Cover of Evidence reviews for endocrine therapy for invasive disease

Evidence reviews for endocrine therapy for invasive disease

Early and locally advanced breast cancer: diagnosis and management

Evidence review D

NICE Guideline, No. 101

Authors

.

London: National Institute for Health and Care Excellence (NICE); .
ISBN-13: 978-1-4731-3008-1
Copyright © NICE 2018.

Endocrine therapy for invasive disease

This evidence report contains information on 3 reviews relating to endocrine therapy for invasive disease.

  • Review question 4.1 What is the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer?
  • Review question 4.2 What is the effectiveness of ovarian suppression in addition to endocrine therapy in pre-menopausal women with oestrogen-positive breast cancer?
  • Review question 10.4 What is the role of chemoprevention in women following initial treatment for ductal carcinoma in situ (DCIS)?

Review question 4.1. What is the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer?

Introduction

Treatment of women with oestrogen receptor-positive (ER-positive) early stage invasive breast cancer with adjuvant endocrine therapy for 5 years reduces recurrence rates in ER-positive breast cancer by about half and breast cancer mortality by about a third.

Tamoxifen, a selective oestrogen receptor modulator is effective in premenopausal or postmenopausal women and can therefore be used regardless of the menopausal status of the patient. Aromatase inhibitors reduce the non-ovarian production of oestrogen and can be used in postmenopausal women to greatly reduce systemic oestrogen levels and thus to avoid stimulation of ER-positive breast cancer.

Unlike most cancers, the risk of relapse for ER-positive invasive breast cancer remains significant even after completing 5 years of endocrine therapy. The aim of this review is to identify the optimal duration of endocrine therapy to minimise the risk of disease recurrence in women with ER-positive breast cancer.

PICO table

See Table 1 for a summary of the population, intervention, comparison and outcome (PICO) characteristics of this review.

Table 1. Summary of the protocol (PICO table).

Table 1

Summary of the protocol (PICO table).

For full details see review protocol in appendix A.

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual; see the methods chapter for further information.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy.

Clinical evidence

Included studies

Ten studies (number of participants, N=22,221) were included in the review (Davies, 2013; Fisher, 1996; Fisher, 2001; Goss, 2005; Jakesz, 2007; Mamounas, 2008; Muss, 2008; Stewart, 1996; Stewart, 2001; Tormey, 1996), which report data from 7 trials: Austrian Breast and Colorectal Cancer Study Group (ABCSG) 6a (number of publications, k=1), Adjuvant Tamoxifen Longer Against Shorter (ATLAS; k=1), National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 (k=2), NSABP B-33 (k=1), MA.17 trial (k=2), Scottish Adjuvant Tamoxifen Trial (k=2), and Tormey, 1996 (k=1).

Four trials compared tamoxifen taken for longer than 5 years with tamoxifen taken for 5 years only: the Scottish Adjuvant Tamoxifen Trial and Tormey (1996) compared tamoxifen to be taken indefinitely/until relapse with 5 years of adjuvant tamoxifen; the ATLAS and B-14 trials both compared 10 years of tamoxifen with 5 years of tamoxifen (with the addition of 5 years of placebo following tamoxifen in B-14).

Three trials compared tamoxifen followed by an aromatase inhibitor with tamoxifen alone: MA.17 compared 5 years of tamoxifen followed by 5 years of letrozole against 5 years of tamoxifen followed by 5 years of placebo, B-33 compared 5 years of tamoxifen followed by 5 years of exemestane with 5 years of tamoxifen followed by 5 years of placebo, and ABCSG 6a compared 5 years of tamoxifen followed by anastrozole for 3 years with 5 years of tamoxifen only.

Only one study (Jakesz, 2007) reported data for critical outcomes by any subgroups of interest; however, the only subgroup reported was individuals with grade 3 cancer. Due to significant heterogeneity and the critical nature of survival outcomes, unplanned subgroup analysis was conducted for disease-free and overall survival outcomes to investigate differences in estimated effects between those studies where tamoxifen was continued and those where individuals switched to an aromatase inhibitor.

The clinical studies included in this evidence review are summarised in Table 2 and evidence from these are summarised in the clinical GRADE evidence profile below (Table 3). See also the study selection flow chart in appendix C, forest plots in appendix E, and study evidence tables in appendix D.

Excluded studies

Studies not included in this review with reasons for their exclusions are provided in appendix K.

Summary of clinical studies included in the evidence review

Table 2. Summary of included studies.

Table 2

Summary of included studies.

See appendix D for full evidence tables.

Quality assessment of clinical studies included in the evidence review

The clinical evidence profile for this review question (duration of endocrine therapy) is presented in Table 3. The quality of evidence ranges from very low to high. Main reasons for downgrading evidence include significant heterogeneity and imprecision around the estimates due to a small number of events of interest and wide confidence intervals.

Table 3. Summary clinical evidence profile: Comparison 1. Endocrine therapy for greater than 5 years versus endocrine therapy for 5 years only.

Table 3

Summary clinical evidence profile: Comparison 1. Endocrine therapy for greater than 5 years versus endocrine therapy for 5 years only.

See appendix F for full GRADE tables.

Economic evidence

Included studies

One relevant study was identified in a literature review of published cost-effectiveness analyses on this topic; Erman 2014 (see appendix H and appendix I for summary and full evidence tables). The study considered the cost-effectiveness of extended tamoxifen or extended aromatase inhibitors in comparison to standard tamoxifen. The analysis was a cost-utility analysis measuring effectiveness in terms of quality adjusted life years (QALYs).

Excluded studies

See Supplement 1: Health economic literature search for the list of excluded studies.

Summary of studies included in the economic evidence review

The base case results of Erman 2014 showed that extended tamoxifen and extended aromatase inhibitors were both cost-effective in comparison to a standard tamoxifen regimen. Extended tamoxifen was found to be less costly and more effective than standard tamoxifen (i.e. dominant) while extended aromatase inhibitors were more effective and more costly but likely to be cost-effective with a very small ICER of $178 per QALY (CAD). Using dominance rank to determine the optimal strategy, it was found that extended aromatase inhibitors were more effective and more costly than extended tamoxifen with an ICER of $3,402 per QALY likely to be considered cost-effective.

Probabilistic sensitivity analysis showed that at a threshold of $50,000 per QALY (CAD), the probability of being cost-effective was 70% for extended aromatase inhibitors, 30% for extended tamoxifen and 0.003% for standard tamoxifen.

The analysis was deemed to be only partially applicable to the decision problem in the UK setting as it was conducted from the perspective of the Canadian health care system. Some potentially serious limitations were identified in the analysis including the absence of some potentially key input parameters from the sensitivity analysis (most notably utility weights).

