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Evidence reviews for endocrine therapy for invasive disease
Evidence review D
NICE Guideline, No. 101
Authors
National Guideline Alliance (UK).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.
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
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.
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
Davies 2013
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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.
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
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.
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.
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
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.
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 A. Review protocols
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
| # | Searches |
|---|---|
| 1 | exp Breast Neoplasms/ |
| 2 | exp “Neoplasms, Ductal, Lobular, and Medullary”/ |
| 3 | Carcinoma, Intraductal, Noninfiltrating/ |
| 4 | Carcinoma, Lobular/ |
| 5 | Carcinoma, Medullary/ |
| 6 | 1 or 2 or 3 or 4 or 5 |
| 7 | exp Breast/ |
| 8 | breast.tw. |
| 9 | 7 or 8 |
| 10 | (breast adj milk).tw. |
| 11 | (breast adj tender$).tw. |
| 12 | 10 or 11 |
| 13 | 9 not 12 |
| 14 | exp Neoplasms/ |
| 15 | 13 and 14 |
| 16 | (breast$ adj5 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or leiomyosarcoma$ or dcis or duct$ or infiltrat$ or intraduct$ or lobul$ or medullary or tubular)).mp. |
| 17 | (mammar$ adj5 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or leiomyosarcoma$ or dcis or duct$ or infiltrat$ or intraduct$ or lobul$ or medullary or tubular)).mp. |
| 18 | Paget’s Disease, Mammary/ |
| 19 | (paget$ and (breast$ or mammary or nipple$)).tw. |
| 20 | 15 or 16 or 17 or 18 or 19 |
| 21 | 6 or 20 |
| 22 | exp Aromatase Inhibitors/ |
| 23 | aromatase inhibitor$.mp. |
| 24 | anastrazole.mp. |
| 25 | arimidex.mp. |
| 26 | letrozole.mp. |
| 27 | femara.mp. |
| 28 | exemestane.mp. |
| 29 | aromasin.mp. |
| 30 | Tamoxifen/ |
| 31 | (Nolvadex or tamoxifen$).mp. |
| 32 | or/22-31 |
| 33 | 21 and 32 |
| 34 | Time Factors/ |
| 35 | (duration$ or timing).tw. |
| 36 | (sequenc$ or sequential).tw. |
| 37 | extended.tw. |
| 38 | (continu$ or stop$).tw. |
| 39 | ((optimal or different) adj (regimen$ or treatment or therapy or course)).tw. |
| 40 | (length adj2 (regimen$ or treatment or therapy or course)).tw. |
| 41 | or/34-40 |
| 42 | 33 and 41 |
| 43 | (“MA.17” or MA17 or ATTOM or ATLAS).tw. |
| 44 | 21 and 43 |
| 45 | 42 or 44 |
| 46 | limit 45 to yr=“1996 -Current” |
| 47 | Limit 46 to RCTs and SRs, and general exclusions filter applied |
Database: Embase
Last searched on Embase Classic+Embase 1947 to 2017 September 26.
Date of last search: 27 September 2017
| # | Searches |
|---|---|
| 1 | exp breast cancer/ |
| 2 | exp breast carcinoma/ |
| 3 | exp medullary carcinoma/ |
| 4 | exp intraductal carcinoma/ |
| 5 | exp breast tumor/ |
| 6 | 1 or 2 or 3 or 4 or 5 |
| 7 | exp breast/ |
| 8 | breast.tw. |
| 9 | 7 or 8 |
| 10 | (breast adj milk).tw. |
| 11 | (breast adj tender$).tw. |
| 12 | 10 or 11 |
| 13 | 9 not 12 |
| 14 | exp neoplasm/ |
| 15 | 13 and 14 |
| 16 | (breast$ adj5 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or leiomyosarcoma$ or dcis or duct$ or infiltrat$ or intraduct$ or lobul$ or medullary or tubular)).tw. |
| 17 | (mammar$ adj5 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or leiomyosarcoma$ or dcis or duct$ or infiltrat$ or intraduct$ or lobul$ or medullary or tubular)).tw. |
| 18 | exp Paget nipple disease/ |
| 19 | (paget$ and (breast$ or mammary or nipple$)).tw. |
| 20 | 15 or 16 or 17 or 18 or 19 |
| 21 | 6 or 20 |
| 22 | exp aromatase inhibitor/ |
| 23 | aromatase inhibitor$.mp. |
| 24 | anastrazole.mp. |
| 25 | arimidex.mp. |
| 26 | letrozole.mp. |
| 27 | femara.mp. |
| 28 | exemestane.mp. |
| 29 | aromasin.mp. |
| 30 | tamoxifen/ |
| 31 | (Nolvadex or tamoxifen$).mp. |
| 32 | or/22-31 |
| 33 | 21 and 32 |
| 34 | time factor/ |
| 35 | (duration$ or timing).tw. |
| 36 | (sequenc$ or sequential).tw. |
| 37 | extended.tw. |
| 38 | (continu$ or stop$).tw. |
| 39 | ((optimal or different) adj (regimen$ or treatment or therapy or course)).tw. |
| 40 | (length adj2 (regimen$ or treatment or therapy or course)).tw. |
| 41 | or/34-40 |
| 42 | 33 and 41 |
| 43 | (“MA.17” or MA17 or ATTOM or ATLAS).tw. |
| 44 | 21 and 43 |
| 45 | 42 or 44 |
| 46 | limit 45 to yr=“1996 -Current” |
| 47 | Limit 46 to RCTs and SRs, and general exclusions filter applied |
Database: Cochrane Library via Wiley Online
Date of last search: 27 September 2017
| # | Searches |
|---|---|
| #1 | MeSH descriptor: [Breast Neoplasms] explode all trees |
| #2 | MeSH descriptor: [Neoplasms, Ductal, Lobular, and Medullary] explode all trees |
| #3 | MeSH descriptor: [Carcinoma, Intraductal, Noninfiltrating] explode all trees |
| #4 | MeSH descriptor: [Carcinoma, Lobular] this term only |
| #5 | MeSH descriptor: [Carcinoma, Medullary] this term only |
| #6 | #1 or #2 or #3 or #4 or #5 |
| #7 | MeSH descriptor: [Breast] explode all trees |
| #8 | breast:ti,ab,kw (Word variations have been searched) |
| #9 | #7 or #8 |
| #10 | (breast next milk):ti,ab,kw (Word variations have been searched) |
| #11 | (breast next tender*):ti,ab,kw (Word variations have been searched) |
| #12 | #10 or #11 |
| #13 | #9 not #12 |
| #14 | MeSH descriptor: [Neoplasms] explode all trees |
| #15 | #13 and #14 |
| #16 | (breast* near/5 (neoplasm* or cancer* or tumo?r* or carcinoma* or adenocarcinoma* or sarcoma* or leiomyosarcoma* or dcis or duct* or infiltrat* or intraduct* or lobul* or medullary or tubular)):ti,ab,kw (Word variations have been searched) |
| #17 | (mammar* near/5 (neoplasm* or cancer* or tumo?r* or carcinoma* or adenocarcinoma* or sarcoma* or leiomyosarcoma* or dcis or duct* or infiltrat* or intraduct* or lobul* or medullary or tubular)):ti,ab,kw (Word variations have been searched) |
| #18 | MeSH descriptor: [Paget’s Disease, Mammary] this term only |
| #19 | (paget* and (breast* or mammary or nipple*)):ti,ab,kw (Word variations have been searched) |
| #20 | #15 or #16 or #17 or #18 or #19 |
| #21 | #6 or #20 |
| #22 | MeSH descriptor: [Aromatase Inhibitors] explode all trees |
| #23 | aromatase inhibitor*:ti,ab,kw (Word variations have been searched) |
| #24 | (anastrazole or arimidex or letrozole or femara or exemestane or aromasin):ti,ab,kw (Word variations have been searched) |
| #25 | MeSH descriptor: [Tamoxifen] this term only |
| #26 | (Nolvadex or tamoxifen*):ti,ab,kw (Word variations have been searched) |
| #27 | #22 or #23 or #24 or #25 or #26 |
| #28 | #21 and #27 |
| #29 | MeSH descriptor: [Time Factors] this term only |
| #30 | (duration* or timing):ti,ab,kw (Word variations have been searched) |
| #31 | (sequenc* or sequential):ti,ab,kw (Word variations have been searched) |
| #32 | extended:ti,ab,kw (Word variations have been searched) |
| #33 | (continu* or stop*):ti,ab,kw (Word variations have been searched) |
| #34 | ((optimal or different) next (regimen* or treatment or therapy or course)):ti,ab,kw (Word variations have been searched) |
| #35 | (length near/2 (regimen* or treatment or therapy or course)):ti,ab,kw (Word variations have been searched) |
| #36 | #29 or #30 or #31 or #32 or #33 or #34 or #35 |
| #37 | #28 and #36 |
| #38 | (MA.17 or MA17 or ATTOM or ATLAS):ti,ab,kw (Word variations have been searched) |
