Implementation of Adjuvant Bisphosphonates for Early

Implementation of Adjuvant Bisphosphonates for Early Breast Cancer Patients

Adjuvant bisphosphonates to reduce the risk of breast cancer recurrence Implementation V1.2 FINAL Page 1 of 8 Issue Date 20/09/2018

Executive Summary

Following publication of a meta-analysis on the use of adjuvant bisphosphonates in early breast cancer1, the National Institute of Clinical Excellence (NICE) issued an Evidence Summary in 20172 recommending their use in preventing recurrence and improving survival early breast cancer. This should have been implemented and adopted as standard care in but has not been.

Northern Cancer Alliance (NCA) recommends that all provider Trusts ensure they have implemented this NICE guidance and make adjuvant bisphoponates

available without further delay.

Key points for provider Trusts and CCG commissioners

Bisphosphonates are not licensed for this indication and must be used ‘off-label’. NICE can only issue Technology Appraisals on licensed indications.

Bisphosphonates for breast cancer patients are funded by CCGs as part of breast cancer services. They are not funded by NHS England.

The evidence shows that use of adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improves breast cancer survival in postmenopausal women. There is an absolute risk reduction in breast cancer death of 3.3% for postmenopausal women with early (curable) breast cancer.

For every 100 patients treated with adjuvant bisphosphonates, 3 deaths from breast cancer will be prevented per annum. In NCA this means 27 to 45 early breast cancer patients will not progress to metastatic disease and die.

The recommended treatment schedule is a 15-minute infusion of zoledronic acid 4mg in 100ml, which should be given in secondary care as a day case attendance, either on oncology day unit, ambulatory care unit or equivalent.

The NCA Chemotherapy group recommends 3 years of treatment (7 doses) to reduce side effects and capacity burden. NICE recommended that patients have treatment every 6 months for 3 to 5 years but could not distigusih between the tewo treatment durations.

Clinical consensus is that patients should be started on adjuvant zolendronate within 6 months of the completion of hospital based treatment, ie. Surgery, Chemo (including Herceptin) and radiotherapy.

Drug costs are negligible, £7.88 per year, per patient. The main costs of the intervention are the cost of administering IV therapy in secondary care. This activity can generate a tariff of £401 per patient.

Treatment numbers are unknown but estimated to be between 30 and 60 patients per 100,000 population each year, with numbers increasing each year for 3 years until steady state is reached. This means 915 to 1525 patients initially per year in the NCA.

There is concern around capacity, however the weekly impact on oncology day

units is small; an average of only 1 to 3 patients per week initially, rising to 6 to

12 over three years (per day unit)



Background

In 2015 a meta-analysis was published in the Lancet1 which examined the risks and benefits of adjuvant bisphosphonate treatment in breast cancer. The meta-analysis showed adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival in postmenopausal women.

The main bisphosphonates examined were ibandronic acid, zoledronic acid and clodronate. These medicines are licensed for prevention of bone fractures in adults with advanced cancer, for osteoporosis and for hypercalcaemia of malignancy.

The use of bisphosphonates for preventing recurrence or improving survival in patients with early breast cancer is not licensed, so use for this indication is off-label. As these medicines are now all generic (patent expired) they are never likely to be licensed for this indication as new licences only usually occur whilst a medicine is patent protected; thus the manufacturer can recover the cost of investing in new licence. This does not present any concerns as most traditional cytotoxic medicines used to treat cancer are used off-label.

This means that for this indication these drugs were unable to be subject to a NICE Technology Appraisal which if positive would require them to be commissioned for use in the NHS. Instead NICE issued a clinical evidence summary in July 20172

The majority of medicines used to treat cancer are commissioned by NHS England, via a pass through arrangement from local Trusts to the regional specialised commissioning team. Only cancer medicines indication(s) and drug regimen combinations that have been approved by NICE, the Cancer Drug Fund and those that were historically in ‘baseline’ funding may be used.

NHS England does not commission hormonal treatments used in cancer or bisphosphonates as these are considered longer term treatments and are funded by CCGs as part of standard activity tariff funding for breast cancer services.

The lack of a single commissioner and fact that the NICE guidance was not mandatory means local commissioning involvement was needed for this intervention and delay in implementation. This has led to postcode prescribing and variation in access across the UK. In the NCA only 4 out of 9 NHS Trusts have implemented.

Evidence Base

The NICE review is comprehensive and highlights the key findings of the meta-analysis carried out by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)1. The meta-analysis reviewed 26 randomised controlled trials involving nearly 19,000 women with primary breast cancer, over 11,000 of whom were post-menopausal. It showed benefits in post-menopausal women, but no benefits were seen in pre-menopausal women. The benefits of bisphosphonates were similar irrespective of histological type of breast cancer and the use of other treatments such as chemotherapy

Reduced risk of breast cancer spreading to the bones within 10 years by 28%; Absolute risk reduction of 2.2% (from 8.8% to 6.6%)

Reduced risk of breast cancer spreading (to any site, including bone) within 10 years by 18%; Absolute risk reduction of 3.3% (from 21.2% to 17.9%).

Reduced risk of death from breast cancer within 10 years by 18%; Absolute risk reduction of 3.3% (from 18.0% to 14.7%)



NICE noted the meta-analysis has limitations due to ‘the methods being poorly reported’ and noted ‘there is insufficient evidence to determine precise subgroups of postmenopausal women who would benefit, with a suggestion that the benefits might be less in women with low-risk cancers.’ Both European3 and North American (CCO/ASCO)4 expert groups recommend that bisphosphonates are used for postmenopausal women at intermediate or high-risk of recurrence of cancer and clinicians should use of decision-making tools such as Adjuvant! Online.

Safety

Bisphosphonates are not without risk or side effects. There is concern when using bisphosphonates on risk of osteonecrosis of the jaw (incidence 0.7%). Other common adverse effects include gastrointestinal effects with oral agents (such as nausea, dyspepsia, mild oesophagitis and abdominal pain) and bone, joint or muscle pain.

Drug Choice

Based on the evidence from the meta-analysis, both the CCO/ASCO and European consensus guidelines recommends one of following two treatment regimens:

Medicine Usual dosage Cost per unit, excluding VAT

Annual cost, excluding VAT

IV zolendronic acid 4 mg/ 100 ml

6-monthly for 3 to 5 years

£3.94 £7.88

Oral sodium clodronate 800 mg

1600 mg daily for 2 to 3 years

£136.67 £1781.59

Note there was less evidence to support the other bisphosphonates and treatment schedules

Using the costs provided by NICE there is clear a cost difference between the two, with zoledronic acid proving much cheaper.

In addition, zoledronic acid is likely to be much better tolerated, oral clodronate is not a pleasant therapy for patients to take, the tablets are large and difficult to swallow, and are much more likely to cause gastrointestinal adverse effects than IV zoledronic acid. The six-monthly hospital visits for administration of zoledronic acid may be a disadvantage for some patients.

Duration of therapy

The trials included in the meta-analysis have a range of treatment durations hence the varying length of treatment in the NICE recommendation. As there is no clear advantage in longer duration of therapy the shorted duration should be preferred as uses fewer NHS resources reducing side effect burden for patients.

New evidence was presented in late 2017 suggesting that longer duration of therapy is not needed. The phase iii SUCCESS A trial, presented at the 2017 San Antonio Breast Cancer Symposium evaluated 5 years versus 2 years of adjuvant zoledronic acid treatment in high-risk early breast cancer patients.



The trial found no benefit for the longer duration; disease-free survival was the same in each arm, approximately 90% at 40 months.5.

This trial has not yet been published so results should be treated with caution as longer follow up may be needed. However whilst it may be too early to consider only 2 years of treatment, the results support the position that there is no clear benefit for treatment longer than 3 years.

Recommendation

In the NCA zoledronic Acid 4mg IV every 6 months for 3 years (7 doses) is the recommended bisphosphonate for reduce the risk of breast cancer recurrence in

post-menopausal patients with early breast cancer.

Patient Numbers

There is a high level of uncertainty when estimating patient number. When new oncology interventions are introduced patient numbers are often much lower than expected (local cancer drug fund data on file). In this case there is uncertainty around the stratification (and hence numbers) of low risk patients who will not need the intervention and higher risk patients who will.

A figure of 3,200 potentially eligible patients per year was calculated for the Scottish population (5.4 Million) which has a similar demographic to North East and Cumbria6.

Using this calculation gives a figure of 592 potential patients per million per annum or 59 per 100,000 per year for NCA area.

However, this is likely to be the absolute maximum and, after low risk patients are stratified out, a more realistic estimate would be between 30 to 50 patients per 100,000 per year for the NCA.

Commissioning position

This is a low-cost NICE recommended therapy, which is commissioned in Scotland and many areas of UK that could save approximately 27 to 45 lives in the North East (see below), therefore should be implemented without delay.

It was only a technicality of drug licensing that has prevented it being a mandatory NICE technology appraisal.

The majority of medicines used to treat cancer are commissioned by NHS England, via a pass-through arrangement from local Trusts to the regional specialised commissioning team. NHS England does not commission bisphosphonates (or hormonal treatments) as these are considered longer term treatments and, consequently, they are funded by CCGs as part of funding breast cancer services.

The intervention (drug and delivery cost) must be funded by CCGs.

The current access to adjuvant bisphosphonates across the NCA is varied and inequitable; it is in use in some Trusts (Durham and Darlington, North Tees & Hartlepool and Sunderland) and not in others, this mirrors the situation across UK.



Cost of the Intervention

There should be no barrier due the drug costs; zoledronic acid is only £7.88 per patient per year (plus some additional costs for vitamin D supplementation for some patients.) It has been approved for this indication by most Trust Drug and Therapeutic Committees /Prescribing Committees. (e.g. it was approved by North of Tyne APC in 2017)

A barrier to universal adoption has been concerns from secondary care oncology day units over the capacity to manage the extra activity to deliver treatment for the prevalent patient population over next three years.

In addition, CCGs may have concerns on funding the new activity due to unknown numbers. CCGs need to agree the increase in Tariff’s with their provider Trust(s).

How this activity is coded can vary and each organisation should check with its own coding teams. For example, from Durham and Darlington suggest each day case visit to secondary for delivery of adjuvant zoledronic acid 15-minute infusion can be coded to Primary Diagnosis C50.9 (malignant neoplasm of breast, unspecified) and OPCS Procedure Code X29.2 (Continuous intravenous infusion of therapeutic substance). This will generate an HRG (Healthcare Resource Group) Tariff of £401 (JA12L)7

Therefore, each zoledronic acid patient will cost approximately £810 per annum (2 x £401 activity plus £7.88 drug cost). This compares with cost of sodium clodronate of £1781.59 per year.

Recommendation

As each provider Trust implements the NICE guideline they must discuss the extra annual activity that will be chargeable (via coding) with their CCG commissioners,

agree what income the CCG will provide. As numbers will rise for three years providers and CCGs must ensure the activity associated with the intervention is

monitored as part of on-going contractual discussions.

Impact for NCA Trusts

In NCA the potential patient numbers and costs are as below:

Provider Trust Approx.

population

Annual Patient Numbers Year 0ne

Cost of Activity (£) Drug cost (£)

30 per 100,000

50 per 100,000

30 per 100,000

50 per 100,000

30 per 100,000

50 per 100,000

North Cumbria 320,000 96 160 76,992 128,320 756 1,261

Newcastle 260,000 78 130 62,556 104,260 615 1,024

Northumbria 499,000 150 250 120,059 200,099 1,180 1,966

Queen Elizabeth Gateshead 191,000 57 96 45,955 76,591 452 753

South Tyneside 153,000 46 77 36,812 61,353 362 603

Sunderland 343,000 103 172 82,526 137,543 811 1,351

Durham and Darlington 596,000 179 298 143,398 238,996 1,409 2,348

James Cook Middlesbrough 411,000 123 206 98,887 164,811 972 1,619

North Tees and Hartlepool 276,000 83 138 66,406 110,676 652 1,087



Note - as treatment is given for three years patient numbers will increase in year two and year three before reaching steady state.

Savings

There is an incidental saving to CCGs on DEXA scans (which are not needed during treatment with adjuvant bisphosphonates) of £58 per scan per patient per year (HRG Tariff RD50Z)7)

. As a result, across the NCA Provider Trusts saving could be:


population

Annual Patient Numbers Year 0ne

DEXA Scan Savings

30 per 100,000

50 per 100,000

30 per 100,000

50 per 100,000

North Cumbria 320,000 96 160 5,568 9,280

Newcastle 260,000 78 130 4,524 7,540

Northumbria 499,000 150 250 8,683 14,471

Queen Elizabeth Gateshead 191,000 57 96 3,323 5,539

South Tyneside 153,000 46 77 2,662 4,437

Sunderland 343,000 103 172 5,968 9,947

Durham and Darlington 596,000 179 298 10,370 17,284

James Cook Middlesbrough 411,000 123 206 7,151 11,919

North Tees and Hartlepool 276,000 83 138 4,802 8,004

TOTAL 915 1,525

Reduction in deaths from breast cancer There is also a wider saving to the NHS based on number of lives saved, this is difficult to estimate but if the treatment works there is an absolute risk reduction in death of 3.3% and in risk metastatic disease in bones of 2.2%. This means there will be a 2 to 3% reduction in cases of metastatic breast cancer per annum. Given total numbers in NCA of between 915 to 1,525 patients to be treated this means up to 27 to 45 early deaths can be prevented. (0.03 x 915 and 0.03 x 1525 respectively).