Evidence statements

Comparison 1. Endocrine therapy for greater than 5 years versus endocrine therapy for 5 years only
Critical outcomes
Treatment-related morbidity
  • There is very low quality evidence from 3 RCTs (N=7157) that there is no clinically important effect of duration of endocrine therapy on hot flushes at 2 month to 4 year follow-up.
  • There is high quality evidence from 4 RCTs (N=14581) that there is no clinically important effect of duration of endocrine therapy on any secondary cancer at 5.6 to 7.6 year follow-up.
  • There is high quality evidence from 3 RCTs (N=14388) that there is no clinically important effect of duration of endocrine therapy on contralateral breast cancer at 6 to 7.6 year follow-up.
  • There is moderate quality evidence from 3 RCTs (N=14388) that endocrine therapy for greater than 5 years produces clinically meaningful increases in endometrial cancer at 6 to 7.6 year follow-up relative to endocrine therapy for 5 years only.
  • There is moderate quality evidence from 4 RCTs (N=20438) that there is no clinically important effect of duration of endocrine therapy on bone fractures at 2 month to 7.6 year follow-up.
  • There is high quality evidence from 3 RCTs (N=7567) that there is no clinically important effect of duration of endocrine therapy on arthralgia at 2 month to 4 year follow-up.
  • There is high quality evidence from 3 RCTs (N=18876) that there is no clinically important effect of duration of endocrine therapy on cardiac disease/events at 2 month to 7.6 year follow-up.
  • There is low quality evidence from 1 RCT (N=5149) that there is no clinically important effect of duration of endocrine therapy on hypertension at 4 year follow-up.
  • There is high quality evidence from 1 RCT (N=5126) that endocrine therapy for greater than 5 years produces clinically meaningful increases in osteoporosis at 4 year follow-up relative to endocrine therapy for 5 years only.
  • There is high quality evidence from 1 RCT (N=5149) that there is no clinically important effect of duration of endocrine therapy on myalgia at 4 year follow-up.
  • There is low quality evidence from 2 RCTs (N=1755) that endocrine therapy for greater than 5 years produces clinically meaningful increases in grade 3+ toxicities at 2.5 to 5.6 year follow-up relative to endocrine therapy for 5 years only.
  • There is moderate quality evidence from 2 RCTs (N=6005) that endocrine therapy for greater than 5 years produces clinically meaningful increases in vaginal dryness at 2 month to 4 year follow-up relative to endocrine therapy for 5 years only. However, this was not statistically significant.
  • There is low quality evidence from 2 RCTs (N=6005) that there is no clinically important effect of duration of endocrine therapy on vaginal bleeding at 2 month to 4 year follow-up.
  • There is very low quality evidence from 2 RCTs (N=2008) that there is no clinically important effect of duration of endocrine therapy on vaginal discharge at 2 month to 4 year follow-up.
  • There is low quality evidence from 1 RCT (N=12894) that there is no clinically important effect of duration of endocrine therapy on stroke at 7.6 year follow-up.
  • There is moderate quality evidence from 1 RCT (N=1152) that there is no clinically important effect of duration of endocrine therapy on irregular menstruation at 4 year follow-up.
  • There is moderate quality evidence from 3 RCTs (N=14902) that endocrine therapy for greater than 5 years produces clinically meaningful increases in phlebitis/thromboembolic events at 2 month to 7.6 year follow-up relative to endocrine therapy for 5 years only.
Disease-free survival
  • There is evidence from 1 RCT (N=171) that there is no clinically important effect of duration of endocrine therapy on disease-free survival at 5 year follow-up for women with grade 3 tumours. It was not possible to judge imprecision, and therefore the quality of this evidence, as number of events were not reported.
  • There is low quality evidence from 4 RCTs (N=8480) that there is no clinically important effect of duration of endocrine therapy on disease-free survival at 5.6 to 15 year follow-up for women who continue tamoxifen.
  • There is high quality evidence from 3 RCTs (N=7575) that endocrine therapy for greater than 5 years produces clinically meaningful increases in disease-free survival compared with endocrine therapy for 5 years only at 2.5 to 5 year follow-up for women who switch from tamoxifen to an aromatase inhibitor after 5 years.
Overall survival
  • There is moderate quality evidence from 4 RCTs (N=8533) that there is no clinically important effect of duration of endocrine therapy on overall survival at 5.6 to 15 year follow-up for women who continue tamoxifen.
  • There is moderate quality evidence from 2 RCTs (N=6022) that there is no clinically important effect of duration of endocrine therapy on overall survival at 4 to 5 year follow-up for women who switch from tamoxifen to an aromatase inhibitor after 5 years.
Important outcomes
Compliance/adherence
  • There is low quality evidence from 4 RCTs (N=19558) that there is no clinically important effect of duration of endocrine therapy on compliance.
Treatment-related mortality
  • No evidence was found for this outcome.
Health-related quality of life
  • There is high quality evidence from 1 RCT (N=382) that there is no clinically important effect of duration of endocrine therapy on HRQoL as measured change from baseline by SF-36 physical and mental health scores at 2 year follow-up.
  • There is high quality evidence from 1 RCT (N=386) that there is no clinically important effect of duration of endocrine therapy on HRQoL as measured change from baseline by MENQOL vasomotor, psychosocial, physical and sexual scores at 2 year follow-up.
Economic evidence statement
  • There is evidence from one cost-utility analysis showing that extended tamoxifen was dominant in comparison to standard tamoxifen, while extended aromatase inhibitors have an ICER of $178 per QALY in comparison to standard tamoxifen and an ICER of $3,402 per QALY in comparison to extended tamoxifen. The analysis was partially applicable with some potentially serious limitations.

The committee’s discussion of the evidence

Interpreting the evidence
The outcomes that matter most

As this review question is related to the duration of therapy required to prevent disease recurrence, the committee identified disease-free survival and overall survival as critical outcomes. Treatment-related morbidities was also a critical outcome as extending treatment affords greater opportunity for side effects of treatment to occur, and the optimal duration may be a balance of effectiveness and potential side-effects. Compliance/adherence, treatment-related mortality and health-related quality of life were selected as important outcomes.

These outcomes are important to service users as increased survival is normally prioritised. However, the tolerability of, and adherence to, treatments will be affected by the severity of side effects and the impact these have on quality of life.

No evidence was identified for treatment-related mortality.

The quality of the evidence

The quality of the evidence for this review was assessed using GRADE. For disease-free survival the evidence was of a low quality for the mixed population and for those who continued tamoxifen due to large amount of heterogeneity. However, it was not possible to explore heterogeneity in the tamoxifen studies as the subgroups of interest to the committee were not reported in trials that contributed to this estimate. For disease-free survival in the population who switched to an aromatase inhibitor, the evidence was of high quality.

For overall survival the evidence was of moderate quality. There was serious inconsistency in the tamoxifen studies (but again this could not be explored due to a lack of evidence reported for the subgroups) and only a small number of events of interest were reported for the population who switched to an aromatase inhibitor.

The quality of evidence for treatment-related morbidity ranged from very low to high quality. The low quality was mainly due to uncertainty around the estimate due to small number of events of interest and wide confidence intervals

Compliance evidence was all low quality due to unexplained heterogeneity (and as the subgroups of interest were only identified by the committee for critical outcomes this heterogeneity could not be investigated). Finally, for health-related quality of life the evidence was of high quality.

Based on the high quality of the evidence relating to improvements in disease-free survival in those who switched to an aromatase inhibitor after 5 years of tamoxifen, the committee made a strong recommendation. It was recommended that aromatase inhibitors were offered to post-menopausal women following 2 to 5 years of tamoxifen, rather than the 5 year evidence shown in the current review, as the previous guideline CG80 (NICE 2009) recommended an aromatase inhibitor was offered after 2–3 years of tamoxifen; this recommendation was retained (as the current review only examined >5 years of endocrine therapy compared with 5 years of treatment) and combined with the current recommendation for clarity. The low quality of evidence available for the tamoxifen studies meant that the committee were only able to make a weak recommendation here. There was also no evidence available that evaluated extended duration of treatment for those post-menopausal women who started endocrine therapy with an aromatase inhibitor. The committee were therefore unable to make a recommendation for this therapy option, but agreed that they did not need to make a research recommendation as there are already ongoing trials addressing issue.

Benefits and harms

The main benefit demonstrated by the evidence was an improved disease-free survival (an additional 3% of people were free from disease at 2.5 years when switched after 5 years from tamoxifen to an aromatase inhibitor).

However, the harms identified with the increased duration of endocrine therapy included increased rates of endometrial cancer, osteoporosis, grade 3 toxicities and phlebitis/thromboembolic events. The committee noted that some of these treatment-related morbidities were serious and may negate the beneficial effects of the additional duration of treatment, and that the additional duration of treatment may increase the likelihood of a patient experiencing any side-effect. However, the committee agreed that people prioritise survival over other outcomes, and that the evidence review had confirmed that extending treatment does not lead to a significant reduction in health-related quality of life.

Furthermore, the committee noted that the absolute differences in rates of side effects are small for the comparison between interventions, and that the numbers needed to harm (i.e. the number of people you would need to treat for one additional incidence of the side effect to occur, number need to harm, NNH) are large (based on moderate to high quality evidence). The NNH values are also lower than the number needed to treat (i.e. the number of people you would need to treat for one additional person to be free from disease at 2.5 years, NNT) as shown here:

  • NNT for disease-free survival in those switched to an aromatase inhibitor = 33
  • NNH for osteoporosis = 45
  • NNH for endometrial cancer = 125
  • NNH for phlebitis/thromboembolic events = 250

Finally, the committee recognised that the recommendations may lead to over-treatment in low risk individuals. However, as the committee also made a recommendation to discuss the benefits and harms with individual person, this should also mitigate the risk of over-treatment in people where the harms may outweigh the benefits.

Cost effectiveness and resource use

One relevant study was identified in a literature review of published cost-effectiveness analyses on this topic; Erman 2014. The study considered the cost-effectiveness of extended tamoxifen or extended aromatase inhibitors in comparison to standard tamoxifen. The study was conducted from the perspective of the Canadian health care system and was therefore only partially applicable to the UK NHS context.

The base case results showed that extended tamoxifen and extended aromatase inhibitors were both cost-effective in comparison to standard tamoxifen. Extended tamoxifen was found to be less costly and more effective than standard tamoxifen (i.e. dominant) while extended aromatase inhibitors were more effective and more costly but likely to be cost-effective with a very small ICER of $178 per QALY (CAD). Using dominance rank to determine the optimal strategy, it was found that extended aromatase inhibitors were more effective and more costly than extended tamoxifen with an ICER of $3,402 per QALY likely to be considered cost-effective. Probabilistic sensitivity analysis showed that at a threshold of $50,000 per QALY (CAD), the probability of being cost-effective was 70% for extended aromatase inhibitors, 30% for extended tamoxifen and 0.003% for standard tamoxifen.