| #39 | #21 and #38 |
| #40 | #37 or #39 Publication Year from 1996 to 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
| # | Searches |
|---|---|
| 1 | exp Breast Neoplasms/ |
| 2 | exp “Neoplasms, Ductal, Lobular, and Medullary”/ |
| 3 | Carcinoma, Intraductal, Noninfiltrating/ |
| 4 | Carcinoma, Lobular/ |
| 5 | Carcinoma, Medullary/ |
| 6 | 1 or 2 or 3 or 4 or 5 |
| 7 | exp Breast/ |
| 8 | breast.tw. |
| 9 | 7 or 8 |
| 10 | (breast adj milk).tw. |
| 11 | (breast adj tender$).tw. |
| 12 | 10 or 11 |
| 13 | 9 not 12 |
| 14 | exp Neoplasms/ |
| 15 | 13 and 14 |
| 16 | (breast$ adj5 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or leiomyosarcoma$ or dcis or duct$ or infiltrat$ or intraduct$ or lobul$ or medullary or tubular)).mp. |
| 17 | (mammar$ adj5 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or leiomyosarcoma$ or dcis or duct$ or infiltrat$ or intraduct$ or lobul$ or medullary or tubular)).mp. |
| 18 | Paget’s Disease, Mammary/ |
| 19 | (paget$ and (breast$ or mammary or nipple$)).tw. |
| 20 | 15 or 16 or 17 or 18 or 19 |
| 21 | 6 or 20 |
| 22 | exp Ovariectomy/ |
| 23 | (ovariectom$ or oophorectom$).ti,ab. |
| 24 | (removal adj3 ovar$).ti,ab. |
| 25 | ((radiation or irradiation or radiotherap$) adj3 ovar$).ti,ab. |
| 26 | exp Ovary/ |
| 27 | exp Radiation/ |
| 28 | (ovar$ adj3 (suppress$ or ablat$)).ti,ab. |
| 29 | 26 and 27 |
| 30 | 22 or 23 or 24 or 25 or 28 or 29 |
| 31 | 21 and 30 |
| 32 | Luteinizing Hormone/ |
| 33 | lutein$ hormon$ releas$.mp. |
| 34 | (LHRH$ or LH-RH$).mp. |
| 35 | exp Gonadotropin-Releasing Hormone/ |
| 36 | gonadotrop$ releas$ hormon$.mp. |
| 37 | (GnRH$ or GnRHA$).mp. |
| 38 | (goserelin$ or zolade$ or novgos or buserelin$ or suprefact or suprecur or leuprolid$ or leuprorelin$ or lupron or nafarelin$ or synarel or triptorelin$ or decapeptyl or gonapeptyl).mp. |
| 39 | (hormon$ adj3 (suppress$ or ablat$)).mp. |
| 40 | 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 |
| 41 | 21 and 40 |
| 42 | 31 or 41 |
| 43 | limit 42 to yr=“1992 -Current” |
| 44 | Limit 43 to RCTs and SRs, and general exclusions filter applied |
Database: Embase
Last searched on Embase Classic+Embase 1947 to 2017 September 27.
Date of last search: 28 September 2017
| # | Searches |
|---|---|
| 1 | exp breast cancer/ |
| 2 | exp breast carcinoma/ |
| 3 | exp medullary carcinoma/ |
| 4 | exp intraductal carcinoma/ |
| 5 | exp breast tumor/ |
| 6 | 1 or 2 or 3 or 4 or 5 |
| 7 | exp breast/ |
| 8 | breast.tw. |
| 9 | 7 or 8 |
| 10 | (breast adj milk).tw. |
| 11 | (breast adj tender$).tw. |
| 12 | 10 or 11 |
| 13 | 9 not 12 |
| 14 | exp neoplasm/ |
| 15 | 13 and 14 |
| 16 | (breast$ adj5 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or leiomyosarcoma$ or dcis or duct$ or infiltrat$ or intraduct$ or lobul$ or medullary or tubular)).tw. |
| 17 | (mammar$ adj5 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or leiomyosarcoma$ or dcis or duct$ or infiltrat$ or intraduct$ or lobul$ or medullary or tubular)).tw. |
| 18 | exp Paget nipple disease/ |
| 19 | (paget$ and (breast$ or mammary or nipple$)).tw. |
| 20 | 15 or 16 or 17 or 18 or 19 |
| 21 | 6 or 20 |
| 22 | exp ovariectomy/ |
| 23 | (ovariectom$ or oophorectom$).ti,ab. |
| 24 | (removal adj3 ovar$).ti,ab. |
| 25 | ((radiation or irradiation or radiotherap$) adj3 ovar$).ti,ab. |
| 26 | exp ovary/ |
| 27 | exp radiation/ |
| 28 | (ovar$ adj3 (suppress$ or ablat$)).ti,ab. |
| 29 | 26 and 27 |
| 30 | 22 or 23 or 24 or 25 or 28 or 29 |
| 31 | 21 and 30 |
| 32 | exp gonadorelin/ |
| 33 | lutein$ hormon$ releas$.mp. |
| 34 | (LHRH$ or LH-RH$).mp. |
| 35 | exp growth hormone releasing factor/ |
| 36 | gonadotrop$ releas$ hormon$.mp. |
| 37 | (GnRH$ or GnRHA$).mp. |
| 38 | (goserelin$ or zolade$ or novgos or buserelin$ or suprefact or suprecur or leuprolid$ or leuprorelin$ or lupron or nafarelin$ or synarel or triptorelin$ or decapeptyl or gonapeptyl).mp. |
| 39 | (hormon$ adj3 (suppress$ or ablat$)).mp. |
| 40 | 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 |
| 41 | 21 and 40 |
| 42 | 31 or 41 |
| 43 | limit 42 to yr=“1992 -Current” |
| 44 | Limit 43 to RCTs and SRs, and general exclusions filter applied |
Database: Cochrane Library via Wiley Online
Date of last search: 28 September 2017
| # | Searches |
|---|---|
| #1 | MeSH descriptor: [Breast Neoplasms] explode all trees |
| #2 | MeSH descriptor: [Neoplasms, Ductal, Lobular, and Medullary] explode all trees |
| #3 | MeSH descriptor: [Carcinoma, Intraductal, Noninfiltrating] explode all trees |
| #4 | MeSH descriptor: [Carcinoma, Lobular] this term only |
| #5 | MeSH descriptor: [Carcinoma, Medullary] this term only |
| #6 | #1 or #2 or #3 or #4 or #5 |
| #7 | MeSH descriptor: [Breast] explode all trees |
| #8 | breast:ti,ab,kw (Word variations have been searched) |
| #9 | #7 or #8 |
| #10 | (breast next milk):ti,ab,kw (Word variations have been searched) |
| #11 | (breast next tender*):ti,ab,kw (Word variations have been searched) |
| #12 | #10 or #11 |
| #13 | #9 not #12 |
| #14 | MeSH descriptor: [Neoplasms] explode all trees |
| #15 | #13 and #14 |
| #16 | (breast* near/5 (neoplasm* or cancer* or tumo?r* or carcinoma* or adenocarcinoma* or sarcoma* or leiomyosarcoma* or dcis or duct* or infiltrat* or intraduct* or lobul* or medullary or tubular)):ti,ab,kw (Word variations have been searched) |
| #17 | (mammar* near/5 (neoplasm* or cancer* or tumo?r* or carcinoma* or adenocarcinoma* or sarcoma* or leiomyosarcoma* or dcis or duct* or infiltrat* or intraduct* or lobul* or medullary or tubular)):ti,ab,kw (Word variations have been searched) |
| #18 | MeSH descriptor: [Paget’s Disease, Mammary] this term only |
| #19 | (paget* and (breast* or mammary or nipple*)):ti,ab,kw (Word variations have been searched) |
| #20 | #15 or #16 or #17 or #18 or #19 |
| #21 | #6 or #20 |
| #22 | MeSH descriptor: [Ovariectomy] explode all trees |
| #23 | (ovariectom* or oophorectom*):ti,ab,kw (Word variations have been searched) |
| #24 | (removal near/3 ovar*):ti,ab,kw (Word variations have been searched) |
| #25 | ((radiation or irradiation or radiotherap*) near/3 ovar*):ti,ab,kw (Word variations have been searched) |
| #26 | MeSH descriptor: [Ovary] explode all trees |
| #27 | MeSH descriptor: [Radiation] explode all trees |
| #28 | (ovar* near/3 (suppress* or ablat*)):ti,ab,kw (Word variations have been searched) |
| #29 | #26 and #27 |
| #30 | #22 or #23 or #24 or #25 or #28 or #29 |
| #31 | #21 and #30 |
| #32 | MeSH descriptor: [Luteinizing Hormone] explode all trees |
| #33 | lutein* hormon* releas*:ti,ab,kw (Word variations have been searched) |
| #34 | (LHRH* or LH-RH*):ti,ab,kw (Word variations have been searched) |
| #35 | MeSH descriptor: [Gonadotropin-Releasing Hormone] explode all trees |
| #36 | gonadotrop* releas* hormon*:ti,ab,kw (Word variations have been searched) |
| #37 | (GnRH* or GnRHA*):ti,ab,kw (Word variations have been searched) |
| #38 | (goserelin* or zolade* or novgos or buserelin* or suprefact or suprecur or leuprolid* or leuprorelin* or lupron or nafarelin* or synarel or triptorelin* or decapeptyl or gonapeptyl):ti,ab,kw (Word variations have been searched) |
| #39 | (hormon* near/3 (suppress* or ablat*)):ti,ab,kw (Word variations have been searched) |
| #40 | #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 |
| #41 | #21 and #40 |
| #42 | #31 or #41 Publication Year from 1992 to 2016 |
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.