The lifetime costs of treating metastatic breast cancer to the NHS are very hard to estimate and would be shared among provider Trusts, NHS England and CCG commissioners. Given the cost of drugs used and repeated number of admissions and clinic visits it would not be unreasonable to estimate an annual cost of at least £20,000 per patient (it is likely to be much higher).

A crude estimate for illustration purposes only is on basis of 2 to 3 % absolute risk reduction, is for every 100 patients treated the NHS would save £40,000 to £60,000.

Using the estimate of 27 to 45, NCA savings could be £540,000 to £900,000.

Barriers to Implementation

The impact on oncology day unit capacity is widely perceived as a major barrier to implementation. It is true there will be a large number of additional treatments per annum but in reality the treatments are straightforward only requiring 30 minutes of nurse and chair time and no additional pharmacy time.



When viewed as weekly numbers as below, the impact on oncology day units is small and should be manageable given oncology day units have to constantly absorb additional NICE approvals e.g. immunotherapies.


population

Annual Patient Numbers

Weekly Numbers Year One

Weekly Numbers Year Two

Weekly Numbers Year Three

30 per 100,000

50 per 100,000

30 per 100,000

50 per 100,000

30 per 100,000

50 per 100,000

30 per 100,000

50 per 100,000

North Cumbria 320,000 96 160 2 3 4 6 6 9

Newcastle 260,000 78 130 2 3 3 5 5 8

Northumbria 499,000 150 250 3 5 6 10 9 14

QE Gateshead 191,000 57 96 1 2 2 4 3 6

South Tyneside 153,000 46 77 1 1 2 3 3 4

Sunderland 343,000 103 172 2 3 4 7 6 10

Durham and Darlington

596,000 179 298 3 6 7 11 10 17

James Cook

Middlesbrough 411,000 123 206 2 4 5 8 7 12

North Tees &

Hartlepool 276,000 83 138 2 3 3 5 5 8

Opportunities for Providers

Provider Trusts could look at setting up a weekly clinic slot and schedule the bisphosphonates at same time, e.g. evening session. A minimum of one qualified chemotherapy nurse, plus another qualified member of staff to check drugs would be needed. Funding will depend on negotiations with local CCGs for activity tariff.

However lack of funding should not be a barrier to implementation for this NICE approved intervention.

Conclusions

If the remaining Trusts in NCA who have not implemented do not start offering adjuvant bisphosphonates, then there will not be a reduction in breast cancer deaths.

The uncertainty on capacity impact of the intervention has been a barrier to implementation; however that driven by concerns over the higher numbers when 5 years of treatment was proposed.

By supporting the recommendations of this paper for 3 years treatment rather than 5 the capacity impact is manageable.

Given the very small numbers in year one, Trusts have time to implement in year and then negotiate with CCGs for increase in tariff activity for future years as numbers rise.

CCGs should be assured that the overall cost of this intervention will be offset by the reduction in costs associated with DEXA scans and the savings made by preventing metastatic breast cancers and potentially saving 3 lives per 100

Author Steve Williamson, Consultant Cancer Pharmacist On behalf of Norther Cancer Alliance Chemotherapy Group, August 2018



References (click tom open relevant documents 1 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG),

Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 2015;386(10001): 1353-1361

Lancet 2015 386 1353-61 EBCTCG Bisphosphonates.pdf

2 Early breast cancer (preventing recurrence and improving survival): adjuvant bisphosphonates Evidence summary Published: 25 July 2017 nice.org.uk/guidance/es15 ENC 03

early-breast-cancer-preventing-recurrence-and-improving-survival-adjuvant-bisphosphonates-pdf-1158117021637.pdf

3 Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel. Hadji P, Coleman RE, Wilson C, Powles TJ, Clézardin P, Aapro M et al. Ann Oncol. 2016 Mar;27(3):379-90. doi: 10.1093/annonc/mdv617. Epub 2015 Dec 17

Bisphophonates European Panel 2015.pdf

4 Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline Journal of Clinical Oncology 35, no. 18 (June 2017) 2062-2081 DOI: 10.1200/JCO.2016.70.7257

JCO.2016.70B bisphosphonates.pdf

5 Extended adjuvant bisphosphonate treatment over five years in early breast cancer does not improve disease-free and overall survival compared to two years of treatment: Phase III data from the SUCCESS A study Janni W, Friedl TWP, Fehm T, et al 2017 San Antonio Breast Cancer Symposium. Abstract GS1-06. Presented December 6, 2017.

See :Link

6 Adjuvant bisphosphonates – Scotland Report Available on request from https://breastcancernow.org/ Contact [email protected] 160825_breast_canc

er_now_-_summary_of_adjuvant_bisphosphonates_-_scotland_0.pdf

7 NHS Improvement: 2017/18 and 2018/19 National Tariff: currencies and prices. Available at https://improvement.nhs.uk/resources/national-tariff-1719/ last accessed 20/08/18

See Link

https://www.abstracts2view.com/sabcs/view.php?nu=SABCS17L_87&terms=

https://www.abstracts2view.com/sabcs/view.php?nu=SABCS17L_87&terms=

https://breastcancernow.org/

mailto:[email protected]

https://improvement.nhs.uk/resources/national-tariff-1719/

Articles

www.thelancet.com Vol 386 October 3, 2015 1353

Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trialsEarly Breast Cancer Trialists’ Collaborative Group (EBCTCG)*

SummaryBackground Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer.

Methods We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs).

Findings We received data on 18 766 women (18 206 [97%] in trials of 2–5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87–1·01; 2p=0·08), distant recurrence (0·92, 0·85–0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83–0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73–0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78–0·94; 2p=0·002), distant recurrence (0·82, 0·74–0·92; 2p=0·0003), bone recurrence (0·72, 0·60–0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73–0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75–0·97; 2p=0·02).

Interpretation Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began.

Funding Cancer Research UK, Medical Research Council.

Copyright © Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Open Access article distributed under the terms of CC BY.

IntroductionCirculating tumour cells can be attracted to surfaces within the bone where they can displace haemopoietic stem cells and bind to the osteoblastic niche.1 These disseminated malignant cells can remain quiescent for years. Then, for reasons that are not well understood, they can exit this dormant state, start to proliferate, and establish macro-metastases in the bone or elsewhere.2,3 Bisphosphonates have profound effects on osteoclasts, and affect T-cell function, so could also be effective as adjuvant treatments, particularly in preventing or delaying bone recurrence.4–6 For this reason, and because bisphosphonates can be added to the aromatase inhibitor treatment of post menopausal breast cancer to restrict adverse skeletal effects of oestrogen deprivation, reliable evidence is needed about the effects of bisphosphonates on breast cancer outcomes.

Improvements in bone-metastasis-free survival, disease-free survival, and overall survival in women with early breast cancer have been reported in some adjuvant trials of oral clodronate7,8 or of intravenous zoledronic acid.9,10 However, in other trials of adjuvant bisphos phonates no significant benefits were seen in analyses that included all randomised patients, although both planned and exploratory subset analyses suggested benefits either in postmenopausal women11 or in older women.12,13 This led to the hypothesis11–13 that treatment is of benefit only in patients with low concentrations of reproductive hormones (ie, those who are postmenopausal or undergoing ovarian suppression therapy).14–16

To help clarify whether adjuvant bisphosphonates reduce the risk of bone and other metastases, and whether meno-pausal status affects efficacy, we undertook collab orative

Lancet 2015; 386: 1353–61

This online publication has been corrected. The first corrected version appeared at thelancet.com on Dec 31, 2015. The second appeared on June 22, 2017.

Published Online July 24, 2015 http://dx.doi.org/10.1016/S0140-6736(15)60908-4

See Comment page 1319

*Full list of members available at http://www.ctsu.ox.ac.uk/research/meta-trials/ebctcg/ebctcg-page

Correspondence to: EBCTCG Secretariat, Clinical Trial Service Unit, Nuffield Department of Population Health, Richard Doll Building, Oxford OX3 7LF, UK [email protected]

http://crossmark.crossref.org/dialog/?doi=10.1016/S0140-6736(15)60908-4&domain=pdf

Articles

1354 www.thelancet.com Vol 386 October 3, 2015

meta-analyses of all unconfounded randomised trials that compared breast cancer outcomes in those allocated adjuvant bisphosphonate versus those who were not.

MethodsIdentification of studies and collection of dataThe methods of identifying trials, seeking collaboration, data collection, collation, checking, and pres entation are as in previous Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) reports.17–19 Trials were eligible if they began before 2008 and randomly assigned women be-tween a bisphosphonate of any type, dose, and schedule versus a control group (open label or placebo) with no bisphosphonate, all other treatments being similar in both groups. Information was sought during 2012–14 for each individual patient on date of randomisation, allocated treat-ment, age, menopausal status, tumour diameter, grade, spread to locoregional lymph nodes, HER2 and oestrogen and progesterone receptor (ER/PR) status, dates and sites of any breast cancer recurrence, other second pri mary cancer, bone fracture, and the date and cause of death.

The main definitions and analysis methods are those used in previous EBCTCG reports,17–19 but with some amendments that reflect the potential effect of bisphosphonates on bone metastases (appendix).

OutcomesThe pre-defined coprimary endpoints were any recurrence of breast cancer (distant, locoregional, or new primary in the contralateral breast); distant recurrence, ignoring any

previous locoregional or contralateral recurrence; and breast cancer mortality (estimated by log-rank subtraction, as in previous EBCTCG reports18,19).

Secondary outcomes were all-cause mortality; death without recurrence; bone recurrence as the first distant recurrence (with or without concurrent other recurrence); other first (extraskeletal) distant recurrence (with all analyses of distant recurrence ignoring any previous locoregional or contralateral recurrence); locoregional recurrence as first event (ipsilateral breast, chest wall, or locoregional lymph nodes); contralateral new primary breast cancer as first event; and any bone fractures.

Statistical analysesTime-to-event analyses were stratified by age, ER status, nodal status, and trial. Within each stratum, they compared all those allocated bisphosphonate versus all those allocated control, regardless of treatment compliance (yielding intention-to-treat analyses). Log-rank statistics were used to assess the effects (bisphosphonate vs control) on various outcomes, and, for each, to estimate first-event rate ratios (RRs) and their CIs. We did statistical analyses using EBCTCG in-house Fortran programs.

Pre-specified primary subgroup investigations were of site of first distant recurrence (bone, other), menopausal status (premenopausal, perimenopausal, post menopausal [natural or induced, either potentially reversibly, using luteinising hormone-releasing hormone analogues, or permanently by oophorectomy] or, if menopausal status was unavailable, years of age, grouped as <45, 45–54, ≥55 years), and class of bisphosphonate (amino bisphos-phonate [zoledronic acid, ibandronate, pamidronate, risedronate, alendronate], other [clodronate]). Exploratory investigations were undertaken of potential interactions between treatment efficacy and ER status, nodal status, histological grade, use or not of adjuvant chemotherapy, and follow-up period. If appropriate, tests comparing effects in different subgroups were for trend rather than heterogeneity.

We pre-specified that comparisons of treatment efficacy within subgroups would exclude local and contralateral recurrence if the prior hypothesis that bisphosphonates would reduce distant but not local or contralateral recurrence was established from analyses of the overall results in all randomised patients. As bone recurrence was the only type of recurrence significantly reduced by bisphosphonates we used this instead as the primary endpoint for subgroup comparisons, but the appendix includes subgroup analyses for any distant recurrence. Because the ABCSG-129 and AZURE11,14 trials had helped generate the hypothesis of the relevance of menopausal status to the effects of treatment, we provide sensitivity analyses of this hypothesis that treated these trials as hypothesis-generating, with the remaining trials hypothesis-testing. The policy on data sharing from this study is available online.

See Online for appendix

Studies identified Studies with data received

Trials (n) Patients (n) Trials (n) Patients (n) %* Years†

Up to 1 year of treatment

<1 year clodronate 2 120 1 72 60% 0·5

<1 year aminobisphosphonate 2 208 1 40 19% 0·1

1 year aminobisphosphonate 7 1088 3 448 41% 1·0

Total for ≤1 year of treatment 11 1416 5 560 40% 0·9

2–5 years of treatment

2 years clodronate 4 3978 3 3912 98% 2·0

3–5 years clodronate 1 1069 1 1069 100% 3·0

2 years aminobisphosphonate 10 3654 8 3514 96% 2·0

3–5 years aminobisphosphonate 12 11 910‡ 9 9711 82%‡ 4·5

Total for 2–5 years of treatment 27 20 611‡ 21 18 206 88%‡ 3·5

Any clodronate regimen 7 5167 5 5053 98% 2·6

Any aminobisphosphonate§ 31 16 860‡ 21 13 713 81%‡ 3·8

Total, all regimens 38 22 027‡ 26 18 766 85%‡ 3·4

*Number of patients with data received as a percentage of all randomised patients in identified studies. †Mean scheduled treatment duration (weighted in proportion to numbers of patients with data received). ‡Includes two trials (2116 patients) still in progress; excluding these, the total with data received is 94%. §The aminobisphosphonates in these trials were zoledronic acid (9290 patients with data received, 1582 recurrences [46% of all recurrences]), ibandronate (3072 patients, 380 recurrences [11%]), pamidronate (953 patients, 473 recurrences [14%]), risedronate (398 patients, 13 recurrences [0·4%]), and alendronate (no trials with data received); the only non-aminobisphosphonate in these trials was clodronate (5053 patients, 1005 [29%] recurrences).

