addition to reference and abstract lists, were searched in February 2009. No language restrictions were used. The Clinical Trial Register (http:// www.clinicaltrial.gov) was searched to identify additional unpublished trials. The following free text search terms were used; breast cancer, breast neoplasm, breast carcinoma, breast tumour, breast tumor, tamoxifen, nolvadex, aromatase inhibitor, anastrozole, arimidex, letrozole, exemestane, aromasin and femara. MeSH terms included aromatase inhibitors, tamoxifen and breast neoplasm. The Description of included studies Our search identied 836 references (see Fig. 1), of which 677 could be excluded from screening the title alone or because they were duplicates. The abstracts, or the paper if required, of 159 potential RCTs were evaluated further. 132 were excluded because they did not full the requirements in the inclusion/exclusion form. Meta-analyses were undertaken in the Review Manager Software (version 5.0) and based on the intention-to-treat principle. Hazard ratios for survival outcomes, and relative risks for adverse events, were calculated with 95% condence interval for each subgroup. The random effect model was used in the meta-analyses to take into account the variability that exists between patients. Heterogeneity was assessed with the MantelHaentszel Chi-square test and I2 test. All p-values are two-sided.

Fig. 1. Flow chart of the process of inclusion of trials for review.

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Two ongoing studies (TEAM and NSABP B-42) were excluded prior to the analysis as no data was yet available.26,27 The ABCSG trial 6 was excluded as it studied aminoglutethimide in combination with tamoxifen.28 The Italian co-operative trial, which explored aminoglutethimide as sequenced therapy, failed to recruit the planned number of participants and was excluded due to lack of outcome data.29 Nine trials of 28 632 patients in total were included in this review. See Table 1 for trial characteristics. The included trials are divided into three subgroups depending on their treatment regime; monotherapy (AI vs. tamoxifen), sequenced therapy (tamoxifen switched to an AI vs. tamoxifen on its own) and extended therapy (extended AI treatment following adjuvant therapy for 5 years vs. placebo or no treatment). Two studies, ATAC (ISRCTN18233230) and BIG 1-98 (NCT00004205), report data on AI as monotherapy.18,3038 BIG 1-98 consisted of four arms (letrozole monotherapy, tamoxifen monotherapy, sequential tamoxifen followed by letrozole, and sequential letrozole followed by tamoxifen). Results from the monotherapy subgroup only are included in this review, as the sequential arms are compared with letrozole, rather than tamoxifen.38 Four trials were identied for sequenced therapy; ABCSG trial 8 (NCT00291759), ARNO-95 (NCT00287534), IE study (ISRCTN11883920) and ITA (NCT00286117).16,22,39-42 Three RCTs on extended therapy were identied; MA.17 (NCT00003140), NSABP B-33 and ABCSG trial 6a (NCT00300508).20,43-45 Four studies included QoL as outcome measures (NSABP B-33, and substudies of the ATAC trial, the IE study and MA.17).45,46-48 The latest reports on adverse events in the included trials were used for the safety analyses. Methodological quality The following studies were assessed as of high quality; the ATAC trial, BIG 1-98, IE study and MA.17. ABCSG 6a, ARNO-95 and ITA were open-labelled and of weaker methodological quality. NSABP B-33 was transformed from a blinded trial into an open-labelled study when it was stopped prematurely. The methodological quality of the ABCSG 8 could not be assessed, as it is yet unpublished. Monotherapy The ATAC trial compared anastrozole and tamoxifen for ve years and the results after 100 months are included in this review.