| # | Searches |
|---|---|
| 1 | exp breast cancer/ use oemezd |
| 2 | exp breast carcinoma/ use oemezd |
| 3 | exp medullary carcinoma/ use oemezd |
| 4 | exp intraductal carcinoma/ use oemezd |
| 5 | exp breast tumor/ use oemezd |
| 6 | exp Breast Neoplasms/ use prmz |
| 7 | exp “Neoplasms, Ductal, Lobular, and Medullary”/ use prmz |
| 8 | Carcinoma, Intraductal, Noninfiltrating/ use prmz |
| 9 | Carcinoma, Lobular/ use prmz |
| 10 | Carcinoma, Medullary/ use prmz |
| 11 | 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 |
| 12 | exp breast/ use oemezd |
| 13 | exp Breast/ use prmz |
| 14 | breast.tw. |
| 15 | 12 or 13 or 14 |
| 16 | (breast adj milk).tw. |
| 17 | (breast adj tender$).tw. |
| 18 | 16 or 17 |
| 19 | 15 not 18 |
| 20 | exp neoplasm/ use oemezd |
| 21 | exp Neoplasms/ use prmz |
| 22 | 20 or 21 |
| 23 | 19 and 22 |
| 24 | (breast$ adj5 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or leiomyosarcoma$ or dcis or duct$ or infiltrat$ or intraduct$ or lobul$ or medullary or tubular)).tw. use oemezd |
| 25 | (mammar$ adj5 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or leiomyosarcoma$ or dcis or duct$ or infiltrat$ or intraduct$ or lobul$ or medullary or tubular)).tw. use oemezd |
| 26 | (breast$ adj5 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or leiomyosarcoma$ or dcis or duct$ or infiltrat$ or intraduct$ or lobul$ or medullary or tubular)).mp. use prmz |
| 27 | (mammar$ adj5 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or leiomyosarcoma$ or dcis or duct$ or infiltrat$ or intraduct$ or lobul$ or medullary or tubular)).mp. use prmz |
| 28 | exp Paget nipple disease/ use oemezd |
| 29 | Paget’s Disease, Mammary/ use prmz |
| 30 | (paget$ and (breast$ or mammary or nipple$)).tw. |
| 31 | 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 |
| 32 | 11 or 31 |
| 33 | Tamoxifen/ use prmz |
| 34 | tamoxifen/ use oemezd |
| 35 | (Nolvadex$ or tamoxifen$).mp. |
| 36 | exp Aromatase Inhibitors/ use prmz |
| 37 | exp aromatase inhibitor/ use oemezd |
| 38 | aromatase inhibitor$.mp. |
| 39 | (anastrazol$ or arimidex$ or letrozol$ or femara$ or exemestan$ or aromasin$).mp. |
| 40 | exp Selective Estrogen Receptor Modulators/ use prmz |
| 41 | Raloxifene Hydrochloride/ use prmz |
| 42 | exp selective estrogen receptor modulator/ use oemezd |
| 43 | raloxifene/ use oemezd |
| 44 | (raloxifen$ or evista$).mp. |
| 45 | 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 |
| 46 | 32 and 45 |
| 47 | exp Primary Prevention/ use prmz |
| 48 | exp Chemoprevention/ use prmz |
| 49 | exp primary prevention/ use oemezd |
| 50 | exp chemoprophylaxis/ use oemezd |
| 51 | (chemoprevent$ or chemoprophylax$).tw. |
| 52 | (prevent$ adj3 (breast$ adj2 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or leiomyosarcoma$ or dcis or duct$ or infiltrat$ or intraduct$ or lobul$ or medullary or tubular))).tw. |
| 53 | (prevent$ adj3 (mammar$ adj2 (neoplasm$ or cancer$ or tumo?r$ or carcinoma$ or adenocarcinoma$ or sarcoma$ or leiomyosarcoma$ or dcis or duct$ or infiltrat$ or intraduct$ or lobul$ or medullary or tubular))).tw. |
| 54 | 47 or 48 or 49 or 50 or 51 or 52 or 53 |
| 55 | 46 and 54 |
| 56 | remove duplicates from 55 |
| 57 | prevent$.m_titl. |
| 58 | 46 and 57 |
| 59 | 56 or 58 |
| 60 | remove duplicates from 59 |
| 61 | Limit 60 to RCTs and SRs, and general exclusions filter applied |
Database: Cochrane Library via Wiley Online
Date of last search: 29 March 2017.
| # | Searches |
|---|---|
| #1 | MeSH descriptor: [Breast Neoplasms] explode all trees |
| #2 | MeSH descriptor: [Neoplasms, Ductal, Lobular, and Medullary] explode all trees |
| #3 | MeSH descriptor: [Carcinoma, Intraductal, Noninfiltrating] explode all trees |
| #4 | MeSH descriptor: [Carcinoma, Lobular] this term only |
| #5 | MeSH descriptor: [Carcinoma, Medullary] this term only |
| #6 | #1 or #2 or #3 or #4 or #5 |
| #7 | MeSH descriptor: [Breast] explode all trees |
| #8 | breast:ti,ab,kw (Word variations have been searched) |
| #9 | #7 or #8 |
| #10 | (breast next milk):ti,ab,kw (Word variations have been searched) |
| #11 | (breast next tender*):ti,ab,kw (Word variations have been searched) |
| #12 | #10 or #11 |
| #13 | #9 not #12 |
| #14 | MeSH descriptor: [Neoplasms] explode all trees |
| #15 | #13 and #14 |
| #16 | (breast* near/5 (neoplasm* or cancer* or tumo?r* or carcinoma* or adenocarcinoma* or sarcoma* or leiomyosarcoma* or dcis or duct* or infiltrat* or intraduct* or lobul* or medullary or tubular)):ti,ab,kw (Word variations have been searched) |
| #17 | (mammar* near/5 (neoplasm* or cancer* or tumo?r* or carcinoma* or adenocarcinoma* or sarcoma* or leiomyosarcoma* or dcis or duct* or infiltrat* or intraduct* or lobul* or medullary or tubular)):ti,ab,kw (Word variations have been searched) |
| #18 | MeSH descriptor: [Paget’s Disease, Mammary] this term only |
| #19 | (paget* and (breast* or mammary or nipple*)):ti,ab,kw (Word variations have been searched) |
| #20 | #15 or #16 or #17 or #18 or #19 |
| #21 | #6 or #20 |
| #22 | MeSH descriptor: [Aromatase Inhibitors] explode all trees |
| #23 | aromatase inhibitor*:ti,ab,kw (Word variations have been searched) |
| #24 | (anastrazol* or arimidex* or letrozol* or femara* or exemestan* or aromasin*):ti,ab,kw (Word variations have been searched) |
| #25 | MeSH descriptor: [Tamoxifen] this term only |
| #26 | (Nolvadex* or tamoxifen*):ti,ab,kw (Word variations have been searched) |
| #27 | MeSH descriptor: [Selective Estrogen Receptor Modulators] explode all trees |
| #28 | MeSH descriptor: [Raloxifene Hydrochloride] explode all trees |
| #29 | (raloxifen* or evista*):ti,ab,kw (Word variations have been searched) |
| #30 | #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 |
| #31 | #21 and #30 |
| #32 | MeSH descriptor: [Primary Prevention] explode all trees |
| #33 | MeSH descriptor: [Chemoprevention] explode all trees |
| #34 | (chemoprevent* or chemoprophylax*):ti,ab,kw (Word variations have been searched) |
| #35 | (prevent* near/3 (breast* near/2 (neoplasm* or cancer* or tumo?r* or carcinoma* or adenocarcinoma* or sarcoma* or leiomyosarcoma* or dcis or duct* or infiltrat* or intraduct* or lobul* or medullary or tubular))):ti,ab,kw (Word variations have been searched) |
| #36 | (prevent* near/3 (mammar* near/2 (neoplasm* or cancer* or tumo?r* or carcinoma* or adenocarcinoma* or sarcoma* or leiomyosarcoma* or dcis or duct* or infiltrat* or intraduct* or lobul* or medullary or tubular))):ti,ab,kw (Word variations have been searched) |
| #37 | prevent*:ti (Word variations have been searched) |
| #38 | #32 or #33 or #34 or #35 or #36 or #37 |
| #39 | #31 and #38 |