While the analysis was not directly applicable, it does suggest that that extended aromatase inhibitors or tamoxifen are cost-effective in comparison to standard tamoxifen. While the magnitude of the costs may vary between countries, it is likely that the same effects would be observed. Therefore, the additional costs of tamoxifen or aromatase inhibitors are likely to be offset, at least partially offset by downstream cost savings, while the improvements in clinical effectiveness would translate into QALY gains. It then seems likely that the strategy would be cost-effective in cost per QALY terms.

The committee carefully considered the potential resource impact in this topic area as they were aware of the large number of women that are likely to be affected by the recommendations. However, while the population affected may be large, the cost of interventions are very low. The cost of aromatase inhibitors and tamoxifen were estimated based on prices reported in the electronic market information tool (eMit). Letrozole 2.5mg was reported to cost £1.52 for a pack of 28, anastrozole 1mg was reported to cost £0.74 for a pack of 28, exemestane 25mg was reported to cost £4.16 for a pack of 30 and tamoxifen 20mg was reported to cost £1.44 for a pack of 30. This equates to an estimated cost per dose of £0.05, £0.03, £0.14 and £0.05 for letrozole, anastrozole, exemestane and tamoxifen, respectively. The committee discussed whether the extended treatment might require additional consultations but this was thought unlikely as consultations tend to occur frequently when treatment is commenced but stop after a few years of treatment. However, it is possible that there may be an additional consultation to review medications at 5 years.

The committee commented that the recommendations reflect current practice for some centres as some women already receive extended treatment. Therefore the overall cost impact of implementing the recommendation nationwide will be smaller and any cost increases associated with continued medication will vary based on current local protocols.

Overall, when taking all factors into account, it was thought that the recommendations were likely to be cost-effective and unlikely to have a substantial resource impact of more than £1 million per year.

Other factors the committee took into account

The committee questioned the relevance of the Scottish adjuvant tamoxifen trial and NSABP-14 trial as these were older trials in which people received treatment during the 1980s. However, no specific information in the publications was identified that was inconsistent with current practice so a sensitivity analysis was not performed to evaluate the inclusion of these trials.

The committee agreed that the ATLAS and Adjuvant Tamoxifen Treatment Offers More? (aTTom) trials are likely to be consistent with current standards. Evidence from ATLAS included in the current review showed a benefit in terms of disease-free survival (82% vs. 79%) and overall survival (81% vs. 79%) for individuals who continued tamoxifen to 10 years compared with those that took it for 5 years. It was not possible to include the results of the aTTom trial in the evidence review as they are only available in abstract form (Gray, 2013) with insufficient evidence to calculate hazard ratios. The results, however, are consistent with ATLAS which showed breast cancer recurrence rates of 17% vs. 19% and overall survival rates of 76% and 74% for individuals that continued tamoxifen to 10 years compared with those that took it for 5 years; risk ratios for both outcomes decreased (favouring continued tamoxifen) as the trial continued.

Based on the results of ATLAS and aTTom the committee agreed that extending the duration of tamoxifen should be considered, despite the non-significant pooled effects observed for disease-free survival and overall in the evidence review.

References

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Review question 4.2. What is the effectiveness of ovarian suppression in addition to endocrine therapy in premenopausal women with oestrogen-positive breast cancer?

Introduction

Adjuvant endocrine therapy for oestrogen positive (ER-positive) early breast cancer is well established. For premenopausal women, tamoxifen is the standard drug although the aromatase inhibitors can be given to premenopausal women if the ovaries are suppressed using gonadotropin-releasing hormone (GnRH) analogues or ablated by surgery or radiation.

Theoretically, the absence of circulating oestrogen with ovarian function suppression/ablation (OFS) in addition to tamoxifen or switching to aromatase inhibitors (which are more efficacious in postmenopausal women) should improve long term outcomes including local and distant relapse from breast cancer. However, OFS has additional side effects for young women including menopausal symptoms with the potential for additional adverse effects on bone and cardiovascular health.

International expert opinion (Burstein, 2016) suggests premenopausal women who receive chemotherapy or are considered high risk are offered OFS while the European Society for Medical Oncology (ESMO) Clinical Practice guidelines (Senkus, 2015) suggest a discussion with individual women based on risk and the potential side effect profile

This review aims to determine the effectiveness of OFS in addition to endocrine therapy in premenopausal women.

PICO table

See Table 4 for a summary of the population, intervention, comparison and outcome (PICO) characteristics of this review.

Table 4. Summary of the protocol (PICO table).

Table 4

Summary of the protocol (PICO table).

For full details see review protocol in appendix A.

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual; see the methods chapter for further information.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy.

Clinical evidence

Included studies

Six publications from four randomised trials (N=8762) were included in the review: Adjuvant Breast Cancer (ABC) Ovarian Ablation or Suppression Trial (k=1), E-3191 (k=1), Suppression of Ovarian Function Trial (SOFT; k=1), and Zoladex In Pre-menopausal Patients trial (ZIPP; k=3). The ABC Ovarian Ablation or Suppression Trial, E-3191 trial and the SOFT trial compare tamoxifen and ovarian suppression achieved by luteinizing-hormone releasing hormone (LHRH) agonists, oophorectomy, or radiation with tamoxifen alone, whereas the ZIPP trial compares tamoxifen and the LHRH agonist goserelin to tamoxifen alone.

All of the studies included some women with unknown, or negative oestrogen-receptor status. These studies were retained as their exclusion would have resulted in no clinical evidence for this review question. Furthermore, women in the ABC Ovarian Ablation or Suppression Trial and some women in the ZIPP trial were receiving concurrent chemotherapy. These studies were not excluded due to the small number of included studies but sensitivity analysis was planned to determine if the inclusion of such studies affects the overall estimate of effect. However, sensitivity analysis was not performed for survival outcomes as tests for heterogeneity were non-significant.

Only one study (Francis, 2015) reported data for subgroups of interest: Age (<35/35–39/40+), grade (1/2/3), human epidermal growth factor receptor 2 (HER2) status (+/-) and previous chemotherapy (Yes/No).

The clinical studies included in this evidence review are summarised in Table 5 and evidence from these are summarised in the clinical GRADE evidence profile below (Table 6). See also the study selection flow chart in appendix C, forest plots in appendix E, and study evidence tables in appendix D.

Excluded studies

Studies not included in this review with reasons for their exclusions are provided in appendix K.

Summary of clinical studies included in the evidence review

Table 5. Summary of included studies.

Table 5

Summary of included studies.

See appendix D for full evidence tables.

Quality assessment of clinical studies included in the evidence review

The clinical evidence profile for this review question (effectiveness of ovarian suppression in addition to endocrine therapy) is presented in Table 6.

Table 6. Summary clinical evidence profile: Comparison 1. Ovarian suppression plus tamoxifen versus tamoxifen alone.

Table 6

Summary clinical evidence profile: Comparison 1. Ovarian suppression plus tamoxifen versus tamoxifen alone.

See appendix F for full GRADE tables.

Economic evidence

A systematic review of the economic literature was conducted but no relevant studies were identified which were applicable to this review question. Economic modelling was not undertaken for this question because other topics were agreed as higher priorities for economic evaluation.