They initially included a trial arm of combined anastrozole and tamoxifen, which was stopped prematurely as no efcacy benet could be demonstrated. The BIG 1-98 trial compared letrozole and tamoxifen for ve years. Pooled data from the two trials demonstrated a statistical signicant benet in DFS in favour of AI treatment for ve years compared with tamoxifen (HR 0.89, [0.830.96] p 0.002) (see Fig. 2). No difference was seen in overall survival (HR 0.94, [0.821.08] p 0.39) (see Fig. 3). Sequenced therapy The IE Study compared sequenced therapy with tamoxifen followed by exemestane for ve years in total, versus tamoxifen on its own. There was a high number of drop-outs in both intervention and control groups (1012/2372 and 1026/2352 respectively). The ITA study and ARNO-95 both examined sequenced therapy with tamoxifen followed by anastrozole compared with tamoxifen alone for ve years. When their data on DFS was pooled together there was a statistical signicant benet seen in patients on sequenced therapy (HR 0.72, [0.630.83] p < 0.00001) (see Fig. 2). Sequenced therapy with tamoxifen and anastrozole was also studied in ABCSG trial 8. Their data is not yet published; however it was presented at the San Antonio conference in December 2008. Relapse free survival (RFS) is their main outcome, which is different to DFS in that it does not include death. Their unpublished data suggest a benet in RFS for sequenced therapy (HR 0.79, [0.650.95] p 0.038). Meta-analysis of OS for the three published trials showed a weak statistically signicant benet in favour of the switching regime (HR 0.72 [0.521.00] p 0.05) (gure provided in online material). A statistically more robust result (HR for OS 0.78, [0.680.91] p 0.001), in favour of sequenced therapy, could be seen when data from ABCSG 8 was included in the meta-analysis (see Fig. 3). Extended therapy The trial ABCSG 6a, continuing on from ABCSG 6, compared anastrozole versus no further treatment, following ve years of adjuvant therapy. There was a large number of drop-outs in both intervention and control groups (128/386 and 109/466 respectively). Their main outcome was RFS, similarly to ABCSG 8. Patients

Table 1 Characteristics of included studies. Yrs years, ATAC Arimidex, Tamoxifen, Alone or in Combination, BIG 1-98 The Breast International Group 1-98, ABCSG 8 Austrian Breast and Colorectal Cancer Study Group trial 8. ARNO-95 Arimidex-Nolvadex trial 95, ITA Italian tamoxifen anastrozole trial, IE study Intergroup Exemestane Study, ABCSG 6a Austrian Breast and Colorectal Cancer Study Group trial 6a, NSABP B-33 National Surgical Adjuvant Breast and Bowel Project B-33 Trial. Intervention regime Monotherapy ATAC BIG 1-98 Total Control Follow-up (months) 100 76 Study sample 6241 4922 11163 3714 979 4724 448 9865 852 5170 1582 7604 Age Node-positive Node-negative

Anastrozole 5 yrs Letrozole 5 yrs

Tamoxifen 5 yrs Tamoxifen 5 yrs

64.1 61

34.0% 57.3%

50.0% 41.3%

Sequenced therapy ABCSG 8 Tamoxifen 2 yrs/anastrozole 3 yrs ARNO-95 IE Study ITA Total Tamoxifen 2 yrs/anastrozole 3 yrs Tamoxifen 23 yrs /exemestane 23 yrs Tamoxifen 23 yrs/anastrozole 23 yrs

Tamoxifen 5 yrs TamoxIfen 5 yrs Tamoxifen 5 yrs Tamoxifen 5 yrs

72 30.1 55.7 64

33.5% < 60 66.5%  60 60.7 60.3 63

25.4% 26.5% 44.2% >99%

74.6% 73.5% 51.8% <1%

Extended therapy ABCSG 6a Anastrozole following 5 yrs of adjuvant therapy MA.17 Letrozole following 5 yrs of tamoxifen NSABP B-33 Exemestane following 5 yrs of tamoxifen Total

No treatment Placebo Placebo

62.3 64 30

68.2 62.2 49% < 60, 51%  60

32.5% 32.5% 48%

64% 50% 52%

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Hazard Ratio Study or Subgroup 1.1.1 Monotherapy BIG 1-98 ATAC Subtotal (95% CI) -0.1278 0.0589 -0.1054 0.0477 47.4% 52.6% 100.0% 0.88 [0.78, 0.99] 0.90 [0.82, 0.99] 0.89 [0.83, 0.96] log[Hazard Ratio] SE Weight IV, Random, 95% CI

Hazard Ratio IV, Random, 95% CI

Heterogeneity: Tau = 0.00; Chi = 0.09, df = 1 (P = 0.77); I = 0% Test for overall effect: Z = 3.08 (P = 0.002) 1.1.2 Sequenced therapy ITA ARNO-95 IE study Subtotal (95% CI) -0.5621 0.1998 -0.4155 0.2078 -0.2744 0.0733 18.6% 17.4% 64.0% 100.0% 0.57 [0.39, 0.84] 0.66 [0.44, 0.99] 0.76 [0.66, 0.88] 0.72 [0.63, 0.83]

Heterogeneity: Tau = 0.00; Chi = 2.07, df = 2 (P = 0.36); I = 3% Test for overall effect: Z = 4.68 (P < 0.00001)