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 1Flow 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 2Flow 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 3Flow 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 4Disease free survival at 2.5 to 15 year follow-up
Note. Number of events in each arm not reported for Scottish Adjuvant Tamoxifen Trial
Figure 5Disease free survival at 2.5 to 15 year follow-up: tamoxifen and aromatase inhibitor subgroups
Note. Number of events in each arm not reported for Scottish Adjuvant Tamoxifen Trial
Figure 6Overall survival at 4 to 15 year follow-up
Note. Number of events in each arm not reported for Scottish Adjuvant Tamoxifen Trial
Figure 7Overall survival at 4 to 15 year follow-up: tamoxifen and aromatase inhibitor subgroups
Note. Number of events in each arm not reported for Scottish Adjuvant Tamoxifen Trial
Figure 8Compliance: did not comply with assigned treatment
Figure 9Treatment-related morbidity: hot flushes at 2 month to 4 year follow-up
Figure 10Treatment-related morbidity: secondary cancer at 5.6 to 7.6 year follow-up
Figure 11Treatment-related morbidity: bone fractures at 2 month to 7.6 year follow-up
Figure 12Treatment-related morbidity: arthralgia at 2 month to 4 year follow-up
Figure 13Treatment-related morbidity: cardiac disease/event at 2 month to 7.6 year follow-up
Figure 14Treatment-related morbidity: hypertension at 4 year follow-up
Figure 15Treatment-related morbidity: osteoporosis at 4 year follow-up
Figure 16Treatment-related morbidity: myalgia at 4 year follow-up
Figure 17Treatment-related morbidity: any grade 3+ toxicity at 2.5 to 5.6 year follow-up
Figure 18Treatment-related morbidity: vaginal dryness at 2 month to 4 year follow-up
Figure 19Treatment-related morbidity: vaginal bleeding at 2 month to 4 year follow-up
Figure 20Treatment-related morbidity: vaginal discharge at 2 month to 4 year follow-up
Figure 21Treatment-related morbidity: stroke at 7.6 year follow-up
Figure 22Treatment-related morbidity: irregular menstruation at 4 year follow-up
Figure 23Treatment-related morbidity: phlebitis/thromboembolic events at 2 month to 7.6 year follow-up
.&p=BOOKS&id=576823_chdappef24.jpg "Click on image to zoom")
Figure 24HRQoL: change in SF-36 scores from baseline (2 year follow-up)
Better indicated by higher values
.&p=BOOKS&id=576823_chdappef25.jpg "Click on image to zoom")
Figure 25HRQoL: change in MENQOL scores from baseline (2 year follow-up)
Better indicated by lower values
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 26Overall survival at 5 to 9.9 year follow-up
Note. Number of events in each arm not reported for ABC trial
Figure 27Disease-free survival at 5 to 9.9 year follow-up
Figure 28Treatment-related morbidity: vasodilation
Figure 29Treatment-related morbidity: weight gain
Figure 30Treatment-related morbidity: arthralgia
Figure 31Treatment-related morbidity: anxiety/depression/irritability
Figure 32Treatment-related morbidity: sweating
%20at%203%20to%205.6%20year%20follow-up.&p=BOOKS&id=576823_chdappef33.jpg "Click on image to zoom")
Figure 33Treatment-related morbidity: hot flushes (grade 3+) at 3 to 5.6 year follow-up
%20at%205.6%20year%20follow-up.&p=BOOKS&id=576823_chdappef34.jpg "Click on image to zoom")
Figure 34Treatment-related morbidity: hypertension (grade 3+) at 5.6 year follow-up
%20at%205.6%20year%20follow-up.&p=BOOKS&id=576823_chdappef35.jpg "Click on image to zoom")
Figure 35Treatment-related morbidity: cardiac ischemia or infarction (grade 3+) at 5.6 year follow-up
%20at%205.6%20year%20follow-up.&p=BOOKS&id=576823_chdappef36.jpg "Click on image to zoom")
Figure 36Treatment-related morbidity: thrombosis or embolism (grade 3+) at 5.6 year follow-up
%20at%205.6%20year%20follow-up.&p=BOOKS&id=576823_chdappef37.jpg "Click on image to zoom")
Figure 37Treatment-related morbidity: musculoskeletal symptoms (grade 3+) at 5.6 year follow-up
%20at%205.6%20year%20follow-up.&p=BOOKS&id=576823_chdappef38.jpg "Click on image to zoom")
Figure 38Treatment-related morbidity: osteoporosis (grade 3+) at 5.6 year follow-up
%20at%205.6%20year%20follow-up.&p=BOOKS&id=576823_chdappef39.jpg "Click on image to zoom")
Figure 39Treatment-related morbidity: fractures (grade 3+) at 5.6 year follow-up
Figure 40Treatment-related morbidity: vaginal dryness at 3 to 5.6 year follow-up
Figure 41Treatment-related morbidity: changes in libido at 3 to 5.6 year follow-up
%20at%205.6%20year%20follow-up.&p=BOOKS&id=576823_chdappef42.jpg "Click on image to zoom")
Figure 42Treatment-related morbidity: CNS cerebrovascular ischemia (grade 3+) at 5.6 year follow-up
%20at%205.6%20year%20follow-up.&p=BOOKS&id=576823_chdappef43.jpg "Click on image to zoom")
Figure 43Treatment-related morbidity: CNS haemorrhage (grade 3+) at 5.6 year follow-up
Figure 44Treatment-related morbidity: vasomotor symptoms measured by Physical Symptoms and Problem List at 3 year follow-up
Figure 45Treatment-related morbidity: vaginal dryness measured by Physical Symptoms and Problem List at 3 year follow-up
%20at%202%20year%20follow-up.&p=BOOKS&id=576823_chdappef46.jpg "Click on image to zoom")
Figure 46Treatment-related morbidity: changes in total body bone density (g/cm2) at 2 year follow-up
Figure 47Compliance: treatment completed
Figure 48HRQoL: FACT-G
Figure 49HRQoL: FACT-B
Forest plots for 10.4. What is the role of chemoprevention in women following initial treatment for ductal carcinoma in situ (DCIS)?
Comparison 1. Tamoxifen versus no chemoprevention for people with excised DCIS
Figure 50Disease-free survival at 10 year follow-up
Figure 51Local recurrence survival at 10 to 13.6 year follow-up
Figure 52Overall survival at 13.6 year follow-up
Figure 53Treatment-related morbidity: vaginal dryness/discharge at 3.3 to 6.2 year follow-up
Figure 54Treatment-related morbidity: grade 3+ toxicities at 6.2 year follow-up
Figure 55Treatment-related morbidity: phlebitis/thromboembolism at 6.2 year follow-up
Figure 56Treatment-related morbidity: mood changes at 6.2 year follow-up
Figure 57Treatment-related morbidity: menstrual disorders at 6.2 year follow-up
Figure 58Treatment-related morbidity: hot flashes at 3.3 to 6.2 year follow-up
Figure 59Treatment-related morbidity: fluid retention at 6.2 year follow-up
Figure 60Treatment-related morbidity: ocular/visual at 3.3 year follow-up
Figure 61Treatment-related morbidity: dermatological at 3.3 year follow-up
Figure 62Treatment-related morbidity: dysuria/incontinence at 3.3 year follow-up
Figure 63Treatment-related morbidity: vaginal bleeding at 3.3 year follow-up
Figure 64Treatment-related morbidity: endometrial polyps at 3.3 year follow-up
Figure 65Treatment-related morbidity: sweats/weight gain at 3.3 year follow-up
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?
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)?
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?