Evidence statements

Comparison 1. Ovarian suppression plus tamoxifen versus tamoxifen alone
Critical outcomes
Disease-free survival
  • There is moderate quality evidence from 2 RCTs (N=2370) that there is no effect of ovarian suppression on disease-free survival at 5 to 9.9 year follow-up in mixed populations of pre-menopausal women with ER positive invasive breast cancer.
  • There is low quality evidence from 1 RCT (N=233) that there is no effect of ovarian suppression on disease-free survival at 5 year follow-up for pre-menopausal women with ER positive invasive breast cancer aged <35 years.
  • There is low quality evidence from 1 RCT (N=387) that there is no effect of ovarian suppression on disease-free survival at 5 year follow-up for pre-menopausal women with ER positive invasive breast cancer aged 35 to 39 years.
  • There is low quality evidence from 1 RCT (N=1413) that there is no effect of ovarian suppression on disease-free survival at 5 year follow-up for pre-menopausal women with ER positive invasive breast cancer aged >40 years.
  • There is low quality evidence from 1 RCT (N=540) that there is no effect of ovarian suppression on disease-free survival at 5 year follow-up for pre-menopausal women with grade 1, ER positive invasive breast cancer.
  • There is low quality evidence from 1 RCT (N=1006) that ovarian suppression plus tamoxifen produces a clinically meaningful improvement in disease-free at 5 year follow-up compared with tamoxifen alone for pre-menopausal women with grade 2, ER positive invasive breast cancer.
  • There is low quality evidence from 1 RCT (N=439) that there is no effect of ovarian suppression on disease-free survival at 5 year follow-up for pre-menopausal women with grade 3, ER positive invasive breast cancer.
  • There is low quality evidence from 1 RCT (N=1724) that there is no effect of ovarian suppression on disease-free survival at 5 year follow-up for pre-menopausal women with HER2 negative, ER positive invasive breast cancer.
  • There is low quality evidence from 1 RCT (N=236) that ovarian suppression plus tamoxifen produces a clinically meaningful improvement in disease-free at 5 year follow-up compared with tamoxifen alone for pre-menopausal women with HER2 positive, ER positive invasive breast cancer.
  • There is low quality evidence from 1 RCT (N=1084) that there is no effect of ovarian suppression on disease-free survival at 5 year follow-up for pre-menopausal women with ER positive invasive breast cancer who have had chemotherapy.
  • There is low quality evidence from 1 RCT (N=949) that there is no effect of ovarian suppression on disease-free survival at 5 year follow-up for pre-menopausal women with ER positive invasive breast cancer who have not had chemotherapy.
Treatment-related morbidity
  • There is very low quality evidence from 1 RCT (N=920) that ovarian suppression plus tamoxifen produces clinically meaningful increases in vasodilation compared with tamoxifen alone for pre-menopausal women with ER positive invasive breast cancer.
  • There is very low quality evidence from 2 RCTs (N=1265) that ovarian suppression plus tamoxifen produces clinically meaningful increases in weight gain compared with tamoxifen alone for pre-menopausal women with ER positive invasive breast cancer.
  • There is very low quality evidence from 1 RCT (N=920) that ovarian suppression plus tamoxifen produces clinically meaningful increases in arthralgia compared with tamoxifen alone for pre-menopausal women with ER positive invasive breast cancer. However, the effect was not statistically significant.
  • There is low quality evidence from 3 RCTs (N=3276) that ovarian suppression plus tamoxifen produces clinically meaningful increases in anxiety/depression/irritability compared with tamoxifen alone for pre-menopausal women with ER positive invasive breast cancer. However, the effect was not statistically significant.
  • There is low quality evidence from 2 RCTs (N=1265) that ovarian suppression plus tamoxifen produces clinically meaningful increases in sweating compared with tamoxifen alone for pre-menopausal women with ER positive invasive breast cancer.
  • There is low quality evidence from 2 RCTs (N=2356) that ovarian suppression plus tamoxifen produces clinically meaningful increases in grade 3+ hot flushes at 3 to 5.6 year follow-up compared with tamoxifen alone for pre-menopausal women with ER positive invasive breast cancer.
  • There is low quality evidence from 1 RCT (N=2011) that ovarian suppression plus tamoxifen produces clinically meaningful increases in grade 3+ hypertension at 5.6 year follow-up compared with tamoxifen alone for pre-menopausal women with ER positive invasive breast cancer. However, the effect was not statistically significant.
  • There is low quality evidence from 1 RCT (N=2011) that ovarian suppression plus tamoxifen produces clinically meaningful reductions in grade 3+ cardiac ischemia or infarction at 5.6 year follow-up compared with tamoxifen alone for pre-menopausal women with ER positive invasive breast cancer. However, the effect was not statistically significant.
  • There is low quality evidence from 1 RCT (N=2011) that there is no effect of ovarian suppression on grade 3+ thrombosis or embolism at 5.6 year follow-up for premenopausal women with ER positive invasive breast cancer.
  • There is low quality evidence from 1 RCT (N=2011) that there is no effect of ovarian suppression on grade 3+ musculoskeletal symptoms at 5.6 year follow-up for premenopausal women with ER positive invasive breast cancer.
  • There is low quality evidence from 1 RCT (N=2011) that ovarian suppression plus tamoxifen produces clinically meaningful increases in grade 3+ osteoporosis at 5.6 year follow-up compared with tamoxifen alone for pre-menopausal women with ER positive invasive breast cancer. However, the effect was not statistically significant.
  • There is low quality evidence from 1 RCT (N=2011) that there is no effect of ovarian suppression on grade 3+ fractures at 5.6 year follow-up for pre-menopausal women with ER positive invasive breast cancer.
  • There is moderate quality evidence from 2 RCTs (N=2356) that there is no effect of ovarian suppression on vaginal dryness at 3 to 5.6 year follow-up for pre-menopausal women with ER positive invasive breast cancer.
  • There is moderate quality evidence from 2 RCTs (N=2356) that there is no effect of ovarian suppression on changes in libido at 3 to 5.6 year follow-up for pre-menopausal women with ER positive invasive breast cancer.
  • There is low quality evidence from 1 RCT (N=2011) that ovarian suppression plus tamoxifen produces clinically meaningful reductions in grade 3+ CNS cerebrovascular ischemia at 5.6 year follow-up compared with tamoxifen alone for pre-menopausal women with ER positive invasive breast cancer. However, the effect was not statistically significant.
  • There is low quality evidence from 1 RCT (N=2011) that ovarian suppression plus tamoxifen produces clinically meaningful increases in grade 3+ CNS haemorrhage at 5.6 year follow-up compared with tamoxifen alone for pre-menopausal women with ER positive invasive breast cancer. However, the effect was not statistically significant.
  • There is very low quality evidence from 1 RCT (N=60) that there is no effect of ovarian suppression on vasomotor symptoms measured by Physical Symptoms and Problem List at 3 year follow-up for pre-menopausal women with ER positive invasive breast cancer.
  • There is very low quality evidence from 1 RCT (N=63) that there is no effect of ovarian suppression on vaginal dryness measured by Physical Symptoms and Problem List at 3 year follow-up for pre-menopausal women with ER positive invasive breast cancer.
  • There is very low quality evidence from 1 RCT (N=32) that there is no effect of ovarian suppression on bone density at 2 year follow-up for pre-menopausal women with ER positive invasive breast cancer.
Health-related quality of life
  • There is very low quality evidence from 1 RCT (N=188) that there is no effect of ovarian suppression on HRQoL measured by the FACT-G for pre-menopausal women with ER positive invasive breast cancer.
  • There is moderate quality evidence from 1 RCT (N=177) that there is no effect of ovarian suppression on HRQoL measured by the FACT-B for pre-menopausal women with ER positive invasive breast cancer.
Important outcomes
Local recurrence rate
  • No evidence was found for this outcome.
Overall survival
  • There is low quality evidence from 4 RCTs (N=4108) that ovarian suppression plus tamoxifen produces a clinically meaningful improvement in overall survival at 5 to 9.9 year follow-up compared with tamoxifen alone for mixed populations of pre-menopausal women with ER positive invasive breast cancer.
  • There is low quality evidence from one RCT (N=1084) that ovarian suppression plus tamoxifen produces a clinically meaningful improvement in overall survival at 5 year follow-up compared with tamoxifen alone for pre-menopausal women with ER positive invasive breast cancer who had received chemotherapy.
  • There is low quality evidence from one RCT (N=949) that there is no effect of ovarian suppression on overall survival at 5 year follow-up for pre-menopausal women with ER positive invasive breast cancer who had not received chemotherapy.
Compliance
  • There is moderate quality evidence from one RCT (N=227) that there is no effect of ovarian suppression on rates of treatment completion in pre-menopausal women with ER positive invasive breast cancer who had received chemotherapy.
Treatment-related mortality
  • No evidence was found for this outcome.

The committee’s discussion of the evidence

Interpreting the evidence
The outcomes that matter most

The committee prioritised disease-free survival, treatment-related morbidity and health-related quality of life as critical outcomes; the latter outcomes were prioritised over overall survival due to the significant side-effect profile associated with ovarian suppression, including menopausal symptoms and the fact that conception is not possible or not advised for the duration of treatment. This meant that the disease-free survival benefits would need to be balanced against the side-effects. Overall survival, local recurrence rate, compliance with treatment, and treatment-related mortality were selected as important outcomes.

There was no evidence available for local recurrence rate or treatment-related mortality.

The quality of the evidence

The quality of the evidence for this review was assessed using GRADE. For disease-free survival the evidence was moderate quality for the sample as a whole, but low quality for all the subgroups due to small number of events of interest. The evidence was down-graded because of a risk of bias due to unclear randomisation and allocation concealment procedures.

For treatment-related morbidity the evidence quality ranged from very low to moderate, and was downgraded mainly due to uncertainty in the estimate due to the low number of events of interest, but also because of issues with risk of bias due to unclear randomisation and allocation concealment procedures, and indirectness due to concurrent chemotherapy administration in the ZIPP and ABC trials.

Health-related quality of life evidence was moderate for FACT-B and very low for FACT-G. This was because of risk of bias due to unclear randomisation and allocation concealment procedures for both scales. In addition, the evidence for FACT-G was downgraded because of imprecision due to a wide confidence interval and therefore uncertainty about the estimate.

Overall survival evidence was of low quality, and compliance evidence was also moderate due to a small number of events of interest.