0.2 0.5 1 2 Favours experimental Favours control

Fig. 2. Forest plot of Disease Free Survival (DFS). SE standard error, CI condence interval.

on extended therapy were seen to survive longer without any locoregional recurrences, contra-lateral breast cancer or distant metastasis (HR 0.62 [0.400.96] p 0.31). No data on DFS was reported. The MA.17 trial compared letrozole versus placebo as extended therapy. Their ndings suggested a benet in DFS for extended letrozole therapy (HR 0.68, [0.550.83] p 0.0001). Meta-analysis of data from MA.17 and ABCSG 6a showed no difference in OS between extended therapy and placebo or no treatment (HR 0.85 [0.651.11] p 0.24) (see Fig. 3). The placebo-

controlled trial NSABP B-33 studied exemestane as extended therapy. It was stopped early due to efciency benets seen in MA.17. Patients were unblinded and the control group was permitted to switch to exemestane. The results, based on the ITT population prior to unblinding, did not demonstrate any statistically signicant improvement in four-year DFS (HR 0.68, p 0.07, 95%CI not stated). Conclusions on OS could not be drawn because of too few deaths, and their results are therefore not included in the meta-analysis.

Study or Subgroup 2.1.1 Monotherapy BIG 1-98 ATAC Subtotal (95% CI)

log[Hazard Ratio]

SE Weight 43.3% 56.7% 100.0%

Hazard Ratio IV, Random, 95% CI 0.87 [0.74, 1.02] 1.00 [0.89, 1.12] 0.94 [0.82, 1.08]

Hazard Ratio IV, Random, 95% CI

-0.1393 0.0795 0 0.0567

Heterogeneity: Tau = 0.00; Chi = 2.04, df = 1 (P = 0.15); I = 51% Test for overall effect: Z = 0.85 (P = 0.39) 2.1.2 Sequenced therapy ARNO-95 ITA ABSCG trial 8 IE study Subtotal (95% CI) -0.6349 -0.5798 -0.2614 -0.1625 0.3124 0.3598 0.1155 0.0912 7.2% 5.5% 37.4% 49.8% 100.0% 0.53 [0.29, 0.98] 0.56 [0.28, 1.13] 0.77 [0.61, 0.97] 0.85 [0.71, 1.02] 0.78 [0.68, 0.91]

Heterogeneity: Tau = 0.00; Chi = 3.24, df = 3 (P = 0.36); I = 7% Test for overall effect: Z = 3.25 (P = 0.001) 2.1.3 Extended therapy MA.17 ABCSG trial 6a Subtotal (95% CI) -0.1985 0.1862 -0.1165 0.2046 54.0% 46.0% 100.0% 0.82 [0.57, 1.18] 0.89 [0.60, 1.33] 0.85 [0.65, 1.11]

Heterogeneity: Tau = 0.00; Chi = 0.09, df = 1 (P = 0.77); I = 0% Test for overall effect: Z = 1.17 (P = 0.24) 0.2 0.5 1 2 Favours experimental Favours control
Fig. 3. Forest plot of Overall Survival (OS). SE standard error, CI condence interval.