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 17Summary table showing the included health economic evidence for the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer
| Study | Population | Comparators | Costs | Effects | Incr costs | Incr effects | ICER | Uncertainty | Applicability and limitations |
|---|---|---|---|---|---|---|---|---|---|
| Erman 2014 | Post-menopausal women with early stage (stage I-III) HR+ breast cancer. | Comparison against standard tamoxifen |
A series of one-way sensitivity analyses were conducted exploring changes in costs and clinical inputs. The result was found to be sensitive to changes in the cost of aromatase inhibitors and the probability of recurrence when taking aromatase inhibitors or tamoxifen. Probabilistic sensitivity analysis was conducted. At the conventional threshold of $50,000 (CAD) per QALY, the probability of being cost-effective was 70% for extended aromatase inhibitors, 30% for extended tamoxifen and 0.003% for standard tamoxifen. |
The study was deemed to be only partially applicable to the UK because it considered the perspective of the Canadian health care system. The study was generally thought to be of good quality but some potentially serious limitations were noted such as the absence of some potentially key parameters from sensitivity analysis (utility weights). | |||||
| Standard tamoxifen | $9,343.66 (CAD) | 10.12 QALYs | Reference | ||||||
| Extended tamoxifen | $8,623.06 (CAD) | 10.38 QALYs | -$720.60 (CAD) | 0.26 QALYs | Dominant | ||||
| Extended aromatase inhibitors | $9,432.73 (CAD) | 10.62 QALYs | $89.07 (CAD) | 0.50 QALYs | $178.14 (CAD) | ||||
| Dominance rank | |||||||||
| Extended tamoxifen | $8,623.06 (CAD) | 10.38 QALYs | Reference | ||||||
| Standard tamoxifen | $9,343.66 (CAD) | 10.12 QALYs | $720.60 (CAD) | -0.26 QALYs | Dominated | ||||
| Extended aromatase inhibitors | $9,432.73 (CAD) | 10.62 QALYs | $809.66 (CAD) | 0.24 QALYs | $3,402.38 (CAD) per QALY | ||||
|
Comments: Strategies compared using ‘dominance rank’ approach to determine optimal strategy overall. Strategies are first ranked in terms of cost (least costly to most costly). The second intervention in the list is then compared against the first strategy. Subsequent strategies are then compared against the previous strategy that was found to be cost-effective. Strategies compared against standard tamoxifen were not reported in study but have been estimated here as they were of most relevance to the review question. | |||||||||
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
Tables
Table 1Summary of the protocol (PICO table)
| Population | Women (18 or over) with oestrogen-receptor positive invasive breast cancer (M0) after surgery and/or radiotherapy |
|---|---|
| Intervention | Continuous endocrine therapy for more than 5 years |
| Comparison | Continuous endocrine therapy for 5 years |
| Outcome | Critical
|
HRQoL, Health-related quality of life
Table 2Summary of included studies
| Study | Trial | Additional inclusion/exclusion criteria | Interventions/comparison |
|---|---|---|---|
| Davies 2016 | ATLAS |
|
|
| Fisher 1996 | B-14 |
|
|
| Fisher 2001 | B-14 |
|
|
| Goss 2005 | MA.17 |
|
|
| Jakesz 2007 | ABCSG 6a |
|
|
| Mamounas 2008 | B-33 |
|
|
| Muss 2008 | MA.17 |
|
|
| Stewart 1996 | Scottish Adjuvant Tamoxifen Trial |
|
|
| Stewart 2001 | Scottish Adjuvant Tamoxifen Trial |
|
|
| Tormey 1996 |
|
|
ABCSG, Austrian Breast and Colorectal Cancer Study Group; ATLAS, Adjuvant Tamoxifen Longer Against Shorter; ER, oestrogen receptor; ET, endocrine therapy; PR, progesterone receptor; QoL, quality of life; TAM, tamoxifen
Table 3Summary clinical evidence profile: Comparison 1. Endocrine therapy for greater than 5 years versus endocrine therapy for 5 years only
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of Participants (studies) | Quality of the evidence (GRADE) | |
|---|---|---|---|---|---|
| Assumed risk: ET=5yrs | Corresponding risk: ET>5yrs | ||||
| Disease-free survival - Whole sample (2.5 to 15 year follow-up) | 2.5yr DFS 93% |
2.5yr DFS 94% (94% to 95%) |
HR 0.85 (0.78 to 0.93) |
16055 (7 studies) | Low1,2 |
| Disease-free survival - Grade 3 (5 year follow-up) | NR | Cannot be calculated |
HR 0.73 (0.29 to 1.84) |
171 (1 study) | Number of events were not reported - insufficient information to judge imprecision, and therefore overall quality |
| Disease-free survival - Continued tamoxifen (5.6 to 15 year follow-up) | 5.6yr DFS 67% |
5.6yr DFS 69% (67% to 71%) |
HR 0.92 (0.84 to 1.01) |
8480 (4 studies) | Low2,3 |
| Disease-free survival - Switched to AI (2.5 to 5 year follow-up) | 2.5yr DFS 93% |
2.5yr DFS 96% (95% to 96%) |
HR 0.61 (0.5 to 0.74) |
7575 (3 studies) | High |
| Overall survival (4 to 15 year follow-up) | 4yr OS 98% |
4yr OS 98% (98% to 98%) |
HR 0.91 (0.83 to 1) |
14555 (6 studies) | Moderate4,5 |
| Overall survival - Continued tamoxifen (5.6 to 15 year follow-up) | 5.6yr OS 89% |
5.6yr OS 90% (89% to 91%) |
HR 0.92 (0.84 to 1.02) |
8533 (4 studies) | Moderate5,6 |
| Overall survival - Switched to AI (4 to 5 year follow-up) | 4yr OS 98% |
4yr OS 98% (98% to 99%) |
HR 0.85 (0.65 to 1.12) |
6022 (2 studies) | Moderate7 |
| Compliance - did not comply with/complete assigned treatment | 87 per 1000 |
98 per 1000 (38 to 245) |
RR 1.12 (0.44 to 2.81) |
19558 (4 studies) | Low2,8 |
| Treatment-related morbidity - hot flushes (2 month to 4 year follow-up) | 475 per 1000 |
565 per 1000 (441 to 726) |
RR 1.19 (0.93 to 1.53) |
7157 (3 studies) | Very low9,10 |
| Treatment-related morbidity - secondary cancer – Any (5.6 to 7.6 year follow-up) | 125 per 1000 |
126 per 1000 (116 to 137) |
RR 1.01 (0.93 to 1.1) |
14581 (4 studies) | High5 |
| Treatment-related morbidity - secondary cancer - Contralateral breast (6 to 7.6 year follow-up) | 68 per 1000 |
61 per 1000 (54 to 70) |
RR 0.9 (0.79 to 1.02) |
14388 (3 studies) | High2 |
| Treatment-related morbidity - secondary cancer – Endometrial (6 to 7.6 year follow-up) | 10 per 1000 |
18 per 1000 (14 to 24) |
RR 1.87 (1.4 to 2.5) |
14388 (3 studies) | Moderate7 |
| Treatment-related morbidity - bone fractures (2 month to 7.6 year follow-up) | 21 per 1000 |
23 per 1000 (19 to 27) |
RR 1.08 (0.9 to 1.3) |
20438 (4 studies) | Moderate10 |
| Treatment-related morbidity – arthralgia (2 month to 4 year follow-up) | 163 per 1000 |
202 per 1000 (184 to 223) |
RR 1.24 (1.13 to 1.37) |
7567 (3 studies) | High |
| Treatment-related morbidity - cardiac disease/event (2 month to 7.6 year follow-up) | 32 per 1000 |
29 per 1000 (22 to 39) |
RR 0.91 (0.69 to 1.19) |
18876 (3 studies) | High |
| Treatment-related morbidity – hypertension (4 year follow-up) | 50 per 1000 |
51 per 1000 (40 to 64) |
RR 1.01 (0.8 to 1.28) |
5149 (1 study) | Low11 |
| Treatment-related morbidity – osteoporosis (4 year follow-up) | 60 per 1000 |
82 per 1000 (67 to 100) |
RR 1.35 (1.11 to 1.65) |
5126 (1 study) | High |
| Treatment-related morbidity – myalgia (4 year follow-up) | 120 per 1000 |
148 per 1000 (129 to 170) |
RR 1.23 (1.07 to 1.41) |
5149 (1 study) | High |
| Treatment-related morbidity - any grade 3+ toxicity (2.5 to 5.6 year follow-up) | 68 per 1000 |
93 per 1000 (68 to 129) |
RR 1.38 (1 to 1.9) |
1755 (2 studies) | Low12,13 |
| Treatment-related morbidity - vaginal dryness (2 month to 4 year follow-up) | 53 per 1000 |
71 per 1000 (48 to 104) |
RR 1.34 (0.91 to 1.96) |
6005 (2 studies) | Moderate10 |
| Treatment-related morbidity - vaginal bleeding (2 month to 4 year follow-up) | 65 per 1000 |
70 per 1000 (19 to 266) |
RR 1.09 (0.29 to 4.11) |