Due to the quality of the evidence and the lack of benefit reported for the critical outcome of disease-free survival, the committee could only make a weak recommendation for the use of OFS. However, the evidence for the important outcome of overall survival was of moderate quality and showed benefit in the mixed population and those who had received chemotherapy so the committee also made a recommendation that this information should be taken into account.

Benefits and harms

The benefits of OFS in addition to endocrine therapy include improvements in disease-free and overall survival. There is a 1% improvement in overall survival at 5 years in the mixed population, and a 3% improvement in those who had received chemotherapy. There was also a 2% increase in disease-free survival but these results were not significant

It is accepted that OFS will lead to symptoms of early menopause. Whilst symptoms related to this were not all significantly increased in the current evidence review (based on very low to low quality evidence), there were increases in weight gain (number need to harm, NNH, 33), hot flushes (NNH=14), vasodilation (NNH=4) and sweating (NNH=33). In addition, women will be infertile for the duration of treatment, although women would normally be advised not to become pregnant while taking tamoxifen so the OFS may have limited additional impact in this respect.

The committee discussed the balance of benefits and harms, noting that menopausal symptoms and fertility will return after OFS treatment is ended (provided natural menopause has not been reached during this time), and that low to moderate quality evidence found that OFS had no effect on quality of life. In addition, the committee agreed that people tend to prioritise survival over side-effects, and that discussing the potential benefits/harms with women, and targeting those who are most likely to gain benefit (i.e. those who have had a risk deemed high enough to be offered chemotherapy) should help balance the acceptability of treatment side-effects in relation to the perceived risk to the patient.

Cost effectiveness and resource use

A systematic review of the economic literature was conducted but no relevant studies were identified which were applicable to this review question.

The committee discussed the potential costs and savings of recommendations and thought that there could be additional costs associated with the use of ovarian suppression. As well as the costs of the ovarian suppression medication, there would also be costs associated with administration (monthly injections at GP surgery given by a practice nurse). There could also be additional appointments (and potentially procedures) required for the management of menopausal symptoms. For example, bone health monitoring using dual-energy X-ray absorptiometry may be required.

The committee thought that any additional costs associated with ovarian suppression would be offset, at least partially, by savings resulting from improvements in disease related outcomes (DFS and OS). These improvements should reduce the need (or at least delay the need) for future procedures, treatments and hospice care.

Overall, the committee did not anticipate that their recommendations would have a substantial resource impact. The committee noted that ovarian function suppression is already given in many centres and so the nationwide cost of implementing the recommendations is not anticipated to exceed £1 million per year. However there would be increased costs in those centres not currently offering ovarian function suppression.

Other factors the committee took into account

The committee gave greater weight to the SOFT and ECOG trial data from this evidence review as they identified three potential problems with the ABC and ZIPP studies that they believed reduced the applicability of this data to current practice. Firstly, in the ABC study women were given ovarian function suppression for 2 years and in the ZIPP study for 2–3 years. However, current standard practice is to give endocrine therapy (and therefore OFS) for at least 5 years. Secondly, the ZIPP and ABC studies both included chemotherapy administered concurrently with OFS and tamoxifen, and Albain (2009) showed that this combination is inferior. Thirdly, the SOFT trial confirmed that ovarian function had returned after chemotherapy whereas other trials did not confirm this; therefore it is possible that ovaries were not functioning in control arm.

In addition to the evidence presented in the evidence review the committee were aware of a combined analysis from two studies, SOFT and Tamoxifen and Exemestane Trial (TEXT; Pagani, 2014). This combined analysis showed greater benefit for OFS and AI whereas our current studies all used tamoxifen. Therefore, the committee have recommended considering OFS in addition to endocrine therapy despite the lack of significant disease-free survival benefit as a greater effect may have been observed if AIs had been used; a specific drug has not been recommended for endocrine therapy to allow clinician discretion to use AIs or tamoxifen as considered appropriate.

References

  • Adjuvant Breast Cancer Trials Collaborative Group 2007

    Adjuvant Breast Cancer Trials Collaborative Group (2007) Ovarian ablation or suppression in premenopausal early breast cancer: results from the international adjuvant breast cancer ovarian ablation or suppression randomized trial. Journal of the National Cancer Institute, 99, 516–25. [PubMed: 17405996]

  • Albain 2009

    Albain, K. S., Barlow, W. E., Ravdin, P. M., Farrar, W. B., Burton, G. V., Ketchel, S. J., Cobau, C. D., Levine, E. G., Ingle, J. N., Pritchard, K. I., Lichter, A. S., Scheider, D. J., Abeloff, M. D., Henderson, I. C., Muss, H. B., Green, S. J., Lew, D., Livingston, R. B., Martino, S., Osborne, C. K. (2009). Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. The Lancet, 374, 2055–2063. [PMC free article: PMC3140679] [PubMed: 20004966]

  • Baum 2006

    Baum, M., Hackshaw, A., Houghton, J., Rutqvist,, Fornander, T., Nordenskjold, B., Nicolucci, A., Sainsbury, R., Zipp International Collaborators Group (2006) Adjuvant goserelin in premenopausal patients with early breast cancer: Results from the ZIPP study. European journal of cancer, 42, 895–904. [PubMed: 16545560]

  • Burstein 2016

    Burstein, H. J., Lacchetti, C., Anderson H., Buccholz, T. A., Davidson, N. E., Gelmon, K. E., Giordano, S. H., Hudis, C. A., Solky, A. J., Steams, V., Wimer, E. P., Griggs, J. J. (2016). Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression. Journal of Clinical Oncology, 10, 1689–1701. [PubMed: 26884586]

  • Francis 2015

    Francis, P. A., Regan, M. M., Fleming, G. F., Lang, I., Ciruelos, E., Bellet, M., Bonnefoi, H. R., Climent, M. A., Da Prada, G. A., Burstein, H. J., Martino, S., Davidson, N. E., Geyer, C. E., Jr., Walley, B. A., Coleman, R., Kerbrat, P., Buchholz, S., Ingle, J. N., Winer, E. P., Rabaglio-Poretti, M., Maibach, R., Ruepp, B., Giobbie-Hurder, A., Price, K. N., Colleoni, M., Viale, G., Coates, A. S., Goldhirsch, A., Gelber, R. D., Soft Investigators, International Breast Cancer Study, Group (2015) Adjuvant ovarian suppression in premenopausal breast cancer. New England Journal of Medicine, 372, 436–46. [PMC free article: PMC4341825] [PubMed: 25495490]

  • Nystedt 2003

    Nystedt, M., Berglund, G., Bolund, C., Fornander, T., Rutqvist, L.E., (2003) Side effects of adjuvant endocrine treatment in premenopausal breast cancer patients: a prospective randomized study. Journal of Clinical Oncology, 21, 1836–1844. [PubMed: 12721261]

  • Pagani 2014

    Pagani, O., Regan, M. M., Walley, B. A., Fleming, G. F., Colleoni, M., Láng, I., Gomez, H. L., Tondini, C., Burstein, H. J., Perez, E. A., Ciruelos, E., Stearns, V., Bonnefoi, H. R., Martino, S., Geyer Jr., C. E., Pinotti, G., Puglisi, F., Crivellari, D., Ruhstaller, R., Winer, E. P., Rabaglio-Poretti, M., Maibach, R., Ruepp, B., Giobbie-Hurder, A., Price, K. N., Bernhard, J., Luo, W., Ribi, K., Viale G., Coates, A. S., Gelber, R. D., Goldhirsch, A., Francis, P. A., TEXT and SOFT Investigators and the International Breast Cancer Study Group. (2014). Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. The New England Journal of Medicine, 371, 107–118. [PMC free article: PMC4175521] [PubMed: 24881463]

  • Senkus 2015

    Senkus, E., Kyriakides, S., Ohno, S., Penualt-Llorca, F., Poortmans, P., Rutgers, E., Zacrisson, S., Cardoso, F., ESMO Guidelines Committee (2015). Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 25, v8–v30. [PubMed: 26314782]

  • Sverrisdottir 2004

    Sverrisdottir, A., Fornander, T., Jacobsson, H., von Schoultz, E., Rutqvist, L. E., (2004) Bone mineral density among premenopausal women with early breast cancer in a randomized trial of adjuvant endocrine therapy. Journal of Clinical Oncology, 22, 3694–9. [PubMed: 15365065]

  • Tevaarwerk 2014

    Tevaarwerk, A. J., Wang, M., Zhao, F., Fetting, J. H., Cella, D., Wagner, L. I., Martino, S., Ingle, J. N., Sparano, J. A., Solin, L. J., Wood, W. C., Robert, N. J., (2014) Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): A trial of the eastern cooperative oncology group. Journal of Clinical Oncology, 32, 3948–3958. [PMC free article: PMC4251958] [PubMed: 25349302]

Review question 10.4. What is the role of chemoprevention in women following initial treatment for ductal carcinoma in situ (DCIS)?