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Subset analyses of nodal status Attempts were made to undertake subset meta-analyses of node-negative and node-positive patients; however few trials reported data on OS (BIG 1-98 and MA.17) or DFS (BIG 1-98, IE study, MA.17 and NSABP B-33). OS benet for node-positive patients was initially seen in MA.17, although no difference was demonstrated in the follow-up (node ve HR 0.84 [95% CI 0.631.12]).43 No difference in OS was seen in BIG 1-98 (node ve HR 0.82 [0.681.00] vs. node-ve HR 0.91 [0.701.18]). DFS benet for node-positive patients, but not for node-negative were reported in BIG 1-98 (node ve HR 0.83 [0.710.98] vs. node-ve HR 0.89 [0.741.08]), and NSABP B-33 (HR 0.50 [0.290.85] vs. HR 1.13 [0.622.07]). The result from NSABP B-33 should be viewed with some caution because of its study design. DFS benets were seen for both subgroups in the IE study (HR 0.74, [0.590.94], vs. HR 0.72 [0.610.86]), and in MA.17 (HR 0.45 [0.280.72] vs. HR 0.60 [0.440.82]). ATAC and ABCSG 6a used time to recurrence (excluding death) instead of DFS (ATAC HR 0.84 [0.711.00] vs. HR 0.68 [0.510.81], and ABCSG 6a HR 0.61 [0.341.09] vs. HR 0.61 [0.321.16]). Safety analyses Meta-analyses were performed for skeletal, endometrial and cardiovascular adverse events where data was available (see Fig. 4). Signicant differences in fracture risks in favour of tamoxifen were seen in the monotherapy (RR 1.43 [1.261.62] p < 0.0001), and sequenced therapy subgroup (RR 1.36 [1.051.76] p 0.02), whereas no difference was observed between AIs and placebo in the extended setting (RR 1.17 [0.941.46] p 0.15). The risk of endometrial cancer was lower for AIs, compared with tamoxifen (RR 0.34 [0.160.71] p 0.005). The risk was similar between sequenced therapy and tamoxifen (RR 0.45 [0.151.37] p 0.16.), although there was a signicant difference in risk of endometrial hyperplasia (RR 0.14 [0.040.51] p 0.003). No differences were seen for cardiovascular disease (RR for monotherapy 1.13 [0.961.33] p 0.14; RR for sequenced therapy 1.16 [0.921.46] p 0.21, and RR for extended therapy 1.50 [0.415.49] p 0.54). However, a lower risk of thromboembolic events was observed for AIs compared with tamoxifen (RR 0.53 [0.370.74] p 0.0003). Meta-analyses on additional adverse events (i.e. lipids alterations and osteoporosis) could not be performed because of lack of data and varying denitions being used between trials. Quality of life impact No clinically important differences in overall QoL between the intervention and the control were seen in any of the four QoL substudies to the ATAC trial, IE study, MA.17 and NSABP B-33. Not enough data was available to perform meta-analyses; however the differences in median changes between intervention and control are presented in Table 2, together with study characteristics. Three questionnaires were used; the Functional Assessment of Cancer Therapy Breast (FACT-B) (ATAC and IE study), 36-Item Short Form Health Survey (SF-36) (MA.17) and Menopause-specic QoL questionnaire (MENQOL) (NSABP B-33 and MA.17). The number of dropouts increased with time in all trials, the response rate was for example 54.6% at 24 months in MA.17. However, ATAC and IE study reported that 83% and 85.3% respectively, of their questionnaires had been completed. Both intervention and control groups in the ATAC substudy reported a median increase in QoL of 2.9 points over 60 months. A small difference in favour of tamoxifen was seen in the IE study during the trial period of 24 months (0.89 [0.221.99]). A change in ve points is considered clinically important and thus the difference was not signicant. The SF-36 scores of patients

Fig. 4. Forest plot of adverse events. SE standard error, CI condence interval.

receiving letrozole and placebo were similar over 36 months in MA.17. No signicant differences were seen in any of the four MENQOL domains (vasomotor, psychosocial, physical and sexual) in NSABP B-33, while a worsening in QoL related to vasomotor symptoms were reported in MA.17 (p < 0.001) but not in any of the other domains. Results from the MENQOL questionnaire were not included in the table as not enough information was available.

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Table 2 Characteristics of included Quality of Life studies and differences in median scores between intervention and control at 12, 24 and 36 months. ATAC HRQoL Arimidex, Tamoxifen, Alone or in Combination Health Related Quality of Life, IE study QoL Intergroup Exemestane Study Quality of Life, NSABP B-33 National Surgical Adjuvant Breast and Bowel Project B-33 Trial, FACT-B Functional Assessment of Cancer Therapy Breast, SF-36 36-Item Short Form Health Survey, MENQOL Menopause-specic QoL questionnaire, yrs years. Intervention regime Control Study sample 682 582 3612 454 Health questionnaire FACT-B FACT-B SF-36 MENQOL Vasomotor Psychosocial Physical Sexual Median score difference (intervention control) 12 months 1.7 0.3 0.0 24 months 0.4 1.05 0.0 36 months 0.4 No data 0.05

ATAC HRQoL Subscale IE Study QoL Substudy MA.17 QoL Substudy NSABP B-33

Anastrozole Tamoxifen /exemestane Letrozole following 5 yrs of adjuvant therapy Exemestane following 5 yrs of tamoxifen