6005 (2 studies) | Low14 |
| Treatment-related morbidity - vaginal discharge (2 month to 4 year follow-up) | 111 per 1000 |
137 per 1000 (51 to 366) |
RR 1.24 (0.46 to 3.3) |
2008 (2 studies) | Very low11,15 |
| Treatment-related morbidity – stroke (7.6 year follow-up) | 18 per 1000 |
20 per 1000 (16 to 26) |
RR 1.09 (0.85 to 1.39) |
12894 (1 study) | Low13 |
| Treatment-related morbidity - irregular menstruation (4 year follow-up) | 271 per 1000 |
252 per 1000 (206 to 303) |
RR 0.93 (0.76 to 1.12) |
1152 (1 study) | Moderate16 |
| Treatment-related morbidity - phlebitis/thromboembolic events (2 month to 7.6 year follow-up) | 3 per 1000 |
7 per 1000 (4 to 11) |
RR 2.17 (1.32 to 3.57) |
14902 (3 studies) | Moderate7 |
| HRQoL - change in SF-36 scores from baseline (2 year follow-up) - Physical health |
The mean HRQoL - change in SF-36 scores from baseline (2 year follow-up) - physical health in the intervention groups was 1 higher (0.73 lower to 2.73 higher) |
382 (1 study) | High | ||
| HRQoL - change in SF-36 scores from baseline (2 year follow-up) - Mental health |
The mean HRQoL - change in SF-36 scores from baseline (2 year follow-up) - physical health in the intervention groups was 0.6 lower (2.42 lower to 1.22 higher) |
382 (1 study) | High | ||
| HRQoL - change in MENQOL scores from baseline (2 year follow-up) – Vasomotor |
The mean HRQoL - change in MENQOL scores from baseline (2 year follow-up) - physical health in the intervention groups was 0.4 higher (0.15 to 0.65 higher) |
386 (1 study) | High | ||
| HRQoL - change in MENQOL scores from baseline (2 year follow-up) – Psychosocial |
The mean HRQoL - change in MENQOL scores from baseline (2 year follow-up) - physical health in the intervention groups was 0.1 lower (0.31 lower to 0.11 higher) |
379 (1 study) | High | ||
| HRQoL - change in MENQOL scores from baseline (2 year follow-up) – Physical |
The mean HRQoL - change in MENQOL scores from baseline (2 year follow-up) - physical health in the intervention groups was 0 higher (0.21 lower to 0.21 higher) |
386 (1 study) | High | ||
| HRQoL - change in MENQOL scores from baseline (2 year follow-up) - Sexual |
The mean HRQoL - change in MENQOL scores from baseline (2 year follow-up) - physical health in the intervention groups was 0.2 higher (0.08 lower to 0.48 higher) |
263 (1 study) | High | ||
Rates of disease-free survival and overall survival in the control group correspond to the trial with the shortest follow-up period
AI, aromatase inhibitor; CI: Confidence interval; DFS: disease-free survival; ET, endocrine therapy; HRQoL: health-related quality of life; MENQOL, menopause-specific quality of life; NR: Not reported; OS, overall survival; RR: Risk ratio; SF-36, 36-Item Short Form Survey
- 1
Significant heterogeneity - I squared value 82% - heterogeneity explored in subgroup analyses
- 2
Serious indirectness in Scottish Adjuvant Tamoxifen Trial due to population; however, this study does not have very much weight in the analysis
- 3
Significant heterogeneity - I squared value 85% - not possible to further investigate heterogeneity as subgroups of interest identified by the GC were not reported for trials that contributed to this estimate
- 4
Significant heterogeneity - I squared value 53% - heterogeneity explored in subgroup analyses
- 5
Serious indirectness in Scottish Adjuvant Tamoxifen Trial and Tormey 1996 due to population; however, neither of these studies have much weight in the analysis
- 6
Significant heterogeneity - I squared value 71% - not possible to further investigate heterogeneity as subgroups of interest identified by the GC were not reported for trials that contributed to this estimate
- 7
<300 events
- 8
Significant heterogeneity - I squared value 99%. High rates of unexplained heterogeneity as subgroups of interest were only identified by the GC for critical outcomes.
- 9
Random effects model with significant heterogeneity - I squared value 91% high rates of unexplained heterogeneity as subgroups of interest were only identified by the GC for critical outcomes.
- 10
95% CI crosses both no effect (1) and GRADE default value for minimally important difference (1.25)
- 11
<300 events and 95% CI crosses both boundaries for no effect (1) and minimally important differences (0.8 and 1.25) based on GRADE default values
- 12
Serious indirectness in Tormey 1996 due to population but study does not have much weight in the analysis
- 13
<300 events and 95% crosses both no effect (1) and minimally important difference (1.25) based on GRADE default value
- 14
95% CI crosses both boundaries for no effect (1) and minimally important differences (0.8 and 1.25) based on GRADE default values
- 15
Significant heterogeneity - I squared value 87% - high rates of unexplained heterogeneity as subgroups of interest were only identified by the GC for critical outcomes.
- 16
95% CI crosses both no effect (1) and minimally important difference (0.8) based on GRADE default value See appendix F for full GRADE tables.
Table 4Summary of the protocol (PICO table)
| Population | Pre-menopausal adult women (18 or over) with oestrogen-receptor positive invasive breast cancer. |
|---|---|
| Intervention | Endocrine therapy with ovarian suppression:
|
| Comparison | Endocrine therapy without ovarian suppression. |
| Outcome | Critical
|
HRQoL, Health-related quality of life; LHRH, Luteinizing-hormone releasing hormone
Table 5Summary of included studies
| Study | Trial | Additional inclusion/exclusion criteria | Interventions/comparison |
|---|---|---|---|
| Adjuvant Breast Cancer Trials Collaborative Group 2007 | ABC Ovarian Ablation or Suppression |
No previous malignancy (except cervical cancer in situ or basal cell carcinoma) No previous systematic therapy for their current breast cancer Included patients receiving chemotherapy |
Intervention arm (TAM+OFS): 20 mg/day tamoxifen for 5 years and either oophorectomy, ovarian radiation, goserelin at 3.6 mg or leuprorelin acetate at 3.75 mg every 28 days for at least 2 years. Control arm (TAM): 20mg/day tamoxifen for 5 years |
| Baum 2006 | ZIPP |
Normal liver function, renal function and full blood count No hormonal therapy in 6 weeks prior to joining trial No previous treatment for malignancies except for basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix. Excluded if unfit for surgery, severely limited life expectancy, primary carcinoma fixed to underlying muscle/chest wall or was ulcerated, had skin infiltration or axillary nodes that demonstrated deep fixity; unwilling/unable to attend treatment and long-term follow-up Included patients receiving chemotherapy |
Intervention arm (TAM+GOS): Oral tamoxifen (20 or 40 mg daily) and goserelin 3.6 mg subcutaneous injection into abdominal wall. Control arm (TAM): Oral tamoxifen (20 or 40 mg daily |
| Francis 2015 | SOFT | Patients had to have undergone either a total mastectomy with subsequent optional radiotherapy or breast-conserving surgery with subsequent radiotherapy. Either axillary dissection or a sentinel-node biopsy was required |
Intervention arm (TAM + OFS): Oral tamoxifen at a dose of 20 mg daily and ovarian suppression by triptorelin at a dose of 3.75 mg administered by means of intramuscular injection every 28 days, bilateral oophorectomy, or bilateral ovarian irradiation. Treatment duration 5 years. Control arm (TAM): Oral tamoxifen at a dose of 20 mg daily for five years. |
| Nystedt 2003 | ZIPP | Post primary surgery Included patients receiving chemotherapy (but able to extract data separately for those not receiving chemotherapy) | 2 years of endocrine therapy in both groups; details not reported (see Baum 2006) |