Table: Numbers of unconfounded randomised trials of an adjuvant bisphosphonate identified, and numbers with data received, by duration and type of bisphosphonate treatment

For the CTSU policy on data sharing see http://www.ctsu.ox.

ac.uk/research/data-access-policies/data-access-and-

sharing-policy/view

http://www.ctsu.ox.ac.uk/research/data-access-policies/data-access-and-sharing-policy/view

Articles


Role of the funding sourceThe funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The writing committee had full access to all the data in the study and had final responsibility for the decision to submit for publication.

ResultsIndividual patient datasets were provided for 26 trials with 18 766 participants, 97% of all 19 291 women in the 32 completed trials that recorded recurrence data (table, appendix). In four other trials (620 women) recurrence was

not recorded, and from the two ongoing trials (2116 women) outcome data cannot yet be provided. Mean scheduled treatment duration was 3·4 years; 18 206 (97%) of 18 766 participants were in trials of 2–5 years of treatment. Median follow-up was 5·6 woman-years (IQR 3·7–8·0). 3453 women had a recurrence, after which 2106 died.

Recurrence rates were slightly lower with than without bisphosphonates, but this was not significant in analyses that included all 18 766 women (RR 0·94, 95% CI 0·87–1·01; 2p=0·08; figure 1). However, there was a borderline significant reduction in the risk of distant recurrence, ignoring any previous local or contralateral

Figure 1: Recurrence by site and breast cancer mortality in 24 trials of bisphosphonate versus no bisphosphonate (control)Kaplan-Meier graphs showing effects of treatment allocation on 10-year outcomes in all 18 766 patients. (A) Any recurrence. (B) Distant recurrence. (C) Bone recurrence. (D) Breast cancer mortality. O–E=observed minus expected. V=variance of O–E. RR=rate ratio (exp[{O–E}/V]). Error bars are SE.

Recurrence rate/year (%), events/woman-years and log-rank statisticsAllocationBisphosphonateControlRate ratio (95% CI) from (O–E)/V

18 766 women

RR 0·94 (95% CI 0·87–1·01)Log-rank 2p=0·0810-year gain 1·1% (95% CI –0·7 to 2·9)

Control 25·9%

Bisphosphonate 24·9%

Years 0–4 3·63 (1415/38 979) 3·85 (1384/35 984) 0·93 (0·85–1·01) –41·9/593·7

Years 5–9 2·34 (308/13 171) 2·36 (314/13 322) 0·98 (0·81–1·14) –3·1/139·4

Years ≥10 0·87 (15/1724) 0·95 (17/1790) 0·72 (CI 0·01–1·43) –1·8/5·5

17·4%

16·3%

0

10

20

30

40

50

Recu

rrenc

e (%

)

A

Distant recurrence rate/year (%), events/woman-years and log-rank statisticsAllocationBisphosphonateControlRate ratio (95% CI) from (O–E)/V

18 766 women


Control 21·8%


Years 0–4 2·97 (1173/39 559) 3·20 (1170/36 571) 0·91 (0·83–0·99) –47·5/499·9

Years 5–9 1·84 (253/13 746) 1·82 (253/13 931) 0·99 (0·81–1·18) –0·7/114·3

Years ≥10 0·67 (13/1932) 1·08 (21/1941) 0·47 (0·21–1·03) –4·5/5·9

14·8%

13·5%

0

10

20

30

40

50

Dist

ant r

ecur

renc

e (%

)B

Bone recurrence rate/year (%), events/woman-years and log-rank statistics

AllocationBisphosphonateControlRate ratio (95% CI) from (O–E)/V

18 766 women


Control 9·0%


0 5 10

Years 0–4 0·99 (391/39 559) 1·21 (441/36 571) 0·79 (0·66–0·92) –45·0/189·5

Years 5–9 0·76 (104/13 746) 0·71 (99/13 031) 1·02 (0·73–1·31) 0·8/46·8

Years ≥10 0·10 (2/1932) 0·10 (2/1941) 0·61 (0·08–2·25) –0·4/0·9

Years

5·9%

4·7%0

10

20

30

40

50

Bone

recu

rrenc

e (%

)

C

Death rates (%/year: total rate minus rate in women without recurrences) and log-rank statisti

AllocationBisphosphonateControlRate ratio (95% CI)from (O–E)/V

18 766 women

RR 0·91 (95% CI 0·83–0·99)Log-rank 2p=0·0410-year gain 1·7% (95% CI 0·0 to 3·5)

Control 18·4%


0 5 10

Years 0–4 1·83 (1·70–1·97) 1·98 (1·84–2·12) 0·91 (0·81–1·01) –30·5/321·7

Years 5–9 1·81 (1·59–2·03) 1·97 (1·75–2·20) 0·92 (0·75–1·10) –9·5/121·0

Years ≥10 1·21 (0·72–1·69) 1·69 (1·12–2·25) 0·66 (0·18–1·15) –4·5/10·9

Years

9·7%

8·9%

0

10

20

30

40

50

Brea

st ca

ncer

mor

talit

y (%

)

D

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Figure 2: Multiple subgroup analyses of effects on bone recurrence in trials of bisphosphonate versus no bisphosphonate (control)Results are plotted as black squares with horizontal lines that denote 99% rather than 95% CIs to allow for multiple hypothesis testing. Total is plotted as a white diamond that denotes 95% CI. ER=oestrogen receptor. O–E=observed minus expected.

Category Rate ratio (CI)Events/women

Allocatedbisphosphonate

Allocatedcontrol

(a) Age, years (trend χ21=4·9; 2p=0·03)

<45

45–54

55–69

≥70

Age unknown

(b) Menopausal status (trend χ21=3·5; 2p=0·06)

Premenopausal

Perimenopausal

Postmenopausal

(c) ER status (χ21=0·6; 2p=0·4)

ER negative

ER unknown

ER positive

(d) Nodal status (trend χ21=0·5; 2p=0·5)

N0/N–

N1–3

N4+

N other/unknown

(e) Tumour grade (trend χ21=0·4; 2p=0·5)

Well differentiated

Moderately differentiated

Poorly differentiated

Grade unknown

(f) Bisphosphonate type (χ24=0·3; 2p=0·6)

Clodronate

Aminobisphosphonate

(g) Bisphosphonate (χ24=5·9; 2p=0·21)

Clodronate

Zoledronic acid

Pamidronate

Ibandronate

Risedronate

Alendronate

(h) Bisphosphonate dose (χ21=0·4; 2p=0·5)

More intensive

Low intensity

(i) Bisphosphonate duration (trend χ21=0·2; 2p=0·7)

<1 year

2 years

>2 years

(j) Chemotherapy (χ21=0·3; 2p=0·6)

Absence

Presence

(k) Follow-up period, years (trend χ21=2·5; 2p=0·11)

0–1

2–4

5–9

≥10

Total

164/2475 (6·6%)

152/3532 (4·3%)

168/3314 (5·1%)

13/531 (2·4%)

0/4 (0·0%)

151/2141 (7·1%)

173/3224 (5·4%)

196/3022 (6·5%)

22/521 (4·2%)

0/2 (0·0%)

–0·3

–14·2

–25·1

–5·1

71·3

74·3

84·4

7·1

217/3296 (6·6%)

28/461 (6·1%)

252/6099 (4·1%)

212/2875 (7·4%)

19/367 (5·2%)

311/5668 (5·5%)

–7·9

2·0

–42·1

96·4

8·8

128·0

107/1964 (5·4%)

42/637 (6·6%)

348/7255 (4·8%)

135/1684 (8·0%)

47/690 (6·8%)

360/6536 (5·5%)

–15·7

1·2

–26·9

56·4

20·9

169·1

1·00 (0·79–1·26)

0·83 (0·61–1·11)

0·74 (0·56–0·98)

0·49 (0·19–1·29)

0·92 (0·71–1·20)

0·72 (0·57–0·90)

0·76 (0·54–1·07)

1·06 (0·60–1·86)

0·85 (0·70–1·04)

4/277 (1·4%)

169/3081 (5·5%)

324/6498 (5·0%)

4/283 (1·4%)

154/2091 (7·4%)

384/6536 (5·9%)

0·8

–18·5

–26·9

1·7

68·6

166·9

0·76 (0·56–1·04)

0·85 (0·70–1·04)

39/1616 (2·4%)

458/8240 (5·6%)

53/1616 (3·3%)

489/7294 (6·7%)

–6·3

–38·3

21·0

216·2

0·74 (0·48–1·14)

0·84 (0·70–1·00)

0·829 (0·730–0·941)

2p=0·004

70/2638 (2·7%)

225/4323 (5·2%)

160/1205 (13·3%)

42/1690 (2·5%)

68/2631 (2·6%)

231/3352 (6·9%)

183/1190 (15·4%)

60/1737 (3·5%)

0·6

–24·0

–14·3

–6·9

32·3

104·1

76·1

24·6

1·02 (0·72–1·44)

0·79 (0·62–1·02)

0·83 (0·62–1·11)

0·76 (0·45–1·27)

24/877 (2·7%)

196/3667 (5·3%)

156/2801 (5·6%)

121/2511 (4·8%)

26/793 (3·3%)

203/3249 (6·2%)

174/2326 (7·5%)

139/2542 (5·5%)

–1·6

–11·7

–17·6

–4·4

10·9

94·4

76·8

61·4

0·88 (0·68–1·15)

0·80 (0·59–1·07)

0·93 (0·67–1·29)

173/9856 (1·8%)

218/8445 (2·6%)

104/5711 (1·8%)

2/706 (0·3%)

497/9856 (5·0%)

204/8910 (2·3%)

237/7609 (3·1%)

99/5614 (1·8%)

2/758 (0·3%)

542/8910 (6·1%)

–25·0

–20·0

0·8

–0·4

–44·6

85·0

104·6

46·8

0·9

237·1

0·75 (0·56–0·99)

0·83 (0·64–1·06)

1·02 (0·73–1·31)

139/2514 (5·5%)

200/4642 (4·3%)

80/460 (17·4%)

78/2040 (3·8%)

0/200 (0·0%)

(no data)

165/2539 (6·5%)

250/4648 (5·4%)

76/493 (15·4%)

49/1032 (4·7%)

2/198 (1·0%)

–16·7

–24·1

5·1

–8·0

–0·9

67·5

108·7

33·1

27·3

0·5

0·78 (0·57–1·07)

0·80 (0·63–1·03)

1·17 (0·83–1·64)

0·75 (0·46–1·22)

434/7040 (6·2%)

63/2816 (2·2%)

457/6089 (7·5%)

85/2821 (3·0%)

–34·5

–10·1

201·7

35·5

0·84 (0·70–1·01)

0·75 (0·49–1·16)

139/2514 (5·5%)

358/7342 (4·9%)

165/2539 (6·5%)

377/6371 (5·9%)

–16·7

–27·9

67·5

169·7

0·78 (0·57–1·07)

0·85 (0·70–1·03)

Bisphosphonate events

Log-rankO–E

Variance of O–E

1·00·50 1·5 2·0

Control betterBisphosphonate better

Ratio of annual event ratesbisphosphonate : control

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breast recurrence (10-year risk 20·4% bisphosphonate vs 21·8% control; RR 0·92, 95% CI 0·85–0·99; 2p=0·03; figure 1), whereas there was no significant effect on the incidence of local recurrence as first event (RR 1·10, 0·94–1·28; 2p=0·25; appendix) or of contralateral breast cancer as first event (RR 0·96, 0·74–1·25; 2p=0·79). The greater efficacy of bis phosphonates in preventing distant recurrence than in preventing other (local or contralateral) breast cancer recurrence was significant (test for interaction 2p=0·01).

The effect on distant recurrence was mainly because of a reduction in bone recurrence (10-year risk 7·8% vs 9·0%; RR 0·83, 95% CI 0·73–0·94; 2p=0·004; figure 1). There was significantly (p=0·04) greater effect on bone recurrence than on other first distant recurrence (RR 0·98, 95% CI 0·89–1·08; 2p=0·69; appendix), although this apparent lack of efficacy could be partly because delay of bone recurrence with bisphosphonate in a woman who would otherwise have had both bone and other distant recurrence allowed the other recurrence to be the first event.

Breast cancer mortality was borderline significantly lower in patients allocated bisphosphonate than control (10-year risk 16·6% vs 18·4%; RR 0·91, 95% CI 0·83–0·99; 2p=0·04; figure 1), and all-cause mortality was similarly reduced (10-year risk 20·8% vs 22·3%; RR 0·92, 0·85–1·00; 2p=0·06; appendix). Of 2607 deaths from any cause, 501 (19%) were in recurrence-free women; this non-breast cancer mortality appeared to be unaffected by the treatment allocation (RR 0·99, 95% CI 0·82–1·19; 2p=0·91).