Tamoxifen TamoxiFen Placebo Placebo

0.25 0.1 0.25 0.1

0.3 0.55 0.4 0.4

No data

Total

5330

Discussion We report efciency benets seen in treatment regimes that contain aromatase inhibitors. Evidence from all three subgroups showed that treatment regimes that include an aromatase inhibitor prolong disease free survival. The biggest effect was seen for sequenced therapy (HR 0.72 [95% CI 0.630.83] p < 0.00001). This is in accordance with the meta-analysis of sequenced therapy by Jonat and Gnant (HR for DFS 0.59 [0.480.78] p < 0.0001).21 Ingle et al. have presented data from their yet unpublished meta-analyses of monotherapy and sequenced therapy.49 Their results show reduced rates of breast cancer recurrences in patients on AI therapy, both in the monotherapy cohort (absolute reduction 2.7%, standard error [SE] 0.7) and in the sequenced therapy cohort (absolute reduction 3.5%, SE 1.1). So far no study, which we are aware of, has been able to demonstrate a long-term benet in overall survival in the monotherapy and extended therapy setting. An explanation might be that second line treatment can be added to the management of patients in the control group when the cancer recurs, which is not an alternative to patients in the intervention group. Jonat and Gnant found some evidence for prolonged OS in favour of sequenced therapy (HR 0.71 [0.520.98] p 0.0377). Our meta-analysis provides stronger statistical evidence (HR for sequenced therapy: 0.78 [0.680.91] p 0.001). The result should be viewed with some caution as the analysis includes unpublished data from the ABCSG trial 8. This review does not provide information on the efciency of sequenced therapy compared with AI monotherapy. The ndings from the sequential arms of BIG 1-98 showed no differences in DFS or OS compared with letrozole on its own (tamoxifen / letrozole: DFS HR 1.05 [99%CI 0.841.32], OS HR 1.13 [0.831.53], and letrozole / tamoxifen: DFS HR 0.96 [0.761.21], OS HR 0.90 [0.841.32]).38 Further research that directly compares sequenced therapy and AI monotherapy are needed. The reported adverse events were generally consistent with previous studies.57,14,15 The number of total events was low for some of the included trials in the meta-analyses, particularly for endometrial events. Larger studies with longer follow-up are necessary to better assess adverse events, particularly rare conditions such as endometrial cancer. Types of AIs and the presence of lymph node metastasis vary between the trials included in the meta-analyses, and could have an effect on the results. However, it is unlikely as the trials are homogeneous, which was conrmed with the Mantel-Haentszel Chi-square test and I2 test. Variability between patients was further accounted for by using the random effect model. Conicting evidence of the importance of nodal status was provided by the few trials included in this review, although the majority did not show

any difference in efciency benet between node-positive and node-negative patients. Quality of life and cost-effectiveness need to be considered, in addition to the efciency data presented here, when discussing optimal adjuvant regime. Patient groups have highlighted the signicance of QoL on the choice of treatment.1 QoL is further important as it may affect drug adherence. The QoL studies included in this review showed that although side effects varies, the QoL is overall comparable between the studied AI/sequenced therapy and tamoxifen, or placebo in the extended setting.44,4648 Further research that examines QoL as their main outcome is needed to provide patients with information to aid the decisionmaking process. Studies have shown AI therapy to be cost-effective in all three settings.5054 Sequenced therapy with tamoxifen followed by AI treatment was suggested as the most economically preferred option in a Belgian cost-utility analysis by Skedgel et al. that included data from the ATAC trial, IE study and MA.17.50 Conclusions Evidence that AIs should be included in adjuvant therapy for oestrogen sensitive early breast cancer is provided in this review, which is the rst study to include meta-analyses of three treatment regimes: monotherapy, sequenced therapy and extended therapy. Disease free survival was prolonged in all settings, with the biggest effect seen for sequenced therapy. While extended AIs had no impact on overall survival, upfront AIs were as effective as tamoxifen. Importantly, women who switched to AI treatment after two to three years of tamoxifen had prolonged overall survival compared with those who stayed on tamoxifen for ve years. We conclude that sequenced therapy appears to be the preferred treatment regime, even after its cost-effectiveness is considered. Studies that evaluate QoL are needed to provide patients and health care professionals with further information when choosing adjuvant hormonal therapy. Conict of interest statement No conict of interest declared. Acknowledgments We thank R. Jakesz and K. Thomanek for ABCSG trial 8 data, L. Hooper for methodological advice, L. Shepstone for statistical advice and J. de Boniface for translation. This work was supported by the Jean Shanks Foundation Intercalated Grant (to MLJ).

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