| Sverrisdottir 2004 | ZIPP |
Primary surgery consisting of a mastectomy or lumpectomy plus axillary node dissection Histopathologic tumour size greater than 10 mm Exclusion criteria: inoperable breast cancer, prior radiotherapy or neoadjuvant chemotherapy, and prior or concurrent endocrine therapy |
Intervention arm (TAM+GOS): tamoxifen 40 mg/d orally and goserelin 3.6 mg subcutaneously every 28 days. The treatment duration for both tamoxifen and goserelin was 2 years. Control arm (TAM): tamoxifen 40 mg/d orally for two years. |
| Tevaarwerk 2014 | E-3193 |
Node-negative Tumours ≤3 cm in diameter No prior systemic therapy (except ≤12 weeks of tamoxifen). No locally advanced disease. Other adjuvant systemic therapies including chemotherapy were not permitted. |
Intervention arm (TAM + OFS): 20 mg oral tamoxifen per day for 5 years. OFS by LHRH analog goserelin 3.6 mg depot every 4 weeks for 5 years, LHRH analog leuprolide acetate 3.75 mg every 4 weeks for 5 years, surgical ablation, or 4) ovarian ablation radiation (20gy in 10 fractions). No dose reductions permitted Control arm (TAM): 20 mg oral tamoxifen per day for 5 years |
ABC, adjuvant breast cancer; GOS, goserelin; LHRH, Luteinizing-hormone releasing hormone; OFS, ovarian function suppression; SOFT, suppression of ovarian function trial; TAM, tamoxifen; ZIPP, Zoladex in pre-menopausal patients trial
Table 6Summary clinical evidence profile: Comparison 1. Ovarian suppression plus tamoxifen versus tamoxifen alone
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of Participants (studies) | Quality of the evidence (GRADE) | |
|---|---|---|---|---|---|
| Assumed risk: Tamoxifen alone6 | Corresponding risk: Tamoxifen + ovarian suppression | ||||
| Overall survival - Whole sample (5 to 9.9 year follow-up) | 5 yr OS 95% |
5 yr OS 96% [95% to 97%) |
HR 0.81 (0.66 to 1) |
4108 (4 studies) | Low1,2,7 |
| Overall survival - Previous chemotherapy: yes (5 year follow-up) | 5 yr OS 91% |
5 yr OS 94% [91% to 96%) |
HR 0.64 (0.42 to 0.97) |
1084 (1 study) | Low1,2 |
| Overall survival - Previous chemotherapy: no (5 year follow-up) | 5 yr OS 100% |
5 yr OS 99% [96% to 100%) |
HR 3.84 (0.81 to 18.18) |
949 (1 study) | Low1,2 |
| Disease-free survival - Whole sample (5 to 9.9 year follow-up) | 5 yr DFS 85% |
5 yr DFS 87% [84% to 89%) |
HR 0.83 (0.67 to 1.03) |
2370 (2 studies) | Moderate1 |
| Disease-free survival - Age: <35 (5 year follow-up) | 5 yr DFS 67% |
5 yr DFS 76% [64% to 85%) |
HR 0.68 (0.42 to 1.11) |
233 (1 study) | Low1,2 |
| Disease-free survival - Age: 35–39 (5 year follow-up) | 5 yr DFS 80% |
5 yr DFS 84% [76% to 90%) |
HR 0.78 (0.49 to 1.24) |
387 (1 study) | Low1,2 |
| Disease-free survival - Age: 40+ (5 year follow-up) | 5 yr DFS 92% |
5 yr DFS 93% (91% to 95%) |
HR 0.9 (0.66 to 1.22) |
1413 (1 study) | Low1,2 |
| Disease-free survival - Grade: 1 (5 year follow-up) | 5 yr DFS 94% |
5 yr DFS 92% (86% to 96%) |
HR 1.23 (0.66 to 2.29) |
540 (1 study) | Low1,2 |
| Disease-free survival - Grade: 2 (5 year follow-up) | 5 yr DFS 84% |
5 yr DFS 89% (85% to 92%) |
HR 0.67 (0.48 to 0.94) |
1006 (1 study) | Low1,2 |
| Disease-free survival - Grade: 3 (5 year follow-up) | 5 yr DFS 74% |
5 yr DFS 77% (68% to 83%) |
HR 0.85 (0.59 to 1.23) |
439 (1 study) | Low1,2 |
| Disease-free survival - HER2: negative (5 year follow-up) | 5 yr DFS 85% |
5 yr DFS 87% (84% to 90%) |
HR 0.88 (0.69 to 1.13) |
1724 (1 study) | Low2 |
| Disease-free survival - HER2: positive (5 year follow-up) | 5 yr DFS 76% |
5 yr DFS 89% (80% to 94%) |
HR 0.42 (0.22 to 0.8) |
236 (1 study) | Low1,2 |
| Disease-free survival - Previous chemotherapy: yes (5 year follow-up) | 5 yr DFS 77% |
5 yr DFS 81% (76% to 85%) |
HR 0.82 (0.63 to 1.06) |
1084 (1 study) | Low1,2 |
| Disease-free survival - Previous chemotherapy: no (5 year follow-up) | 5 yr DFS 93% |
5 yr DFS 94% (91% to 96%) |
HR 0.83 (0.52 to 1.33) |
949 (1 study) | Low1,2 |
| Treatment-related morbidity: vasodilation (follow-up not-reported) | 168 per 1000 |
438 per 1000 (349 to 549) |
RR 2.6 (2.07 to 3.26) |
920 (1 study) | Very low1,2,7 |
| Treatment-related morbidity: weight gain (follow-up not reported) | 57 per 1000 |
89 per 1000 (60 to 133) |
RR 1.57 (1.05 to 2.35) |
1265 (2 studies) | Very low1,2,7 |
| Treatment-related morbidity: arthralgia (follow-up not-reported) | 9 per 1000 |
24 per 1000 (8 to 75) |
RR 2.79 (0.89 to 8.69) |
920 (1 study) | Very low1,2,7 |
| Treatment-related morbidity: anxiety/depression/irritability (follow-up not reported) | 32 per 1000 |
48 per 1000 (26 to 87) |
RR 1.5 (0.82 to 2.75) |
3276 (3 studies) | Low1,2 |
| Treatment-related morbidity: sweating (follow-up not reported) | 8 per 1000 |
35 per 1000 (14 to 89) |
RR 4.49 (1.79 to 11.24) |
1265 (2 studies) | Low1,2 |
| Treatment-related morbidity: hot flushes (grade 3+; 3 to 5.6 year follow-up) | 71 per 1000 |
159 per 1000 (84 to 300) |
RR 2.23 (1.18 to 4.21) |
2356 (2 studies) | Low1,2 |
| Treatment-related morbidity: hypertension (grade 3+; 5.6 year follow-up) | 54 per 1000 |
75 per 1000 (53 to 105) |
RR 1.39 (0.99 to 1.95) |
2011 (1 study) | Low1,2 |
| Treatment related morbidity: cardiac ischemia or infarction (grade 3+; 5.6 year follow-up) | 4 per 1000 |
1 per 1000 (0 to 9) |
RR 0.25 (0.03 to 2.24) |
2011 (1 study) | Low1,2 |
| Treatment related morbidity: thrombosis or embolism (grade 3+; 5.6 year follow-up) | 17 per 1000 |
17 per 1000 (9 to 33) |
RR 1 (0.51 to 1.95) |
2011 (1 study) | Low1,2 |
| Treatment related morbidity: musculoskeletal symptoms (grade 3+; 5.6 year follow-up) | 63 per 1000 |
54 per 1000 (39 to 78) |
RR 0.87 (0.62 to 1.24) |
2011 (1 study) | Low1,2 |
| Treatment related morbidity: osteoporosis (grade 3+; 5.6 year follow-up) | 1 per 1000 |
3 per 1000 (0 to 29) |
RR 3 (0.31 to 28.82) |
2011 (1 study) | Low1,2 |
| Treatment related morbidity: fractures (grade 3+; 5.6 year follow-up) | 8 per 1000 |
8 per 1000 (3 to 21) |
RR 1 (0.38 to 2.66) |
2011 (1 study) | Low1,2 |
| Treatment related morbidity: vaginal dryness (3 to 5.6 year follow-up) | 358 per 1000 |
426 per 1000 (386 to 469) |
RR 1.19 (1.08 to 1.31) |
2356 (2 studies) | Moderate1 |
| Treatment-related morbidity: changes in libido (3 to 5.6 year follow-up) | 363 per 1000 |
406 per 1000 (370 to 446) |
RR 1.12 (1.02 to 1.23) |
2356 (2 studies) | Moderate1 |
| Treatment related morbidity: CNS cerebrovascular ischemia (grade 3+; 5.6 year follow-up) | 4 per 1000 |
1 per 1000 (0 to 9) |
RR 0.25 (0.03 to 2.24) |
2011 (1 study) | Low1,2 |
| Treatment related morbidity: CNS haemorrhage (grade 3+; 5.6 year follow-up) | 0 per 1000 |
0 per 1000 (0 to 0) |
RR 3 (0.12 to 73.63) |
2011 (1 study) | Low2 |
| Treatment-related morbidity: vasomotor symptoms measured by Physical Symptoms and Problem List (3 year follow-up) |
The mean treatment-related morbidity: vasomotor symptoms measured by Physical Symptoms and Problem List in the intervention groups was 0.1 higher (0.44 lower to 0.64 higher) |
60 (1 study) | Very low1,2,3,7 | ||
| Treatment-related morbidity: vaginal dryness measured by Physical Symptoms and Problem List (3 year follow-up) |
The mean treatment-related morbidity: vaginal dryness measured by Physical Symptoms and Problem List in the intervention groups was 0.17 lower (0.5 lower to 0.16 higher) |
63 (1 study) | Very low1,2,3,7 | ||
| Changes in total body bone density (g/cm2; 2 year follow-up) |
The mean changes in total body bone density (g/cm2) in the intervention groups was 0 higher (0.01 lower to 0.02 higher) |