Introduction

Ductal carcinoma in situ (DCIS) is non-invasive and considered the earliest form of breast cancer. Abnormal cells are located inside milk ducts in the breast and have not spread or invaded other parts of the breast. Its detection has significantly increased since routine mammographic screening. The management of DCIS includes surgical intervention and with radiotherapy as appropriate.

Chemoprevention may be used in people who have been treated for DCIS to prevent the development of breast cancer. The most commonly used chemoprevention is with hormone therapy involving oestrogen receptor (ER) blockers (tamoxifen or raloxifene) or aromatase inhibitors (AIs; anastrozole, exemestane and letrozole). These hormone therapies are an established treatment for women with ER-positive invasive breast cancer. At the time of the previous guideline CG80 (NICE 2009), evidence was felt to be conflicting around use of hormonal therapies (chemoprevention) after adequate surgical treatment of DCIS.

The aim of this review is to assess the role of chemoprevention in women with DCIS, which will consider the benefits of reducing breast cancer recurrence and secondary breast cancers, compared to the side effects of increased risks of endometrial cancers and thromboembolic complications.

PICO table

See Table 7 for a summary of the population, intervention, comparison and outcome (PICO) characteristics of this review.

Table 7. Summary of the protocol (PICO table).

Table 7

Summary of the protocol (PICO table).

For full details see review protocol in appendix A.

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual; see the methods chapter for further information.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy.

Clinical evidence

Included studies

Four studies (n=3,496) identified by the literature search were included in the review (Cuzick, 2011; Fisher, 1999, Guerrieri-Gonzaga, 2006; Wapnir, 2011), which report data from 3 trials: Guerrieri-Gonzaga, 2006 (k=1), National Surgical Adjuvant Breast and Bowel Project (NSAPB) B34 (k=2), and UK, Australia and New Zealand (UK/ANZ; k=1).

All included studies compared tamoxifen against no chemoprevention. Three studies reported data for critical outcomes for subgroups of interest: breast-conserving surgery (BCS) followed by radiotherapy (k=3) and BCS with no radiotherapy (k=1). No evidence was available for chemoprevention following mastectomy.

The clinical studies included in this evidence review are summarised in Table 8 and evidence from these are summarised in the clinical GRADE evidence profile below (Table 9). See also the study selection flow chart in appendix C, forest plots in appendix E, and study evidence tables in appendix D.

Excluded studies

Studies not included in this review with reasons for their exclusions are provided in appendix K.

Summary of clinical studies included in the evidence review

Table 8. Summary of included studies.

Table 8

Summary of included studies.

See appendix D for full evidence tables.

Quality assessment of clinical studies included in the evidence review

The clinical evidence profile for this review question (chemoprevention in DCIS) is presented in Table 9. The quality of evidence ranges from very low to high. Main reasons for downgrading evidence was imprecision around the estimates due to a small number of events of interest and wide confidence intervals.

Table 9. Summary clinical evidence profile: Comparison 1. Tamoxifen versus no chemoprevention for people with excised DCIS.

Table 9

Summary clinical evidence profile: Comparison 1. Tamoxifen versus no chemoprevention for people with excised DCIS.

See appendix F for full GRADE tables.

Economic evidence

A systematic review of the economic literature was conducted but no relevant studies were identified which were applicable to this review question. Economic modelling was not undertaken for this question because other topics were agreed as higher priorities for economic evaluation.

Evidence statements

Comparison 1. Tamoxifen versus no chemoprevention for people with excised DCIS
Critical outcomes
Disease-free survival
  • There is high quality evidence from 1 RCT (N=1576) that tamoxifen produces clinically meaningful increases in disease-free survival compared with no chemoprevention at 10 year follow-up for people with excised DCIS.
  • There is moderate quality evidence from 1 RCT (N=523) that there is no clinically important effect of tamoxifen on disease-free survival at 10 year follow-up for people with excised DCIS following BCS and radiotherapy.
  • There is moderate quality evidence from 1 RCT (N=1053) that tamoxifen produces clinically meaningful increases in disease-free survival compared with no chemoprevention at 10 year follow-up for people with excised DCIS following BCS alone.
Local recurrence
  • There is moderate quality evidence from 1 RCT (N=1576) that tamoxifen produces clinically meaningful reductions in local recurrence compared with no chemoprevention at 10 year follow-up for people with excised DCIS.
  • There is moderate quality evidence from 1 RCT (N=1799) that tamoxifen produces clinically meaningful reductions in invasive local recurrence compared with no chemoprevention at 13.6 year follow-up for people with excised DCIS following BCS and radiotherapy.
  • There is moderate quality evidence from 1 RCT (N=1799) that there is no clinically important effect of tamoxifen on DCIS local recurrence at 13.6 year follow-up for people with excised DCIS following BCS and radiotherapy.
  • There is moderate quality evidence from 1 RCT (N=523) that there is no clinically important effect of tamoxifen on local recurrence at 10 year follow-up for people with excised DCIS following BCS and radiotherapy.
  • There is moderate quality evidence from 1 RCT (N=1053) that tamoxifen produces clinically meaningful reductions in local recurrence compared with no chemoprevention at 10 year follow-up for people with excised DCIS following BCS alone.
Treatment-related morbidity
  • There is high quality evidence from 2 RCTs (N=1897) that tamoxifen produces clinically meaningful increases in vaginal dryness/discharge at 3.3 to 6.2 year follow-up compared with no chemoprevention for people with excised DCIS.
  • There is low quality evidence from 1 RCT (N=1781) that tamoxifen produces clinically meaningful increases in grade 3+ toxicities at 6.2 year follow-up compared with no chemoprevention for people with excised DCIS. However, the effect was not statistically significant.
  • There is low quality evidence from 1 RCT (N=1781) that tamoxifen produces clinically meaningful increases in phlebitis/thromboembolisms at 6.2 year follow-up compared with no chemoprevention for people with excised DCIS. However, the effect was not statistically significant.
  • There is low quality evidence from 1 RCT (N=1781) that there is no clinically important effect of tamoxifen on mood changes at 6.2 year follow-up for people with excised DCIS.
  • There is moderate quality evidence from 1 RCT (N=1781) that there is no clinically important effect of tamoxifen on menstrual disorders at 6.2 year follow-up for people with excised DCIS.
  • There is high quality evidence from 2 RCTs (N=1897) that there is no clinically important effect of tamoxifen on hot flashes at 3.3 to 6.2 year follow-up for people with excised DCIS.
  • There is high quality evidence from 1 RCT (N=1781) that there is no clinically important effect of tamoxifen on fluid retention at 6.2 year follow-up for people with excised DCIS.
  • There is very low quality evidence from 1 RCT (N=116) that tamoxifen produces clinically meaningful reductions in ocular/visual treatment-related morbidities at 3.3 year follow-up compared with no chemoprevention for people with excised DCIS. However, the effect was not statistically significant.
  • There is very low quality evidence from 1 RCT (N=116) that tamoxifen produces clinically meaningful reductions in dermatological treatment-related morbidities at 3.3 year follow-up compared with no chemoprevention for people with excised DCIS. However, the effect was not statistically significant.
  • There is very low quality evidence from 1 RCT (N=116) that there is no clinically important effect of tamoxifen on dysuria/incontinence at 3.3 year follow-up for people with excised DCIS.
  • There is very low quality evidence from 1 RCT (N=116) that tamoxifen produces clinically meaningful increases in vaginal bleeding at 3.3 year follow-up compared with no chemoprevention for people with excised DCIS. However, the effect was not statistically significant.
  • There is very low quality evidence from 1 RCT (N=116) that tamoxifen produces clinically meaningful increases in endometrial polyps at 3.3 year follow-up compared with no chemoprevention for people with excised DCIS. However, the effect was not statistically significant.
  • There is very low quality evidence from 1 RCT (N=116) that there is no clinically important effect of tamoxifen on sweats/weight gain at 3.3 year follow-up for people with excised DCIS.
Important outcomes
Health-related quality of life
  • No evidence was found for this outcome.
Overall survival
  • There is moderate quality evidence from 1 RCT (N=1799) that there is no clinically important effect of tamoxifen on overall survival at 13.6 year follow-up for people with excised DCIS following BCS and radiotherapy.
Treatment adherence
  • No evidence was found for this outcome.

Economic evidence

A systematic review of the economic literature was conducted but no relevant studies were identified which were applicable to this review question. Economic modelling was not undertaken for this question because other topics were agreed as higher priorities for economic evaluation.