We did many subgroup analyses to investigate the effects of bisphosphonates on any recurrence, distant recurrence, bone recurrence, and breast cancer mortality (appendix). In the overall analyses, among all 18 766 women, the clearest evidence of effect of bis phosphonates was, as anticipated, on bone recurrence, so the most informative subgroup analyses should relate to this endpoint (figure 2). The efficacy of bisphosphonates in reducing bone recurrence appeared to be greater in older women (2p=0·03 for trend with age in treatment effect) or, similarly, in postmenopausal women (2p=0·06 for trend with menopausal status). As menopausal status and age are closely correlated, we cannot determine reliably which is more relevant (appendix). Among the 4616 women younger than 45 years, bone recurrence appeared to be unaffected by the treatment allocation (RR 1·00, 95% CI 0·79–1·26; 2p=0·97), but among the 7388 women 55 years or older there was a highly significant treatment effect (RR 0·72, 0·59–0·88; 2p=0·002). Sensitivity analyses of the possible relevance of age and menopausal status that omitted the hypothesis-generating ABCSG-129 and AZURE11,14 studies still showed significant (2p=0·004) benefit only in post menopausal women (appendix). As was the case for bone recurrence, the reductions in any distant recurrence with bisphosphonate were also significantly greater in older women (2p=0·003 for trend with age) and post menopausal women (2p=0·01).

None of the other subgroup analyses of bone recurrence in figure 2 revealed any significant evidence of heterogeneity of benefit by tumour type (or for other breast cancer outcomes; appendix). Although the benefit appeared somewhat larger in ER-negative than ER-positive disease and in node-positive than node-negative tumours, this apparent heterogeneity of treatment effect did not approach significance and could be a chance finding.

Likewise, there was no significant heterogeneity between the apparent effects on bone recurrence of the different bisphosphonate regimens tested in these trials. For this outcome, the benefits of the non-amino bisphosphonate (clodronate, n=5053) and of the two most widely tested aminobisphosphonates (zoledronic acid, n=9290, and ibandronate, n=3072) appeared similar, but there was no apparent benefit in the smaller oral pamidronate group (n=953).

For bone recurrence, the benefits appeared to be similar in trials of low-intensity anti-osteoporosis schedules (eg, 6-monthly intravenous zoledronic acid) and in trials of more intensive schedules such as those approved for use in metastatic bone disease (eg, monthly zoledronic acid, daily oral ibandronate, or daily oral clodronate). Likewise, the average effect appeared similar in trials that tested different durations of treatment (trials of 2 years bisphosphonate vs none: RR 0·76, 95% CI 0·60–0·97; 2p=0·026; trials of 3–5 years bisphosphonate vs none: RR 0·85, 0·73–0·99; 2p=0·037; figure 2), and in the presence or absence of chemotherapy. There were significant reductions in bone recurrence during years 0–1 and years 2–4 after randomisation but there appeared to be no further reduction thereafter. Again, though, this decrease in treatment effect over time was not significant (trend 2p=0·11), perhaps because there is thus far only limited follow-up after the first 5 years.

The 10-year disease outcomes for premenopausal and postmenopausal women separately are summarised in figure 3 and the appendix. In premenopausal women, treatment appeared to have little effect on bone metastases or breast cancer mortality, whereas in postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78–0·94; 2p=0·002; appendix), distant recurrence (RR 0·82, 0·74–0·92; 2p=0·0003; appendix), bone recurrence (RR 0·72, 0·60–0·86; 2p=0·0002), and breast cancer mortality (RR 0·82, 0·73–0·93; 2p=0·002). In both menopausal subgroups, rates of first distant recurrence at sites other than bone appeared to be unaffected by treatment. In the postmenopausal subgroup, for bone recurrence the absolute gain from treatment was 2·2% (95% CI 0·6–3·8) (10-year risks 6·6% vs 8·8%; RR 0·72, 95% CI 0·60–0·86; 2p=0·0002), whereas for breast cancer mortality the absolute gain was 3·3% (95% CI 0·8–5·7) (10-year risks 14·7% vs 18·0%; RR 0·82, 0·73–0·93; 2p=0·002).

To enhance statistical power, the multiple subgroup analyses of bone recurrence (figure 2) and the corresponding analyses of other outcomes (appendix) can

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Figure 3: Main outcomes in premenopausal (excluding

perimenopausal) and in postmenopausal women in

trials of bisphosphonate versus no bisphosphonate

(control)Kaplan-Meier graphs showing

the effects of treatment allocation on 10-year breast

cancer outcomes. (A) Premenopausal and

(B) postmenopausal bone recurrence. (C) Premenopausal

and (D) postmenopausal distant recurrence outside the bone. (E) Premenopausal and

(F) postmenopausal breast cancer mortality.

O-E=observed minus expected. V=variance of O–E. RR=rate ratio (exp[{O–E}/V]).

Error bars are SE.

Bone recurrence rate/year (%), events/woman-years and log-rank statisticsAllocationBisphosphonateControlRate ratio (95% CI) from (O–E)/V

6171 women RR 0·92 (95% CI 0·75–1·12)Log-rank 2p=0·4210-year gain 0·0% (95% CI –2·1 to 2·2)

Control 10·3%


Years 0–4 1·35 (169/12 510) 1·54 (175/11 390) 0·86 (0·66–1·07) –11·4/77·4

Years 5–9 1·00 (47/4710) 0·69 (36/5196) 1·24 (0·73–1·74) 3·9/18·5

Years ≥10 0·07 (1/1390) 0·07 (1/1424) 0·37 (0·02–2·33) –0·4/0·4

7·4%

6·5%0

10

20

30

40

50

Bone

recu

rrenc

e (%

)A

Bone recurrence rate/year (%), events/woman-years and log-rank statisticsAllocationBisphosphonateControlRate ratio (95% CI) from (O–E)/V

11 767 women RR 0·72 (95% CI 0·60–0·86)Log-rank 2p=0·000210-year gain 2·2% (95% CI 0·6 to 3·8)

Control 8·8%


Years 0–4 0·78 (197/25 220) 1·06 (251/23 642) 0·68 (0·52–0·84) –39·3/101·2

Years 5–9 0·67 (55/8157) 0·76 (60/7870) 0·90 (0·54–1·26) –2·8/26·8

Years ≥100·0 (0/513)0·0 (0/484)

5·4%

3·6%0

10

20

30

40

50

Bone

recu

rrenc

e (%

)

B

Recurrence outside bone rate/year (%), events/woman-years and log-rank statisticsAllocationBisphosphonateControlRate ratio (95% CI) from (O–E)/V

6171 women RR 1·08 (95% CI 0·92–1·26)Log-rank 2p=0·3510-year loss 1·1% (95% CI 1·4 to 3·6)


Control 15·9%

Years 0–4 2·64 (330/12 510) 2·41 (275/11 390) 1·12 (0·93–1·30) 14·2/128·4

Years 5–9 1·25 (59/4710) 1·14 (59/5196) 1·03 (0·64–1·42) 0·7/26·1

Years ≥10 0·43 (6/1390) 0·77 (11/1424) 0·37 (0·13–1·08) –3·0/3·1

12·2%

11·1%

0

10

20

30

40

50

Dist

ant r

ecur

renc

e out

side

bone

(%)

C

Recurrence outside bone rate/year (%), events/woman-years and log-rank statisticsAllocationBisphosphonateControlRate ratio (95% CI) from (O–E)/V

11 767 women RR 0·90 (95% CI 0·79–1·02)Log-rank 2p=0·1010-year gain 1·6% (95% CI –0·4 to 3·5)

Control 13·6%


Years 0–4 1·67 (420/25 220) 1·98 (427/23 642) 0·90 (0·77–1·04) –18·4/182·4

Years 5–9 1·04 (85/8157) 1·17 (92/7870) 0·89 (0·60–1·19) –4·5/39·7

Years ≥10 0·78 (4/513) 1·65 (8/484) 0·38 (0·09–1·34) –1·7/1·8

8·7%

7·8%

0

10

20

30

40

50Di

stan

t rec

urre

nce o

utsid

e bo

ne (%

)

D

Death rates (%/year: total rate minus rate in women without recurrence) and log-rank statistics


6171 women RR 1·00 (95% CI 0·86–1·15)Log-rank 2p=0·9610-year gain 0·1% (95% CI –2·9 to 3·0)

Control 20·7%


0 5 10

Years 0–4 2·43 (2·16–2·69) 2·50 (2·22–2·79) 0·97 (0·81–1·14) –3·3/130·6

Years 5–9 2·26 (1·84–2·67) 2·03 (1·65–2·40) 1·10 (0·81–1·40) 5·0/50·0

Years ≥10 1·13 (0·58–1·68) 1·29 (0·71–1·88) 0·71 (0·34–1·50) –2·3/6·9

Years

12·1%

11·8%

0

10

20

30

40

50

Brea

st ca

ncer

mor

talit

y (%

)

E

Death rates (%/year: total rate minus rate in women without recurrence) and log-rank statistics


11 767 women RR 0·82 (95% CI 0·73–0·93)Log rank 2p=0·00210-year gain 3·3% (95% CI 0·8 to 5·7)

Control 18·0%


0 5 10

Years 0–4 1·56 (1·41–1·72) 1·74 (1·58–1·91) 0·86 (0·72–0·99) –27·1/174·9

Years 5–9 1·57 (1·30–1·84) 2·04 (1·74–2·35) 0·76 (0·55–0·97) –18·0/65·0

Years ≥10 1·30 (0·34–2·26) 2·73 (1·30–4·16) 0·52 (0·18–1·44) –2·4/3·6

Years

8·7%

7·5%

0

10

20

30

40

50

Brea

st ca

ncer

mor

talit

y (%

)

F

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all be restricted to postmenopausal women (appendix). In postmenopausal women, there was significant (p=0·01) heterogeneity between agents in the reductions in bone recurrence, explained by the apparent lack of benefit from pamidronate. The clodronate results did appear somewhat more promising than the aminobisphosphonate results but this difference was not significant for distant recurrence or for bone recurrence, and was of only borderline significance for breast cancer mortality, even though the reduction in postmenopausal breast cancer mortality was significant with clodronate but not with the aggregate of all aminobisphosphonate regimens.

Information on fractures was available from only 13 341 (71%) of 18 766 women. Among them, 422 (6·3%) of 6649 bisphosphonate-allocated patients had a fracture reported, as against 487 (7·3%) of 6692 control patients (RR 0·85, 95% CI 0·75–0·97; 2p=0·02; appendix), and the 5-year fracture risk was reduced from 6·3% to 5·1%, with little effect in years 0–1 and most of the gain in years 2–4. After year 5 there appeared to be little further gain, but in both groups the absolute rates after year 5 were lower than in years 0–4, perhaps reflecting incomplete ascertainment.

DiscussionTaking all women together, regardless of menopausal status, this collaborative meta-analysis of individual patient data from 18 766 women randomised in trials of adjuvant bisphosphonates found a highly significant reduction only in bone recurrence, and not in other breast cancer outcomes. Subgroup analyses suggested benefit just in postmenopausal women, among whom there were highly significant reductions not only in bone recurrence but also in any distant recurrence (bone or other), breast cancer mortality, and overall mortality.

Neither in the overall results nor in the results just among postmenopausal women, however, was there any significant effect on distant recurrence at extra-osseous sites, on locoregional recurrence, or on the incidence of contralateral breast cancer. The lack of effect on new contralateral breast cancers is consistent with findings of the large FIT and HORIZON-PFT fracture prevention trials,20 but contrasts with reports from epidemiological studies that breast cancer incidence is reduced in postmenopausal women taking bisphosphonates for osteoporosis.21,22 Thus, the randomised evidence provides no support for the use of bisphosphonates as a breast cancer chemoprevention strategy.

Though the statistical significance of the apparent interaction between menopausal status and treatment efficacy is not extreme, greater benefit for postmenopausal women had been hypothesised to explain the apparent discordance between the ABCSG-129 and AZURE11,14 trial results. Sensitivity analyses that excluded these two hypothesis-generating datasets only marginally weakened the evidence of an interaction with menopausal status, and the benefit was still significant in the remaining postmenopausal women.

Moreover, there is some preclinical evidence that reproductive hormones can inhibit bisphosphonate efficacy against cancer cells in the bone. The effects of zoledronic acid (100 μg/kg weekly) on the growth of disseminated MDA-231 breast cancer cells in bone were compared in ovariectomised mice (modelling the postmenopausal setting) and in sham-operated mice (modelling the premenopausal setting). Zoledronic acid decreased the number of detectable tumours in bone only in the ovariectomised animals.23 Likewise, in a prostate cancer mouse model the ability of disseminated tumour cells in the bone to form detectable tumours was inhibited by zoledronic acid only in castrated mice, not in sham-operated mice.24

The effects on bone recurrence emphasise the potential importance of host microenvironment factors to metastasis. Further studies are needed to clarify why menopausal status should importantly affect the response to bisphosphonates. The complex interactions between reproductive hormones, tumour biology, bone cell function, and bone marrow stem cells could well change as patients progress from the premenopausal setting, where oestradiol and inhibin are of major importance in bones, to the postmenopausal setting, where activin and other members of the TGF-β superfamily become the main regulators of bone cell metabolism.25 A clearer understanding of some of the other mechanisms involved in the development of bone metastasis is now emerging, although how these relate to menopausal status and reproductive hormones remains unknown.26

Other than the apparent effect of menopausal status or, similarly, age on treatment efficacy, the proportional reductions in bone recurrence and breast cancer mortality with treatment did not depend significantly on other patient or clinico pathological primary tumour character-istics, including ER status, axillary lymph node involve-ment, and tumour grade. Similar reductions were seen in the presence and absence of chemotherapy, suggesting that the benefits of bisphosphonates are approximately additive to those of chemotherapy, and vice versa.