32 (1 study) | Very low1,2,3,7 | ||
| Compliance: treatment completed | 407 per 1000 |
452 per 1000 (354 to 578) |
RR 1.11 (0.87 to 1.42) |
337 (1 study) | Moderate2 |
| HRQoL: FACT-G |
The mean HRQoL: FACT-G in the intervention groups was 1.42 lower (5.06 lower to 2.22 higher) |
188 (1 study) | Very low1,4 | ||
| HRQoL: FACT-B |
The mean HRQoL: FACT-B in the intervention groups was 0.8 lower (5.66 lower to 4.06 higher) |
177 (1 study) | Moderate1,5 | ||
Rates of disease-free survival and overall survival in the control group correspond to the trial with the shortest follow-up period
CNS, central nervous system; CI: Confidence interval; DFS, disease-free survival; FACT-B Functional assessment of cancer therapy – breast cancer; FACT-G Functional assessment of cancer therapy – general; HR: Hazard ratio; OS, overall survival; RR: Risk ratio;
- 1
Unclear allocation concealment and/or randomisation sequence generation
- 2
Optimal information size not met (Number of events=300 for dichotomous outcomes, N=400 for continuous outcomes
- 3
29% of TAM+GOS arm and 11% of TAM arm were ER negative (Swedish subgroup of ZIPP trial)
- 4
MID for FACT-G was 3 points; N<400
- 5
MID for FACT-B total score was 7 points
- 6
Tamoxifen only group illustrative 5 year survival values come from the relevant subgroups in the SOFT trial
- 7
Patients in the ZIPP and ABC trials received concurrent chemotherapy, at similar rates in both arms
Table 7Summary of the protocol (PICO table)
| Population | Adults (18 or over) with DCIS who have undergone initial surgery |
|---|---|
| Intervention |
|
| Comparison | No treatment |
| Outcome | Critical
|
HRQoL, health-related quality of life
Table 8Summary of included studies
| Study | Trial | Additional inclusion/exclusion criteria | Interventions/comparison |
|---|---|---|---|
| Cuzick 2011 | UK/ANZ |
|
|
| Fisher 1999 | NSABP-B34 |
|
|
| Guerrieri-Gonzaga 2006 |
|
| |
| Wapnir 2011 | NSAPB-B34 |
|
|
CNS, central nervous system; DCIS, ductal carcinoma in situ; Gy, gray; NSABP, National Surgical Adjuvant Breast and Bowel Project; TAM, tamoxifen; UK/ANZ, United Kingdom, Australia and New Zealand
Table 9Summary clinical evidence profile: Comparison 1. Tamoxifen versus no chemoprevention for people with excised DCIS
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of Participants (studies) | Quality of the evidence (GRADE) | |
|---|---|---|---|---|---|
| Assumed risk: No chemoprevention | Corresponding risk: Tamoxifen | ||||
| Disease-free survival - Whole sample (10 year follow-up) | 10yr DFS 74% |
10yr DFS 81% (77% to 84%) |
HR 0.71 (0.58 to 0.87) |
1576 (1 study) | High |
| Disease-free survival - BCS+RT (10 year follow-up) | 10yr DFS 87% |
10yr DFS 87% (80% to 92%) |
HR 0.99 (0.61 to 1.60) |
523 (1 study) | Moderate1 |
| Disease-free survival - BCS-RT (10 year follow-up) | 10yr DFS 68% |
10yr DFS 76% (71% to 80%) |
HR 0.71 (0.57 to 0.88) |
1053 (1 study) | Moderate1 |
| Local recurrence – Mixed (10 year follow-up) | 79% free from local recurrence at 10 yrs | 83% free from local recurrence at 10 yrs (79% to 86%) |
HR 0.78 (0.62 to 0.99) |
1576 (1 study) | Moderate1 |
| Local recurrence – Invasive (13.6 year follow-up) | 91% free from local recurrence at 13.6 yrs | 94% free from local recurrence at 13.6 yrs (91% to 96%) |
HR 0.68 (0.49 to 0.95) |
1799 (1 study) | Moderate1 |
| Local recurrence – DCIS (13.6yr follow-up) | 92% free from local recurrence at 13.6 yrs | 93% free from local recurrence at 13.6 yrs (91% to 95%) |
HR 0.84 (0.60 to 1.18) |
1799 (1 study) | Moderate1 |
| Local recurrence - BCS+RT (10 year follow-up) | 91% free from local recurrence at 10 yrs | 92% free from local recurrence at 10 yrs (85% to 95%) |
HR 0.93 (0.50 to 1.74) |
523 (1 study) | Moderate1 |
| Local recurrence - BCSRT (10 year follow-up) | 74% free from local recurrence at 10 yrs | 79% free from local recurrence at 10 yrs (74% to 84%) |
HR 0.77 (0.60 to 0.99) |
1053 (1 study) | Moderate1 |
| Overall survival (13.6 year follow-up) | 13.6yr OS 95% | 13.6yr OS 96% (94% to 97%) |
HR 0.86 (0.66 to 1.12) |
1799 (1 study) | Moderate1 |
| Treatment-related morbidity - vaginal dryness/discharge (3.3 to 6.2 year follow-up) | 198 per 1000 |
321 per 1000 (274 to 375) |
RR 1.62 (1.38 to 1.89) |
1897 (2 studies) | High2 |
| Treatment-related morbidity - grade 3+ toxicities (6.2 year follow-up) | 43 per 1000 |
54 per 1000 (35 to 82) |
RR 1.26 (0.83 to 1.91) |
1781 (1 study) | Low3 |
| Treatment-related morbidity - phlebitis/thromboembolis m (6.2 year follow-up) | 8 per 1000 |
18 per 1000 (7 to 43) |
RR 2.28 (0.94 to 5.52) |
1781 (1 study) | Low3 |
| Treatment-related morbidity - mood changes (6.2 year follow-up) | 107 per 1000 |
106 per 1000 (80 to 138) |
RR 0.99 (0.75 to 1.29) |
1781 (1 study) | Low4 |
| Treatment-related morbidity - menstrual disorders (6.2 year follow-up) | 160 per 1000 |
191 per 1000 (156 to 235) |
RR 1.2 (0.98 to 1.47) |
1781 (1 study) | Moderate5 |
| Treatment-related morbidity - hot flashes (3.3 to 6.2 year follow-up) | 568 per 1000 |
670 per 1000 (624 to 715) |
RR 1.18 (1.1 to 1.26) |
1897 (2 studies) | High2 |
| Treatment-related morbidity - fluid retention (6.2 year follow-up) | 279 per 1000 |
326 per 1000 (284 to 376) |
RR 1.17 (1.02 to 1.35) |
1781 (1 study) | High |
| Treatment-related morbidity - ocular/visual (3.3 year follow-up) | 431 per 1000 |
328 per 1000 (203 to 526) |
RR 0.76 (0.47 to 1.22) |
116 (1 study) | Very low6,7 |
| Treatment-related morbidity - dermatology/skin (3.3 year follow-up) | 431 per 1000 |
293 per 1000 (177 to 483) |
RR 0.68 (0.41 to 1.12) |
116 (1 study) | Very low6,7 |
| Treatment-related morbidity - dysuria/incontinence (3.3 year follow-up) | 86 per 1000 |
86 per 1000 (27 to 282) |
RR 1 (0.31 to 3.27) |
116 (1 study) | Very low4,6 |
| Treatment-related morbidity - vaginal bleeding (3.3 year follow-up) | 69 per 1000 |
121 per 1000 (37 to 390) |
RR 1.75 (0.54 to 5.66) |
116 (1 study) | Very low4,6 |
| Treatment-related morbidity - endometrial polyps (3.3 year follow-up) | 52 per 1000 |
69 per 1000 (16 to 295) |
RR 1.33 (0.31 to 5.7) |
116 (1 study) | Very low4,6 |
| Treatment-related morbidity - sweats/weight gain (3.3 year follow-up) | 138 per 1000 |
156 per 1000 (65 to 374) |
RR 1.13 (0.47 to 2.71) |
116 (1 study) | Very low4,6 |
Rates of disease-free survival, local recurrence and overall survival in the control group correspond to the trial with the shortest follow-up period
BCS: breast-conserving surgery; CI: Confidence interval; DFS, disease-free survival; HR: hazards ratio; OS, overall survival; RR: Risk ratio; RT: radiotherapy
- 1
<300 events
- 2
Very serious indirectness in Guerrieri-Gonzaga 2006 due to population; evidence not downgraded as study only given 4.9% weight in analysis
- 3
<300 events; 95% CI crosses boundary of no effect (1) and minimally important difference (1.25) based on GRADE default values
- 4
<300 events; 95% CI crosses both boundary for no effect (1) and minimally important differences (0.8 and 1.25) based on GRADE default values
- 5
95% CI crosses boundary of no effect (1) and minimally important difference (1.25) based on GRADE default values
- 6
Only 57% of population had excised DCIS
- 7
<300 events; 95% CI crosses boundary of no effect (1) and minimally important difference (0.8) based on GRADE default values
Final
Evidence reviews
developed by the National Guideline Alliance, hosted by the Royal College of Obstetricians and Gynaecologists
Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.
Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.