The committee’s discussion of the evidence

Interpreting the evidence
The outcomes that matter most

Disease-free survival, local recurrence and treatment related-morbidity were selected by the committee as the critical outcomes for this review. Local recurrence was prioritised over overall survival as this review question is examining whether chemoprevention is effective at preventing invasive cancer and return of DCIS in people following treatment of DCIS. DCIS itself does not usually have an impact on overall survival, except by increasing the chance of invasive cancer developing. Treatment-related morbidity also critical as it affects the tolerance of, and adherence to treatment, and quality of life.

Overall survival, HRQoL and treatment adherence were defined as the important outcomes, but no evidence for HRQoL or treatment adherence was identified.

The quality of the evidence

The quality of the evidence was assessed using GRADE. For disease-free survival the evidence was of a high-moderate quality, with the downgrading to moderate mainly due to a small number of events of interest.

For local recurrence and overall survival the evidence was of moderate quality, again downgraded due to small number of events of interest.

The quality of evidence for treatment-related morbidities ranged from high to very low. The main reason for downgrading here was a small number of events and a wide confidence interval.

The recommendations are based on the strong evidence of the benefits of chemoprevention in terms of disease-free survival and local recurrence for those people who do not have radiotherapy.

Benefits and harms

The evidence review identified specific benefits of chemoprevention for people with DCIS who do not have radiotherapy: there was an 8% improvements in DFS at 10 years (NNT 13) and 5% improvement in local recurrence at 10 years (NNT 10).

The main harm identified in the evidence review was a 12% increase in vaginal dryness in those women treated with tamoxifen compared with no chemoprevention (NNH 8). There was also an increased rate of endometrial polyps and thrombophlebitis in the tamoxifen arm but this was not statistically significant.

However, the committee knew from their clinical experience that the occurrence of menopausal symptoms with endocrine therapy is well established (despite lack of evidence in current review) and that this may lead to reduced adherence.

Pre-menopausal women who wish to have children may be less willing to take tamoxifen as, due to its potential teratogenic effects, conception is not recommended for the duration of the tamoxifen treatment.

The committee balanced the benefits and harms of chemoprevention in this population, and took into consideration the fact that the benefits relate to DFS and local recurrence rather than overall survival. There was no evidence available to stratify high and low risk populations in the current review; however, the committee felt there was a risk of over-treatment if chemoprevention was offered to everyone, and the potential amount of benefit would be proportional to the individual’s risk level. The committee therefore chose to stratify the population for risk by assessing if they would have been offered radiotherapy.

Based on this stratification, the committee recommended chemoprevention is offered to those who are recommended radiotherapy but do not have it, and is considered for those who are not recommended radiotherapy, but that the benefits and risks are discussed with the woman.

Cost effectiveness and resource use

A systematic review of the economic literature was conducted but no relevant studies were identified which were applicable to this review question.

The recommendation to offer endocrine therapy may require an increase in resources. However, the cost impact is likely to be minimal as DCIS affects a relatively small number of people in the UK and chemoprevention drugs are inexpensive. In addition to drug costs, there may be some additional monitoring by GP required for people receiving chemoprevention but this would probably be limited to an annual check-up except in people experiencing side effects. The upfront costs associated with the use of chemoprevention are likely to be offset, at least partially, by downstream savings associated with preventing recurrences and future treatment.

Other factors the committee took into account

The only drug looked at in this evidence review was tamoxifen as trials of others were not available. However other drugs are available for endocrine chemoprevention and the committee agreed that benefits of other endocrine therapies were likely to be very similar in this population. The committee therefore recommended endocrine chemoprevention, rather than specifically tamoxifen.

The committee did not make a research recommendation to address the lack of data for other drugs in this situation as they were aware of other trials (e.g., International Breast Cancer Intervention Studies [IBIS]-II; Cuzick, 2014) comparing aromatase inhibitors with tamoxifen; this trial did not meet our inclusion criteria as it compared two different forms of endocrine chemoprevention rather than comparing endocrine chemoprevention with no chemoprevention.

The recommendations made are specific to ER-positive women. This was not specified in the protocol but it is well established that only those with ER-positive DCIS will benefit from endocrine therapy and therefore it would be inappropriate to offer endocrine chemoprevention to ER-negative women.

References

  • Cuzick 2011

    Cuzick, J., Sestak, I., Pinder, S. E., Ellis, I. O., Forsyth, S., Bundred, N. J., Forbes, J. F., Bishop, H., Fentiman, I. S., George, W. D. (2011) Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: Long-term results from the UK/ANZ DCIS trial. Lancet Oncology, 12, 21–29. [PMC free article: PMC3018565] [PubMed: 21145284]

  • Cuzick 2014

    Cuzick, J., Sestak, I., Forbes, J. F., Dowsett, M., Knox, J., Cawthorn, S., Saunders, C., Roche, N., Mansel, R. E., von Minckwitz, G., Bonanni, B., Palva, T., Howell, A., IBIS-II investigators. (2014). Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. The Lancet, 383, 1041–1048. [PubMed: 24333009]

  • Fisher 1999

    Fisher, B., Dignam, J., Wolmark, N., Wickerham, D. L., Fisher, E. R., Mamounas, E., Smith, R., Begovic, M., Dimitrov, N. V., Margolese, R. G., Kardinal, C. G., Kavanah, M. T., Fehrenbacher, L., Oishi, R. H. (1999) Tamoxifen in treatment of intraductal breast cancer: National surgical adjuvant breast and bowel project B-24 randomised controlled trial. Lancet, 353, 1993–2000. [PubMed: 10376613]

  • Guerrieri-Gonzaga 2006

    Guerrieri-Gonzaga, A., Robertson, C., Bonanni, B., Serrano, D., Cazzaniga, M., Mora, S., Gulisano, M., Johansson, H., Intra, M., Latronico, A., Franchi, D., Pelosi, G., Johnson, K., Decensi, A. (2006) Preliminary results on safety and activity of a randomized, double-blind, 2 X 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in premenopausal women. [Erratum: 2006; 24(19): 3321]. Journal of Clinical Oncology, 24, 129–135. [PubMed: 16382122]

  • NICE 2009

    National Institute for Health and Clinical Excellence. (2009) Early and locally advanced breast cancer: diagnosis and treatment. NICE guideline (CG80). [PubMed: 19167201]

  • Wapnir 2011

    Wapnir, I. L., Dignam, J. J., Fisher, B., Mamounas, E. P., Anderson, S. J., Julian, T. B., Land, S. R., Margolese, R. G., Swain, S. M., Costantino, J. P., Wolmark, N. (2011) Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. Journal of the National Cancer Institute, 103, 478–88. [PMC free article: PMC3107729] [PubMed: 21398619]

Appendices

Appendix B. Literature search strategies

Literature search strategies for 4.1. What is the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer?

Database: Medline

Last searched on Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present.

Date of last search: 27 September 2017

Database: Embase

Last searched on Embase Classic+Embase 1947 to 2017 September 26.

Date of last search: 27 September 2017

Database: Cochrane Library via Wiley Online

Date of last search: 27 September 2017

Literature search strategies for 4.2. What is the effectiveness of ovarian suppression in addition to endocrine therapy in pre-menopausal women with oestrogen-positive breast cancer?

Database: Medline

Last searched on Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present.

Date of last search: 28 September 2017

Database: Embase

Last searched on Embase Classic+Embase 1947 to 2017 September 27.

Date of last search: 28 September 2017

Database: Cochrane Library via Wiley Online

Date of last search: 28 September 2017

Literature search strategies for 10.4. What is the role of chemoprevention in women following initial treatment for ductal carcinoma in situ (DCIS)?

Database: Medline & Embase (Multifile)

Last searched on Embase 1974 to 2017 March 28, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present.

Date of last search: 29 March 2017.

Database: Cochrane Library via Wiley Online

Date of last search: 29 March 2017.

Appendix C. Clinical evidence study selection

Clinical evidence study selection for 4.1. What is the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer?

Figure 1. Flow diagram of clinical article selection for duration of endocrine therapy

Clinical evidence study selection for 4.2. What is the effectiveness of ovarian suppression in addition to endocrine therapy in pre-menopausal women with oestrogen-positive breast cancer?

Figure 2. Flow diagram of clinical article selection for ovarian suppression review

Clinical evidence study selection for 10.4. What is the role of chemoprevention in women following initial treatment for ductal carcinoma in situ (DCIS)?

Figure 3. Flow diagram of clinical article selection for chemoprevention in DCIS

Appendix D. Clinical evidence tables

Clinical evidence tables for 4.1. What is the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer?

Table 10. Studies included in the evidence review for duration of endocrine therapy (PDF, 524K)

Clinical evidence tables for 4.2. What is the effectiveness of ovarian suppression in addition to endocrine therapy in premenopausal women with oestrogen-positive breast cancer?

Table 11. Studies included in the evidence review for ovarian suppression (PDF, 459K)

Clinical evidence tables for 10.4. What is the role of chemoprevention in women following initial treatment for ductal carcinoma in situ (DCIS)?