As subgroup analyses can yield erratic results, it is difficult to determine from them whether different bisphosphonate regimens have different effects. The endpoint that should yield the most reliable subgroup analyses is bone recurrence. Both for all women and for postmenopausal women, subgroup analyses of bone recurrence suggested similar effects of oral clodronate and of the aggregate of all aminobisphosphonate regimens (mainly intravenous zoledronic acid). Likewise, they suggested no significant heterogeneity in efficacy between the different aminobisphosphonates, though no benefit was seen with oral pamidronate (which could be real, as oral pamidronate is poorly absorbed, has little effect on bone resorption biomarkers or the underlying metastatic bone disease, and failed to show efficacy in myeloma27,28). Numbers were insufficient to assess the efficacy of the standard treatments for osteoporosis, oral

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risedronate or alendronate, as therapy for early breast cancer. Subgroup analyses based instead on breast cancer mortality suggested a greater effect with clodronate than with aminobisphosphonates. However, as the two drugs appeared to have similar effects on bone recurrence, their apparently different effects on breast cancer mortality could be a chance finding.

Much more reliable comparisons of different bis-phosphonate regimens will emerge from ongoing trials that compare them directly. The SWOG0307 trial (NCT00127205) comparing clodronate versus zoledronic acid versus ibandronate in 5400 patients has completed recruit ment and addresses the choice of agent; the SUCCESS trial (NCT02181101) comparing 5 years versus 2 years of zoledronic acid in 3800 patients has also completed recruitment and addresses duration. Similarly, results from two ongoing trials (HOBOE-premenopausal [NCT00412022] and TEAM-IIb [ISRCTN17633610]), plus longer follow-up of the trials included in this meta-analysis, will eventually provide better evidence on any effect of bisphosphonates in premenopausal women, and will provide more stable estimates of the 10-year outcomes in postmenopausal women.

Consistent with the known effects on bone mineral density and quality, the use of adjuvant bisphosphonates was associated with a small reduction in fracture incidence. Although not highly significant, it can be accepted as real because of evidence of fracture reduction in other types of patient. There was no apparent effect of adjuvant bisphosphonates on non-breast cancer mortality. Major adverse events with bisphosphonates are uncommon, but can include impaired renal function and osteonecrosis of the jaw. From the data provided, we were unable to assess the incidence of osteonecrosis of the jaw, but previous reports suggest it ranges from under 1% with clodronate, ibandronate, or 6-monthly zoledronic acid12,13,29 to about 2% with more intensive zoledronic acid schedules.30

These trials have shown that some years of adjuvant bisphosphonate treatment can reduce breast cancer recurrence rates in bone and improve breast cancer survival, but have provided clear evidence of benefit only in women who are postmenopausal (natural or induced) at the time bisphosphonates are started. The use of bisphosphonates in breast cancer is mainly to reduce bone loss and risk of fracture in postmenopausal women with ER-positive disease treated with aromatase inhibitors. Our results show that such bisphosphonate treatment can, in addition, provide oncological benefit, and suggest that adjuvant bis phosphonates should be considered in a broader range of postmenopausal women.ContributorsAnalyses were planned by R Coleman, R Gray, T Powles, A Paterson, M Gnant, J Bergh, K I Pritchard, J Bliss, and D Cameron, and undertaken by R Bradley, R Gray, H Pan, and R Peto in Oxford. R Coleman, R Gray, T Powles, and A Paterson drafted the report and revised it with advice from all writing committee members. The EBCTCG secretariat (R Bradley, J Burrett, M Clarke, C Davies, F Duane, V Evans, L Gettins, J Godwin, R Gray, H Liu, P McGale, E MacKinnon,

T McHugh, S James, P Morris, H Pan, R Peto, S Read, C Taylor, Y Wang, Z Wang) identified trials, obtained datasets, and had full access to them.

Writing committeeR Coleman (Sheffield Cancer Research Centre, Weston Park Hospital, University of Sheffield, UK); T Powles (Royal Marsden Hospital, Sutton, Surrey, UK); A Paterson (Tom Baker Cancer Centre and University of Calgary, Calgary, Alberta, Canada); M Gnant (Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Austrian Breast & Colorectal Cancer Study Group, Vienna, Austria); S Anderson (Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA); I Diel (Center for Gynecological Oncology, Mannheim, Germany); J Gralow (University of Washington School of Medicine, Seattle, WA, USA); G von Minckwitz (German Breast Group, Neu-Isenburg, Germany); V Moebus (Klinikum Frankfurt Höchst, Frankfurt, Germany); J Bergh (Karolinska Institutet and University Hospital, Stockholm, Sweden); K I Pritchard (Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, Canada); J Bliss (ICR-CTSU, Division of Clinical Studies, The Institute of Cancer Research, London, UK); D Cameron (Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK); V Evans (Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK); H Pan (Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK); R Peto (Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK); R Bradley (Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK); R Gray (Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK).

Groups contributing data to the adjuvant bisphosphonates meta-analysesAustrian Breast Cancer Study Group, Vienna, Austria (R Bartsch, P Dubsky, C Fesl, H Fohler, M Gnant, R Greil, R Jakesz, A Lang, G Luschin-Ebengreuth, C Marth, B Mlineritsch, H Samonigg, C F Singer, G G Steger, H Stöger); British Columbia Cancer Agency, Vancouver, Canada (I Olivotto, J Ragaz); Danish Breast Cancer Cooperative Group, Copenhagen, Denmark (P Christiansen, B Ejlertsen, M Ewertz, M-B Jensen, S Møller, H T Mouridsen); German Adjuvant Breast Group, Frankfurt, Germany (W Eiermann, J Hilfrich, W Jonat, M Kaufmann, R Kreienberg, M Schumacher); German Breast Group, Neu-Isenburg, Germany (J U Blohmer, S D Costa, H Eidtmann, B Gerber, C Jackisch, S Loibl, G von Minckwitz); Hellenic Breast Surgeons Society, Greece (U Dafni, C Markopoulos); Helsinki University, Finland (C Blomqvist, T Saarto); Korean Cancer Study Group, Seoul, South Korea (J-H Ahn, K H Jung); Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy (F Perrone); National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA, USA (S Anderson, G Bass, A Brown [deceased], J Bryant [deceased], J Costantino, J Dignam, B Fisher, C Geyer, E P Mamounas, S Paik, C Redmond, S Swain, L Wickerham, N Wolmark); North Central Cancer Treatment Group, Mayo Clinic, Rochester, MN, USA (E Perez, JN Ingle, V J Suman); ProBONE study group, Marburg, Germany (P Hadji); Royal Marsden Hospital, London and Sutton, UK (R A’Hern, M Dowsett, A Makris, M Parton, K Pennert, T J Powles, I E Smith, J R Yarnold); SABRE trial group (international) (G Clack, C Van Poznak); Tel Aviv Sourasky Medical Center, Israel (T Safra); University of Leeds, UK (R Bell, D Cameron, RE Coleman, D Dodwell, S Hinsley, H C Marshall); University of Saarland, Germany (E Solomayer, T Fehm); University of Sheffield, UK (R E Coleman, J Lester, M C Winter, J M Horsman); Washington University, St Louis, Missouri, USA (R Aft); Z-FAST, ZO-FAST & E-ZO-FAST study groups (international) (A M Brufsky, R Coleman, H A Llombart on behalf of Novartis Pharmaceuticals).

EBCTCG steering committeeJ Bergh (co-chair), K Pritchard (co-chair), K Albain, S Anderson, R Arriagada, W Barlow, E Bergsten-Nordström, J Bliss, F Boccardo, R Bradley*, M Buyse, D Cameron, M Clarke*, A Coates, R Coleman, C Correa, J Costantino, J Cuzick, N Davidson, C Davies*, A Di Leo, M Dowsett, M Ewertz, J Forbes, R Gelber, C Geyer, L Gianni, M Gnant, A Goldhirsch, R Gray*, D Hayes, C Hill, J Ingle, W Janni, E MacKinnon*, M Martín, P McGale*, L Norton, Y Ohashi, S Paik, H Pan*, E Perez, R Peto*, M Piccart, L Pierce, V Raina, P Ravdin, J Robertson, E Rutgers, J Sparano, S Swain, C Taylor*, G Viale, G von Minckwitz, X Wang, T Whelan, N Wilcken, E Winer, N Wolmark, W Wood. *Secretariat.

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Declaration of interestsClinical Trial Service Unit (CTSU) staff policy excludes honoraria or consultancy fees for any member of the Early Breast Cancer Trialists’ Collaborative Group Secretariat. EBCTCG is funded by Cancer Research UK and UK Medical Research Council grants to the CTSU. SA reports grants from National Institutes of Health (U10 CA069974 and U10 CA69651), during the conduct of the study. JBe reports that Karolinska University Hospital and Karolinska Institutet have received payments for academic clinical studies and research grants for molecular biological studies and PET studies from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche, and Sanofi-Aventis; he was Swedish principal investigator (PI) for an adjuvant bisphosphonate study for which oral pamidronate was provided free-of-charge (this formulation is not licensed); he is also Swedish PI for the ongoing ABCSG-18 adjuvant denosumab study (the drug was provided free-of-charge); he reports no personal payments in the past 3 years. DC reports support from Novartis to attend the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium conferences, outside the submitted work. RC reports personal fees from Novartis (for expert testimony), outside the submitted work. MG reports grants and personal fees from Novartis and personal fees from Amgen, during the conduct of the study; outside the submitted work he has received grants and personal fees from Novartis, Roche, and GlaxoSmithKline, grants from Sanofi-Aventis, Pfizer, and Smith Medical, and personal fees from AstraZeneca, Nanostring Technologies, and Accelsiors. JG reports grants from Novartis, Amgen, and Roche, outside the submitted work. VM reports grants and personal fees from Amgen and Roche, grants from Novartis, and personal fees from Celgene, outside the submitted work. KIP reports grants and personal fees from AstraZeneca, Pfizer, Roche, Novartis, and Eisai, and personal fees from Amgen and GlaxoSmithKline, outside the submitted work. JBl, RB, ID, VE, RG, HP, AP, RP, TP, and GvM declare no competing interests.

AcknowledgmentsWe thank the tens of thousands of women who took part in the trials, the many staff in trial centres and participating clinics who helped conduct the trials, and the trialists who shared their data. Funding for individual trials was chiefly from manufacturers (see trial publications) but no commercial funding was sought or used by the secretariat. Funding for the EBCTCG secretariat is through the direct support from Cancer Research UK and the UK Medical Research Council, to the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, UK.

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attraction. Nat Rev Cancer 2011; 11: 411–25.2 Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;

350: 1655–64.3 Guo W. Concise review: breast cancer stem cells: regulatory

networks, stem cell niches, and disease relevance. Stem Cells Transl Med 2014; 3: 942–48.

4 Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2003; 2: 584–93.

5 Thompson K, Roelofs AJ, Jauhiainen M, Mönkkönen H, Mönkkönen J, Rogers MJ. Activation of γδ T cells by bisphosphonates. Adv Exp Med Biol 2010; 658: 11–20.

6 Kanis J, Powles T, Paterson A, et al. Clodronate decreases the frequency of skeletal metastases in women with breast cancer. Bone 1996; 19: 663–67.

7 Powles TJ, Paterson AE, McCloskey E, et al. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer. Breast Cancer Res Treat 2006; 8: R13, 1–7.

8 Diel IJ, Jaschke A, Solomayer EF, et al. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow—a long term follow up. Ann Oncol 2008; 19: 2007–11.

9 Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360: 679–91.

10 Coleman RE, de Boer R, Eidtmann H, et al. Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-fast study): final 60-month results. Ann Oncol 2013; 24: 398–405.

11 Coleman RE, Cameron D, Dodwell D, et al, on behalf of the AZURE investigators. Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. Lancet Oncol 2014; 15: 997–1006.

12 Paterson AHG, Anderson SJ, Lembersky BC, et al. Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol 2012; 13: 734–42.

13 von Minckwitz G, Möbus V, Schneeweiss A, et al. German adjuvant intergroup node-positive study: a phase III trial to compare oral ibandronate versus observation in patients with high-risk early breast cancer. J Clin Oncol 2013; 31: 3531–39.

14 Coleman RE, Marshall H, Cameron D, et al, on behalf of the AZURE investigators. Breast cancer adjuvant therapy with zoledronic acid. N Engl J Med 2011; 365: 1396–405.

15 Coleman R, Gnant M, Morgan G, Clezardin P. Effects of bone-targeted agents on cancer progression and mortality. J Natl Cancer Inst 2012; 104: 1059–67.

16 Hadji P, Coleman R, Gnant M, Green J. The impact of menopause on bone, zoledronic acid, and implications for breast cancer growth and metastasis. Ann Oncol 2012; 23: 2782–90.

17 Early Breast Cancer Trialists’ Collaborative Group. Treatment of early breast cancer: worldwide evidence, 1985–1990. Introduction and methods. Oxford: Oxford University Press, 1990. http://www.ctsu.ox.ac.uk/reports/ebctcg-1990/index_html (accessed July 7, 2015).

18 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365: 1687–717.

19 Early Breast Cancer Trialists’ Collaborative Group. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011; 378: 771–84.

20 Hue TF, Cummings SR, Cauley JA, et al. Effect of bisphosphonate use on risk of postmenopausal breast cancer: results from the randomized clinical trials of alendronate and zoledronic acid. JAMA Intern Med 2014; 174: 1550–57.