Table 12. studies included in the evidence review for chemoprevention in DCIS (PDF, 337K)

Appendix E. Forest plots

Forest plots for 4.1. What is the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer?

Comparison 1. Endocrine therapy for greater than 5 years versus endocrine therapy for 5 years only

Figure 4. Disease free survival at 2.5 to 15 year follow-up

Figure 5. Disease free survival at 2.5 to 15 year follow-up: tamoxifen and aromatase inhibitor subgroups

Figure 6. Overall survival at 4 to 15 year follow-up

Figure 7. Overall survival at 4 to 15 year follow-up: tamoxifen and aromatase inhibitor subgroups

Figure 8. Compliance: did not comply with assigned treatment

Figure 9. Treatment-related morbidity: hot flushes at 2 month to 4 year follow-up

Figure 10. Treatment-related morbidity: secondary cancer at 5.6 to 7.6 year follow-up

Figure 11. Treatment-related morbidity: bone fractures at 2 month to 7.6 year follow-up

Figure 12. Treatment-related morbidity: arthralgia at 2 month to 4 year follow-up

Figure 13. Treatment-related morbidity: cardiac disease/event at 2 month to 7.6 year follow-up

Figure 14. Treatment-related morbidity: hypertension at 4 year follow-up

Figure 15. Treatment-related morbidity: osteoporosis at 4 year follow-up

Figure 16. Treatment-related morbidity: myalgia at 4 year follow-up

Figure 17. Treatment-related morbidity: any grade 3+ toxicity at 2.5 to 5.6 year follow-up

Figure 18. Treatment-related morbidity: vaginal dryness at 2 month to 4 year follow-up

Figure 19. Treatment-related morbidity: vaginal bleeding at 2 month to 4 year follow-up

Figure 20. Treatment-related morbidity: vaginal discharge at 2 month to 4 year follow-up

Figure 21. Treatment-related morbidity: stroke at 7.6 year follow-up

Figure 22. Treatment-related morbidity: irregular menstruation at 4 year follow-up

Figure 23. Treatment-related morbidity: phlebitis/thromboembolic events at 2 month to 7.6 year follow-up

Figure 24. HRQoL: change in SF-36 scores from baseline (2 year follow-up)

Figure 25. HRQoL: change in MENQOL scores from baseline (2 year follow-up)

Forest plots for 4.2. What is the effectiveness of ovarian suppression in addition to endocrine therapy in pre-menopausal women with oestrogen-positive breast cancer?

Comparison 1. Ovarian suppression plus tamoxifen versus tamoxifen alone

Figure 26. Overall survival at 5 to 9.9 year follow-up

Figure 27. Disease-free survival at 5 to 9.9 year follow-up

Figure 28. Treatment-related morbidity: vasodilation

Figure 29. Treatment-related morbidity: weight gain

Figure 30. Treatment-related morbidity: arthralgia

Figure 31. Treatment-related morbidity: anxiety/depression/irritability

Figure 32. Treatment-related morbidity: sweating

Figure 33. Treatment-related morbidity: hot flushes (grade 3+) at 3 to 5.6 year follow-up

Figure 34. Treatment-related morbidity: hypertension (grade 3+) at 5.6 year follow-up

Figure 35. Treatment-related morbidity: cardiac ischemia or infarction (grade 3+) at 5.6 year follow-up

Figure 36. Treatment-related morbidity: thrombosis or embolism (grade 3+) at 5.6 year follow-up

Figure 37. Treatment-related morbidity: musculoskeletal symptoms (grade 3+) at 5.6 year follow-up

Figure 38. Treatment-related morbidity: osteoporosis (grade 3+) at 5.6 year follow-up

Figure 39. Treatment-related morbidity: fractures (grade 3+) at 5.6 year follow-up

Figure 40. Treatment-related morbidity: vaginal dryness at 3 to 5.6 year follow-up

Figure 41. Treatment-related morbidity: changes in libido at 3 to 5.6 year follow-up

Figure 42. Treatment-related morbidity: CNS cerebrovascular ischemia (grade 3+) at 5.6 year follow-up

Figure 43. Treatment-related morbidity: CNS haemorrhage (grade 3+) at 5.6 year follow-up

Figure 44. Treatment-related morbidity: vasomotor symptoms measured by Physical Symptoms and Problem List at 3 year follow-up

Figure 45. Treatment-related morbidity: vaginal dryness measured by Physical Symptoms and Problem List at 3 year follow-up

Figure 46. Treatment-related morbidity: changes in total body bone density (g/cm2) at 2 year follow-up

Figure 47. Compliance: treatment completed

Figure 48. HRQoL: FACT-G

Figure 49. HRQoL: FACT-B

Appendix F. GRADE tables

GRADE tables for 4.1. What is the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer?

Table 13. Clinical evidence profile: Comparison 1. Endocrine therapy for greater than 5 years versus endocrine therapy for 5 years only (PDF, 483K)

GRADE tables for 4.2. What is the effectiveness of ovarian suppression in addition to endocrine therapy in pre-menopausal women with oestrogen-positive breast cancer?

Table 14. Clinical evidence profile: Comparison 1. Ovarian suppression plus tamoxifen versus tamoxifen alone (PDF, 509K)

GRADE tables for 10.4. What is the role of chemoprevention in women following initial treatment for ductal carcinoma in situ (DCIS)?

Table 15. Clinical evidence profile: Comparison 1. Tamoxifen versus no chemoprevention for people with excised DCIS (PDF, 433K)

Appendix G. Economic evidence study selection

Economic evidence study selection for 4.1. What is the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer?

See Supplement 1: Health economics literature review for details of economic study selection.

Economic evidence study selection for 4.2. What is the effectiveness of ovarian suppression in addition to endocrine therapy in pre-menopausal women with oestrogen-positive breast cancer?

See Supplement 1: Health economics literature review for details of economic study selection.

Economic evidence study selection for 10.4. What is the role of chemoprevention in women following initial treatment for ductal carcinoma in situ (DCIS)?

See Supplement 1: Health economics literature review for details of economic study selection.

Appendix H. Economic evidence tables

Economic evidence tables for 4.1. What is the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer?

Table 16. Economic evidence table showing the included health economic evidence for the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer (PDF, 330K)

Economic evidence tables for 4.2. What is the effectiveness of ovarian suppression in addition to endocrine therapy in premenopausal women with oestrogen-positive breast cancer?

No economic evidence was identified for this review question.

Economic evidence tables for 10.4. What is the role of chemoprevention in women following initial treatment for ductal carcinoma in situ (DCIS)?

No economic evidence was identified for this review question.

Appendix I. Health economic evidence profiles

Health economic evidence profiles for 4.1. What is the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer?

Table 17. Summary table showing the included health economic evidence for the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer

Health economic evidence profiles for 4.2. What is the effectiveness of ovarian suppression in addition to endocrine therapy in pre-menopausal women with oestrogen-positive breast cancer?

No economic evidence was identified for this review question.

Health economic evidence profiles for 10.4. What is the role of chemoprevention in women following initial treatment for ductal carcinoma in situ (DCIS)?

No economic evidence was identified for this review question.

Appendix J. Health economic analysis

Health economic analysis for 4.1. What is the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer?

No health economic analysis was carried out for this review question.

Health economic analysis for 4.2. What is the effectiveness of ovarian suppression in addition to endocrine therapy in pre-menopausal women with oestrogen-positive breast cancer?

No health economic analysis was carried out for this review question.

Health economic analysis for 10.4. What is the role of chemoprevention in women following initial treatment for ductal carcinoma in situ (DCIS)?

No health economic analysis was carried out for this review question.

Appendix K. Excluded studies

Excluded studies for 4.1. What is the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer?

Clinical studies

Download PDF (308K)

Economic studies

See Supplement 1: Health economics literature review for list of excluded economic studies.

Excluded studies for 4.2. What is the effectiveness of ovarian suppression in addition to endocrine therapy in pre-menopausal women with oestrogen-positive breast cancer?

Clinical studies

Download PDF (420K)

Economic studies

See Supplement 1: Health economics literature review for list of excluded economic studies.

Excluded studies for 10.4. What is the role of chemoprevention in women following initial treatment for ductal carcinoma in situ (DCIS)?

Clinical studies

Download PDF (337K)

Economic studies

See Supplement 1: Health economics literature review for list of excluded economic studies.

Appendix L. Research recommendations

Research recommendations for 4.1. What is the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer?

No research recommendations were made for this review question.

Research recommendations for 4.2. What is the effectiveness of ovarian suppression in addition to endocrine therapy in pre-menopausal women with oestrogen-positive breast cancer?

No research recommendations were made for this review question.

Research recommendations for 10.4. What is the role of chemoprevention in women following initial treatment for ductal carcinoma in situ (DCIS)?

No research recommendations were made for this review question