21 Chlebowski RT, Chen Z, Cauley JA, et al. Oral bisphosphonate use and breast cancer incidence in postmenopausal women. J Clin Oncol 2010; 28: 3582–90.

22 Rennert G, Pinchev M, Rennert HS. Use of bisphosphonates and risk of postmenopausal breast cancer. J Clin Oncol 2010; 28: 3577–81.

23 Ottewell PD, Wang N, Meek J, et al. Zoledronic acid has differential antitumor activity in the pre- and postmenopausal bone microenvironment in vivo. Clin Can Res 2014; 20: 2922–32.

24 Ottewell PD, Wang N, Brown HK, et al. Castration-induced bone loss triggers growth of disseminated prostate cancer cells in bone. Endocrine-Related Cancer 2014; 21: 769–81.

25 Nicks KM, Fowler TW, Akel NS, et al. Bone turnover across the menopausal transition, the role of gonadal inhibins. Ann NY Acad Sci 2010; 1192: 153–60.

26 Cox TR, Rumney RMH, Schoof EM, et al. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 2015; 522: 106–10.

27 Kristensen B, Ejlertsen B, Mouridsen H, et al. Bisphosphonate treatment in primary breast cancer: results from a randomised comparison of oral pamidronate versus no pamidronate in patients with primary breast cancer. Acta Oncol 2008; 47: 740–46.

28 Brincker H, Westin J, Abildgaard N, et al. Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma—a double blind placebo controlled trial. Br J Haematol 1998; 101: 280–86.

29 Gnant M, Mlineritsch B, Stoeger H, et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozole plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol 2014; 26: 313–20.

30 Rathbone EJ, Brown JE, Marshall HC, et al. Osteonecrosis of the jaw and oral health-related quality of life after adjuvant zoledronic acid: an Adjuvant Zoledronic Acid to Reduce Recurrence Trial subprotocol (BIG1/04). J Clin Oncol 2013; 31: 2685–92.

Early breast cancer (preEarly breast cancer (prevventing recurrence andenting recurrence andimproimproving survival): adjuvant bisphosphonatesving survival): adjuvant bisphosphonates

Evidence summary

Published: 25 July 2017nice.org.uk/guidance/es15

pat hways

KKeey pointsy points

The content of this evidence summary was up-to-date in July 2017. See summaries of product

characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-

to-date information.

Regulatory status:Regulatory status: Bisphosphonates reduce the rate of bone turnover. Six bisphosphonates are

available in the UK (alendronic acid, ibandronic acid, pamidronate, risedronate, clodronate and

zoledronic acid), which have various indications. Bisphosphonates may be used in some people with

breast cancer, within the terms of their licenses, to prevent and treat osteoporosis or skeletal

events, or manage osteolytic lesions, bone pain or hypercalcaemia of malignancy. However, these

treatments are not licensed for preventing recurrence or improving survival in people with early

breast cancer, and use for this indication is off-label.

OvOverviewerview

This evidence summary discusses a meta-analysis of individual participant data from 26

randomised controlled trials (RCTs) including 18,766 women with early breast cancer (the Early

Breast Cancer Trialists' Collaborative Group [EBCTCG] meta-analysis 2015). The meta-analysis

found that, at 10 years compared with control, adjuvant bisphosphonates (in addition to standard

breast cancer treatments) produced small, borderline statistically significant reductions in distant

recurrence (recurrence in the bone or elsewhere, not in the breasts or regional lymph nodes), bone

© NICE 2017. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and-conditions#notice-of-rights).

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https://www.evidence.nhs.uk/formulary/bnf/current

https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency

https://www.nice.org.uk/guidance/published?type=apg,csg,cg,mpg,ph,sg,sc,dg,hst,ipg,mtg,qs,ta,es,ktt,lgb,mib

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60908-4/abstract


recurrence and breast cancer mortality (absolute reductions 1.4%, 1.1% and 1.7% respectively), but

not breast cancer recurrence or all-cause mortality.

When prespecified subgroup analyses according to menopausal status were undertaken, no

benefits were seen in premenopausal women, but the benefits in postmenopausal women were

found to be greater than in the general study population. At 10 years compared with control, the

absolute reductions in the risk of breast cancer mortality, bone recurrence and all-cause mortality

in postmenopausal women were 3.3%, 2.2% and 2.3%, respectively.

The Cancer Care Ontario and the American Society of Clinical Oncology (CCO/ASCO) guideline on

the Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer states that,

although the EBCTCG meta-analysis found bisphosphonate treatment reduced the risk of bone

recurrence and subsequently improved survival in postmenopausal women with early breast

cancer, the absolute benefits were small compared with control and may not result in a clinically

meaningful effect. Nevertheless, a Lancet comment accompanying the EBCTCG meta-analysis

notes that the absolute reduction in the risk of dying from breast cancer among postmenopausal

women (3.3% at 10 years) seen in the meta-analysis is similar to the benefit seen with anthracycline

polychemotherapy versus nonanthracycline polychemotherapy.

The meta-analysis has limitations, primarily because the methods used were poorly reported. For

example, there is no information on how trials were identified, no assessment of trial quality or risk

of bias, no citations for publications for the included and excluded trials, and no indication whether

the populations and treatments studied were homogeneous or not. It is also unclear what standard

treatments were used for breast cancer in the included trials, whether standard treatment differed

between pre- and postmenopausal women, and whether the treatments used reflect current

clinical practice. Combining the data for all bisphosphonates in the meta-analysis was

controversial, as was including small trials not designed to measure the outcomes of interest and

performing a meta-analysis of subgroups. See the evidence strengths and limitations section of this

evidence summary for more details.

The results of the meta-analysis suggest that bisphosphonates may be beneficial in

postmenopausal women and provide an estimate of the average effects of bisphosphonates across

the whole subgroup. However, evidence is insufficient to determine precise subgroups of

postmenopausal women who would or would not benefit. The authors of the CCO/ASCO guideline

note that the benefits might be less in women with low-risk cancers, which might be a factor in

deciding whether to use treatment, particularly when balanced against the risk of adverse events

with bisphosphonates. Similarly, more than half of the experts involved in developing European

consensus guidance on adjuvant bisphosphonates for early breast cancer considered that

Early breast cancer (preventing recurrence and improving survival): adjuvant bisphosphonates (ES15)


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http://thelancet.com/journals/lancet/article/PIIS0140-6736(15)61163-1/fulltext

https://www.nice.org.uk/Glossary?letter=H

http://live-publications.nice.org.uk/evidence-review#evidence-strengths-and-limitations

https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdv617


bisphosphonates should be used only in postmenopausal women at intermediate- or high-risk of

recurrence of cancer.

Several decision-making tools such as Adjuvant! Online, PREDICT and the Nottingham Prognostic

Index are available to help estimate the risk of recurrence and mortality, and the benefits of

standard adjuvant treatments based on various clinical parameters. According to the CCO/ASCO

guideline, similar parameters may be relevant when deciding whether or not bisphosphonates

should be used. If treatment with bisphosphonates is considered appropriate, it should be

discussed with each woman, taking their individual risk of recurrence and death into account and

balancing this against their risk of adverse effects from bisphosphonates.

The optimal choice, dosage and duration of bisphosphonate treatment for preventing recurrence

and improving survival in women with early breast cancer is unclear. Based on the evidence from

the meta-analysis, the CCO/ASCO guideline generally recommends intravenous zoledronic acid

(4 mg every 6 months for 3–5 years) or oral clodronate (1,600 mg daily for 2–3 years) for

postmenopausal women with breast cancer deemed candidates for adjuvant bisphosphonate

therapy (in addition to standard breast cancer treatments). The European consensus guideline also

recommends 6-monthly intravenous zoledronic acid or daily oral clodronate for preventing

metastases and improving disease outcomes in postmenopausal women with early breast cancer.

There is less evidence to support the use of monthly intravenous zoledronic acid and daily oral

ibandronic acid, and little or no evidence to support the use of risedronate and alendronic acid.

Different adverse effect profiles, frequency and route of administration, and cost may affect the

choice of treatment. The EBCTCG meta-analysis did not report adverse effects, but the adverse

effects of bisphosphonates are well-established. An older Cochrane review that considered the use

of bisphosphonates in a broader population with breast cancer concluded that the adverse effects

of bisphosphonates were generally mild and infrequent. Serious, rare adverse events associated

with bisphosphonates include serious oesophageal reactions, osteonecrosis of the jaw, atypical

stress fractures and renal impairment. The MHRA has issued guidance on preventing and managing

these.

Results from ongoing trials may provide more evidence on the effects of bisphosphonates on breast

cancer recurrence and survival in premenopausal women, allow more stable estimates of the

10-year outcomes in postmenopausal women, and provide comparisons of different

bisphosphonate regimens.

A summary to inform local decision-making is shown in table 1.



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https://www.gov.uk/government/publications/bisphosphonates-use-and-safety

TTableable 1 Summary of the e1 Summary of the evidence on effectivvidence on effectiveness, safetyeness, safety, patient factors and resource implications, patient factors and resource implications

EffectivEffectivenesseness

In all women in the EBCTCG meta-analysis (n=18,766), the absolute 10-year risk with

bisphosphonates compared with control was reduced by:

1.4% for distant recurrence (20.4% compared with 21.8%, p=0.03)

1.1% for bone recurrence (7.8% compared with 9.0%, p=0.004), and

1.7% for breast cancer mortality (16.6% compared with 18.4%, p=0.04).

There was no statistically significant reduction in the risk of all-cause mortality or all breast

cancer recurrence.

A subgroup analysis found that in postmenopausal women (n=11,767) the absolute 10-year

risk with bisphosphonates compared with control was reduced by:

3.0% for breast cancer recurrence (22.8% compared with 25.8%, p=0.002)

3.4% for distant recurrence (17.9% compared with 21.2%, p=0.0003)

2.2% for bone recurrence (6.6% compared with 8.8%, p=0.0002) and

3.3% for breast cancer mortality (14.7% compared with 18.0%, p=0.002)

2.3% for all-cause mortality (21.1% compared with 23.5%, p=0.005).

Bisphosphonate use had no statistically significant effect on distant recurrence other than

bone recurrence, or on locoregional recurrence (in the same site as the original tumour or in

the regional lymph nodes) or contralateral breast cancer (in the opposite breast).

Subgroup analyses suggested that benefits were independent of the type and dosage of

bisphosphonate, the tumour characteristics and the use of concomitant chemotherapy. No

subgroup analyses assessed bisphosphonates according to women's estimated risk of

breast cancer recurrence or mortality.



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SafetySafety

Common adverse effects include gastrointestinal effects (such as nausea, dyspepsia, mild

oesophagitis and abdominal pain) and bone, joint or muscle pain. Adverse effects vary

among bisphosphonates, and some are related to the method of administration. See the

individual summaries of product characteristics for more information.

In 12 trials (n=10,124) in early breast cancer included in the Cochrane review, the incidence

of osteonecrosis of the jaw was found to be from 0% to 0.7%.

The MHRA has issued guidance on the use and safety of bisphosphonates, which

summarises important safety issues with bisphosphonates, including oesophageal

reactions, osteonecrosis of the jaw, atypical femoral fractures and adverse effects on renal

function. The MHRA has also warned that osteonecrosis of the external auditory canal has

been reported very rarely with bisphosphonates.



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https://www.gov.uk/drug-safety-update/bisphosphonates-very-rare-reports-of-osteonecrosis-of-the-external-auditory-canal

PPatient factorsatient factors

Some people with breast cancer will be eligible for bisphosphonate treatment according to

the licensed indications; for example, to reduce the risk of osteoporosis associated with

aromatase inhibitors or chemotherapy-induced premature menopause (see the NICE

guideline on early and locally advanced breast cancer: diagnosis and treatment).

No information is available on adjuvant bisphosphonates for preventing recurrence or

improving survival in men with early breast cancer.

The optimal choice, dosage and duration of bisphosphonate treatment for preventing

recurrence and improving survival is unclear. Most trials included in the meta-analysis

lasted 2–5 years.

The bisphosphonates used most commonly in the trials were zoledronic acid (50%),

clodronate (27%) and ibandronic acid (16%). There is little or no evidence to support the

use of risedronate, alendronic acid or pamidronate for preventing recurrence and

improving survival in people with early breast cancer.

Although serious adverse effects are rare, they should be discussed with women

considering adjuvant bisphosphonate therapy and measures should be taken to reduce the

risk of them occurring (see the MHRA guidance).

Oral bisphosphonates such as clodronate are more likely to cause gastrointestinal adverse

effects than intravenous bisphosphonates and some people may find them difficult to

swallow. Nevertheless, some people may prefer oral medication because a hospital visit is

not required.

Zoledronic acid is administered intravenously and, it may be easier for some people to

adhere to 6-monthly intravenous treatment, rather than daily oral treatment. Zoledronic

acid infusion can cause an acute response resulting in flu-like symptoms.

Calcium and vitamin D supplementation is generally recommended when bisphosphonates

are used, particularly if dietary intake is low.



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Resource implicationsResource implications

The annual cost (excluding VAT) of zoledronic acid given at the dosages generally used in

the meta-analysis ranges from around £8 to £47. Clodronate costs around £1780 per year

and ibandronic acid costs around £80 per year (costs taken from Drugs and pharmaceutical

electronic market information and the Drug Tariff; excluding VAT). These costs do not

include any local procurement discounts or other costs incurred, such as dilution and

administration, standard supportive therapy (such as calcium and vitamin D), or any costs

associated with attendance for day case treatment.

Depending on the bisphosphonate used, additional costs that need to be considered include

dental check-ups and monitoring of renal function and vitamin D levels (see the MHRA

guidance).

It is unclear how many additional appointments and investigations will be required with

bisphosphonate treatment on top of those required for standard management of breast

cancer. It is also unclear what savings might be seen as a result of such treatment; for

example, due to a reduction in the need for dual energy X-ray absorptiometry (DEXA) scans

in people taking breast cancer treatments that are associated with osteoporosis, or by

reducing the number of people needing treatment for metastatic disease.

Introduction and current guidanceIntroduction and current guidance

Breast cancer is the most common cancer in women in England and Wales, and also occurs rarely in

men. Most breast cancers are diagnosed at an early stage, when all detected deposits of the disease

are in the breast or nearby lymph nodes and can be removed surgically. Early breast cancer is

subdivided into 2 major categories, in situ disease and invasive cancer. Although most women with

early breast cancer now survive, some have undetected deposits of cancer cells remaining after

surgery in or near the breast, or at distant sites (for example, in bone). These can start to

proliferate, sometimes many years later, resulting in a recurrence of the original breast cancer.

Therefore, adjuvant treatments may be given in addition to surgery for early breast cancer to try to

kill any remaining cancer cells (NICE guideline on early and locally advanced breast cancer:

diagnosis and treatment and EBCTCG: Early Breast Cancer Trialists' Collaborative Group).

The NICE guideline on early and locally advanced breast cancer covers diagnosis and surgical and

pharmacological treatment of women and men with early and locally advanced breast cancer

(currently being updated). An interactive flowchart brings together everything NICE has published

on this subject.



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https://www.gov.uk/government/publications/drugs-and-pharmaceutical-electronic-market-information-emit


http://www.nhsbsa.nhs.uk/PrescriptionServices/4940.aspx



https://www.ctsu.ox.ac.uk/research/ebctcg

https://www.nice.org.uk/guidance/indevelopment/gid-ng10016

https://pathways.nice.org.uk/pathways/early-and-locally-advanced-breast-cancer

In women treated for breast cancer, aromatase inhibitors and chemotherapy-induced premature

menopause are associated with osteoporosis, which increases the risk of bone fractures. Therefore,

NICE guidance on early breast cancer recommends that people with early invasive breast cancer

should have a baseline dual energy X-ray absorptiometry (DEXA) scan to assess bone mineral

density if they:

are starting adjuvant aromatase inhibitor treatment

are starting ovarian ablation or suppression therapy

have treatment-induced menopause.

Bisphosphonates should be offered to women identified by the algorithms in Guidance for the

management of breast cancer treatment-induced bone loss: a consensus position statement from a

UK expert group (see appendix 2 of NICE's full guideline).

The NICE guideline on advanced breast cancer recommends that bisphosphonates should also be

considered for people newly diagnosed with bone metastases to prevent skeletal adverse events

and reduce pain.

Bisphosphonates may also have a role in the prevention of metastatic disease. It has been

hypothesised that, in bone with high turnover, excess osteoclast activity could be associated with

excess production of growth factors, which could in turn affect the survival of tumour

micrometastases. Using bisphosphonates to reduce osteoclast activity might reduce expression of

these factors, thereby preventing the establishment of micrometastatic disease. However, RCTs

examining this possible effect have found mixed results (Brufsky and Mathew 2015).This evidence

summary considers the best available evidence for using bisphosphonates off-label as adjuvant

treatments for early breast cancer, to prevent recurrence and improve survival, rather than for

their licensed indications, such as treating or preventing osteoporosis or skeletal events, or

managing bone pain.

Product oProduct ovverviewerview

Mode of action

Bisphosphonates are adsorbed onto hydroxyapatite crystals in bone, slowing their rate of growth

and dissolution, and inhibiting osteoclast maturation and function, thereby reducing the rate of

bone turnover (British national formulary, March 2017, Brufsky and Mathew 2015).



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http://www.sciencedirect.com/science/article/pii/S0305737208000510



http://www.nice.org.uk/guidance/CG80/evidence


http://thelancet.com/journals/lancet/article/PIIS0140-6736(15)61163-1/abstract



Regulatory status

Six bisphosphonates are available in the UK: alendronic acid (alendronate sodium), ibandronic acid

(ibandronate sodium), pamidronate disodium, risedronate sodium, sodium (and disodium)

clodronate and zoledronic acid (zoledronate).

The following list shows some of the licensed indications and usual dosages for bisphosphonates,

focussing on those that are most relevant to the population included in this evidence summary.

Other licensed indications for bisphosphonates include management of osteoporosis in men,

corticosteroid-induced osteoporosis, hypercalcaemia of malignancy and Paget's disease. The

medicines are administered orally, unless stated otherwise. Where a treatment frequency or

duration is not stated, a single dose is used. See the summaries of product characteristics or British

national formulary for more detailed information on the licensed indications and dosages for

individual bisphosphonates.

Treating osteoporosis in postmenopausal women:

alendronic acid 10 mg daily or 70 mg weekly

ibandronic acid 150 mg monthly or 3 g intravenously (IV) every 3 months

risedronate sodium 5 mg daily or 35 mg weekly

zoledronic acid 5 mg IV yearly.

Preventing skeletal events in people with breast cancer and bone metastases:

ibandronic acid 50 mg daily or 6 mg IV every 3–4 weeks

zoledronic acid 4 mg IV every 3–4 weeks.

Managing osteolytic lesions and bone pain in people with breast cancer or multiple myeloma

and bone metastases:

pamidronate disodium 90 mg IV every 4 weeks

sodium clodronate 1,600 mg daily.

Bisphosphonates may be used in some people with breast cancer, within the terms of their licenses,

to prevent osteoporosis or skeletal events, or manage osteolytic lesions, bone pain or

hypercalcaemia of malignancy. However, these treatments are not licensed for preventing

recurrence or improving survival in people with early breast cancer, and use for this indication is



Page 9 of44




off-label. In line with the guidance from the General Medical Council (GMC) on prescribing

unlicensed medicines, the prescriber should take full responsibility for determining the needs of

the patient and whether using bisphosphonates is suitable outside its authorised indications.

Supporting information and advice is also available from the GMC.

Dosing information

Dosing information varies for the licensed indications for the bisphosphonates and, although the

usual dosages are briefly listed above, more detail can be found in the summaries of product

characteristics.

Dosing information for bisphosphonates for adjuvant use to prevent recurrence and improve

survival in people with early breast (off-label indication) is discussed in the estimated impact for the

NHS section of this evidence summary.

Cost

Table 2 lists a range of costs for the 6 bisphosphonates at the usual dosages covering most of the

licensed indications. Dosages shown do not represent the full range that can be used and do not

imply therapeutic equivalence. The costs shown are for 4 weeks' treatment, unless the

bisphosphonate is generally administered as a single dose.

The costs shown for IV treatments do not cover the full range of available products. Also, costs are

for the medicines only (excluding VAT) and do not include any local procurement discounts or other

costs incurred, such as dilution and administration, standard supportive therapy (such as calcium

and vitamin D), or any costs associated with attendance for day case treatment.

TTableable 2 Costs of bisphosphonates2 Costs of bisphosphonates

MedicineMedicine DosageDosageaa and quantityand quantity Cost per 28Cost per 28 dadays or single dose, as indicated,ys or single dose, as indicated,

eexxcluding Vcluding VAATT

10 mg daily x 28 tablets £1.69bAlendronic acid

70 mg weekly x 4 tablets £0.72b

50 mg daily x 28 tablets £6.27bIbandronic acid

150 mg monthly x 1 tablet £1.13b



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http://www.gmc-uk.org/guidance/ethical_guidance/14327.asp


http://www.gmc-uk.org/guidance/28349.asp



http://live-publications.nice.org.uk/estimated-impact-for-the-nhs#estimated-impact-for-the-nhs

http://live-publications.nice.org.uk/estimated-impact-for-the-nhs#estimated-impact-for-the-nhs

1 mg/ml x 2 ml vial x 1 single

dose

£23.26c

1 mg/ml x 3 ml syringe x

1 single dose

£10.27c

Pamidronate

disodium

9 mg/ml x 10 ml vial x

1 single dose

£4.10c

5 mg daily x 28 tablets £18.85bRisedronate

sodium35 mg weekly x 4 tablets £0.85b

Sodium

clodronate

1,600 mg daily, 800 mg x

56 tablets

£136.67b

5 mg/100 ml bag x 1 single

dose

£7.36cZoledronic acid

4 mg/100 ml bag x 1 single

dose

£3.94c

a Dosages are taken from the relevant SPCs. Those shown do not represent the full range that

can be used and do not imply therapeutic equivalenceb Costs taken from the Drug Tariff, June 2017; excluding VATc Average price paid in English NHS hospital trusts over the last 4 months of 2015 taken from

Drugs and pharmaceutical electronic market information; excluding VAT

Evidence reEvidence reviewview

This evidence summary includes the best available evidence to support the off-label use of

adjuvant bisphosphonates to prevent recurrence and improve survival in people with early breast

cancer. A literature search was conducted which identified 89 references (see search strategy for

full details). These references were screened using their titles and abstracts and 6 references were

obtained and assessed for relevance.

One study was included in this evidence summary, the Early Breast Cancer Trialists' Collaborative

Group (EBCTCG) meta-analysis (2015). A summary of this study is shown in the table below (see

evidence tables for full details).

TTableable 3 Summary of included study3 Summary of included study



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http://live-publications.nice.org.uk/search-strategy#search-strategy



http://live-publications.nice.org.uk/evidence-tables#evidence-tables

StudyStudy PPopulationopulation IntervIntervention and comparisonention and comparison PrimaryPrimary

outcomesoutcomes

EBCTCG 2015

Meta-analysis

of individual

participant

data from

26 RCTsa

18,766 womena

with early

breast cancer

(not defined)

Adjuvant bisphosphonate treatment (mainly

zoledronic acid 50%, clodronate 27% and

ibandronic acid 16%) compared with no

bisphosphonate treatment (including placebo)

Recurrence

of breast

cancer

Distant

recurrence

of cancerb

Breast

cancer

mortality

a 11,767 women were postmenopausal, 6171 women were premenopausal and 828 women

were perimenopausalb Recurrence in the bone or elsewhere, not in the breasts or regional lymph nodes

AbbreAbbreviations:viations: EBCTCG, Early Breast Cancer Trialists' Collaborative Group; RCT, randomised

controlled trial

The remaining 5 references were excluded and are listed in excluded studies with reasons for their

exclusion. They include a 2012 Cochrane review that assessed the effects of bisphosphonates and

other bone agents for breast cancer (including 12 RCTs in early breast cancer, n=10,124), which has

been superseded by the EBCTCG meta-analysis.

Clinical effectiveness

Of 18,766 women included in the EBCTCG meta-analysis (2015), over a median follow-up of

5.6 woman-years, breast cancer recurred in 3,453 women (18.4%), after which 2,106 women

(11.2%) died. Overall, use of bisphosphonates compared with control resulted in no statistically

significant reduction in the recurrence of breast cancer, but there were statistically significant

reductions in distant recurrence (mainly because of a reduction in bone recurrence) and breast

cancer mortality. With bisphosphonates compared with control, the absolute 10-year risk was

reduced by:

1.1% for breast cancer recurrence (24.9% compared with 25.9%; rate ratio [RR] 0.94, 95%

confidence interval [CI] 0.87 to 1.01; p=0.08, not statistically significant)



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http://www.nice.org.uk/Glossary?letter=M

https://www.nice.org.uk/Glossary?letter=R


http://live-publications.nice.org.uk/excluded-studies#excluded-studies



https://www.nice.org.uk/Glossary?letter=S


https://www.nice.org.uk/Glossary?letter=C

1.4% for distant recurrence (20.4% compared with 21.8%; RR 0.92, 95% CI 0.85 to 0.99;

p=0.03)

1.1% for bone recurrence (7.8% compared with 9.0%; RR 0.83, 95% CI 0.73 to 0.94; p=0.004),

and

1.7% for breast cancer mortality (16.6% compared with 18.4%; RR 0.91, 95% CI 0.83 to 0.99;

p=0.04)

1.6% for all-cause mortality (20.8% compared with 22.3%; RR 0.92, 95% CI 0.85 to 1.00,

p=0.06, not statistically significant).

In the prespecified subgroup analyses (which may have been post-hoc for the individual trials

included in the meta-analysis), no statistically significant benefits from bisphosphonate use were

seen in premenopausal women (n=6,171) compared with control. In postmenopausal women

(n=11,767, natural or induced menopause), there were statistically significant reductions in breast

cancer recurrence, distant recurrence (recurrence in the bone or elsewhere, not in the breasts or

regional lymph nodes), bone recurrence and breast cancer mortality. The absolute reductions with

bisphosphonates compared with control in postmenopausal women at 10 years were:

3.0% for breast cancer recurrence (22.8% compared with 25.8%; RR 0.86, 95% CI 0.78 to 0.94;

p=0.002)

3.4% for distant recurrence (17.9% compared with 21.2%; RR 0.82, 95% CI 0.74 to 0.91;

p=0.0003)

2.2% for bone recurrence (6.6% compared with 8.8%; RR 0.72, 95% CI 0.60 to 0.86; p=0.0002)

and

3.3% for breast cancer mortality (14.7% compared with 18.0%; RR 0.82, 95% CI 0.73 to 0.93;

p=0.002)

2.3% for all-cause mortality (21.1% compared with 23.5%; RR 0.86, 95% CI 0.77 to 0.96,

p=0.005).

Bisphosphonate use had no statistically significant effect on distant recurrence other than bone

recurrence, or on locoregional recurrence (in the same site as the original tumour or in the regional

lymph nodes) or contralateral breast cancer (in the opposite breast) in all women or in the

postmenopausal subgroup.



Page 13 of44

Subgroup analyses looking at bone recurrence and breast cancer mortality suggested that the

efficacy of bisphosphonates is greater in women aged 55 years or older, compared with younger

women. However, menopausal status and age are closely correlated so it is difficult to know which

characteristic is most relevant. Reductions in bone recurrence and breast cancer mortality did not

depend on tumour characteristics (including oestrogen receptor status, nodal status or tumour

grade). No subgroup analyses assessed bisphosphonates according to women's estimated risk of

breast cancer recurrence or mortality.

No statistically significant difference was found between non-aminobisphosphonates (clodronate)

and aminobisphosphonates (zoledronic acid and ibandronic acid). There was no apparent benefit

with the non-aminobisphosphonate pamidronate (taken orally), but the number of women taking

this bisphosphonate was low (n=953) and so the meta-analysis may have had insufficient statistical

power to detect a benefit. The number of women taking risedronate (n=398) was also low and

insufficient to assess its efficacy, and no women received alendronic acid or intravenous (IV)

pamidronate in the trials included in the meta-analysis.

For bone recurrence, there was no statistically significant difference between low-intensity

bisphosphonate schedules (such as 6-monthly IV zoledronic acid) and high-intensity schedules

(such as monthly IV zoledronic acid, daily oral ibandronic acid or daily oral clodronate). Similar

reductions with bisphosphonates were seen in the presence or absence of chemotherapy,

suggesting any benefits are additive to chemotherapy.

An overview of the key results for clinical effectiveness can be found in results tables.

Safety and tolerability

The most common adverse effects of bisphosphonates are gastrointestinal effects (such as nausea,

dyspepsia, mild oesophagitis and abdominal pain) and bone, joint or muscle pain. Other less

common adverse effects include more serious oesophageal reactions (such as oesophagitis and

oesophageal ulcers, strictures and erosions), osteonecrosis of the jaw and atypical stress fractures

(NICE clinical knowledge summaries on osteoporosis - prevention of fragility fractures). Adverse

effects vary among bisphosphonates. See the individual summaries of product characteristics

(SPCs) for more information.

The EBCTCG meta-analysis (2015) did not report adverse effects. The bisphosphonates used most

commonly in the trials in the meta-analysis were oral clodronate and IV zoledronic acid. Adverse

effects reported in between 1 in 10 and 1 in 100 people taking sodium clodronate for the licensed

indications are asymptomatic hypocalcaemia, diarrhoea, nausea, vomiting and increased



Page 14 of44



http://live-publications.nice.org.uk/results-tables#results-tables

https://cks.nice.org.uk/osteoporosis-prevention-of-fragility-fractures



transaminases (within the normal range) (Bonefos SPC). Adverse effects reported in between

1 in 10 and 1 in 100 people taking zoledronic acid 4 mg for the licensed indications are anaemia,

headache, conjunctivitis, nausea, vomiting, decreased appetite, bone pain, myalgia, arthralgia,

generalised pain, renal impairment, fever, flu-like syndrome, increased blood creatinine and urea,

and hypocalcaemia. Hypophosphataemia occurs in more than 1 in 10 people taking zoledronic acid

(Zometa SPC).

A 2012 Cochrane review of 34 randomised controlled trials (RCTs) that assessed the effects of

bisphosphonates and other bone agents for breast cancer (including 12 RCTs in early breast cancer,

n=10,124) reported adverse events. It concluded that the adverse effects of bisphosphonates were

generally mild and infrequent. The main adverse effect seen with IV zoledronic acid was renal

toxicity, which was related to the dose and infusion time. No significant renal toxicity was seen with

IV pamidronate or IV ibandronic acid. The main adverse effect seen with oral clodronate and oral

ibandronic acid was mild gastrointestinal toxicity. The authors noted that there have been reports

of osteonecrosis of the jaw with long-term use of bisphosphonates. In the trials in early breast

cancer included in the Cochrane review, the incidence of osteonecrosis of the jaw was found to be

from 0% to 0.7%, highlighting the need for good oral care before and during treatment in people

taking bisphosphonates long-term.

The MHRA has issued guidance on the use and safety of bisphosphonates, which summarises

important safety issues with bisphosphonates, including oesophageal reactions, osteonecrosis of

the jaw, atrial fibrillation, atypical femoral fractures and adverse effects on renal function. Since

this was published in 2014, the MHRA has also warned that osteonecrosis of the external auditory

canal has been reported very rarely with bisphosphonates.

Evidence strengths and limitations

The EBCTCG meta-analysis (2015) was a large, meta-analysis of individual participant data from

RCTs. Of the 32 trials (n=19,291) identified that recorded recurrence, data were not obtained for

6 trials; however, these included only 525 women and would have been unlikely to change the key

outcomes of the meta-analysis. Data were obtained for 26 trials (n=18,766, 97% of participants).

Citations for publications for the included and excluded trials were not reported.

The methods of identifying trials, seeking collaboration, data collection, collation, checking, and

presentation have not been fully reported, apart from to note these were undertaken as in previous

EBCTCG reports. In addition, no assessment of quality or risk of bias of the individual trials is

provided, including randomisation, allocation concealment, blinding and adjudication of outcomes.

Most of the trials included in the meta-analysis were open-label; outcome assessment was often



Page 15 of44

http://www.medicines.org.uk/emc/medicine/311

http://www.medicines.org.uk/emc/medicine/25058






https://www.ctsu.ox.ac.uk/research/ebctcg/further-information/original-methods-for-ebctcg-meta-analyses


https://www.nice.org.uk/Glossary?letter=A

not blinded (although this will have limited effect on measures of recurrence and survival); and

some of the trials were industry-sponsored. The subgroup analyses in the EBCTCG meta-analysis

were prespecified, but may not have been prespecified in the individual trials: details are not

reported.

The paper does not report if the populations and treatments studied were homogeneous. For

example, it is unclear whether differences in the standard breast cancer management of pre- and

postmenopausal women may account for the differences in benefits in these populations, rather

than bisphosphonates. It is also unclear what chemotherapy was used for breast cancer, whether it

was similar across the trials, and whether choice of chemotherapy reflects current clinical practice.

Breast cancer survival has improved significantly over the last few decades because of better

treatments and better identification of risk groups. It is possible that bisphosphonates only

benefited women who had suboptimal treatment in the older trials. Nevertheless, the 2 largest

trials included in the EBCTCG meta-analysis, the ABCSG-12 (n=1,083) and AZURE (BIG 01/04)

trials (n=3,360) enrolled participants until 2006, and sensitivity analyses excluding these trials still

found benefits of bisphosphonates in postmenopausal women.

Overall, the authors of the Cancer Care Ontario and the American Society of Clinical Oncology

(CCO/ASCO) guideline on the Use of adjuvant bisphosphonates and other bone-modifying agents

in breast cancer considered that the EBCTCG had strict inclusion criteria and protocols and the

results of the EBCTCG meta-analysis are of high-quality, with the limitation that some outcomes

have not yet been completely reported. However, they highlighted that combining the data for all

bisphosphonates in the meta-analysis was controversial, as was including small trials not designed

to measure the outcomes of interest; for example, some trials were designed to look at bone

mineral density and did not report recurrence or survival. This also means that there may have

been no adjudication of these outcomes in those trials. Furthermore, it has been questioned

whether a meta-analysis of subgroups should be used to inform clinical decision making because

subgroup analyses are prone to error and generally considered more appropriate for hypothesis

generation for future trials than changing practice (Jacobs et al. 2015).

The EBCTCG used log-rank statistics to assess the effects of bisphosphonates compared with

control on various outcomes, and to estimate rate ratios and their confidence intervals. Log-rank

analyses allow analyses of the effects of treatment in separate years, which may improve medical

understanding but can also carry some statistical uncertainties. Estimates for a given year can only

be based on trials that have follow-up and data reported in that year. The median follow-up in the

meta-analysis was 5.6 years and the interquartile range was 3.7 years to 8.0 years. This means that

75% of women were followed up for 8 years or less. It is unclear how many women were followed

up for 10 years but the number is likely to be low when subgroups are considered.



Page 16 of44

https://www.nice.org.uk/Glossary?letter=H

https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdu544

http://www.sciencedirect.com/science/article/pii/S147020451470302X?via%3Dihub



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620967/

Although data on safety outcomes were reportedly collected, adverse effects were not reported in

the EBCTCG meta-analysis; however, the adverse effect profile of bisphosphonates is well-

established. The trials in the meta-analysis included women only and no information is available on

using bisphosphonates to prevent recurrence of breast cancer in men. When considering

menopausal status, women with natural menopause and premature menopause induced by

chemotherapy or oophorectomy were included in the same subgroup. Only 1 trial (ABCSG-12,

n=1,803), which studied zoledronic acid, included women with induced menopause. The majority of

participants in the meta-analysis (83%) also received adjuvant chemotherapy, and bisphosphonate

treatment generally started 0–12 weeks after surgery or chemotherapy. Clodronate has not been

studied specifically in people receiving aromatase inhibitors (CCO/ASCO guideline).

Little or no information is available for some commonly used bisphosphonates, such as risedronate

and alendronic acid. No benefit was seen with oral pamidronate but the authors of the meta-

analysis note that this might be expected because the oral formulation is poorly absorbed and

pamidronate has been shown to have little or no effect on markers of bone resorption, metastatic

bone disease and myeloma. Only limited information from subgroup analyses is available

comparing different bisphosphonates, or different dosages of bisphosphonates (low- or high-

intensity schedules). Most of the participants (97%) were in trials lasting 2–5 years, and the optimal

duration of treatment is unclear.

The authors of the meta-analysis note that more reliable comparisons of different bisphosphonate

regimens may emerge from ongoing trials that compare them directly; for example, the

SWOG 0307 trial (NCT00127205) comparing clodronate, zoledronic acid and ibandronic acid over

3 years (n=5,400), and the SUCCESS trial (NCT02181101) comparing 5 years' and 2 years'

treatment with zoledronic acid (n=3,800). Results of an interim analysis from SWOG 0307 have

been published as an abstract only, suggesting there were no significant differences between the

groups in 5-year disease-free survival or overall survival, but there were some differences in

adverse events (Gralow et al. 2015). Full publication of the trial is needed before the relevance of

the results can be assessed.

A literature search was undertaken in June 2016 for the CCO/ASCO guideline on the use of

adjuvant bisphosphonates and other bone-modifying agents in breast. In addition to trials of

bisphosphonates with data included in the EBCTCG meta-analysis, the search found results for

SWOG S0307 and a few small trials on clodronate and zoledronic acid. However, the authors noted

that data on survival and recurrence were reported in abstracts only and that the results do not

currently change the conclusions of the EBCTCG meta-analysis. Results from ongoing trials

(including HOBOE [NCT00412022] and TEAM-IIb [ISRCTN17633610]), and longer follow-up of

the trials included in the EBCTCG meta-analysis, may provide more evidence on the effects of



Page 17 of44

https://clinicaltrials.gov/ct2/show/NCT00127205



http://www.isrctn.com/ISRCTN17633610

bisphosphonates in premenopausal women, and allow more stable estimates of the 10-year

outcomes in postmenopausal women.

An overview of the quality assessment for the included study can be found in the evidence tables.

Estimated impact for the NHSEstimated impact for the NHS

Other treatments

In the trials in the EBCTCG meta-analysis (2015), bisphosphonates were administered in addition

to other treatments for breast cancer; for example, chemotherapy and surgery.

In the trials included in the meta-analysis, 9,290 women received zoledronic acid, 5,053 women

received clodronate, 3,072 women received ibandronic acid, 953 women received pamidronate

and 398 women received risedronate sodium. The bisphosphonates were usually administered at

the following dosages, for the listed durations:

intravenous (IV) zoledronic acid 4 mg 3- or 4-weekly or 6-monthly for 3–5 years (some trials

used intermediate frequencies such as 3-monthly, or monthly for an initial period then

6-monthly)

oral clodronate 1,600 mg daily for 2–3 years

oral ibandronic acid 50 mg daily for 2 years

oral pamidronate 150 mg twice daily for 4 years

oral risedronate 35 mg weekly for 1–2 years.

Based on the evidence, the CCO/ASCO guideline generally recommends IV zoledronic acid (4 mg

every 6 months for 3–5 years) or oral clodronate (1,600 mg daily for 2–3 years) for postmenopausal

women with breast cancer deemed candidates for adjuvant bisphosphonate therapy (in addition to

standard breast cancer treatments, and calcium and vitamin D supplementation). The lower dose of

zoledronic acid is recommended because the EBCTCG meta-analysis found no statistically

significant difference between less- and more-intensive dosage schedules in terms of bone

recurrence, and adverse effects are less common and less severe with less-intensive regimens.

European consensus guidance on adjuvant bisphosphonates for early breast cancer also

recommends that IV zoledronic acid (4 mg every 6 months) or oral clodronate (1,600 mg daily) are

the preferred agents for preventing recurrence of breast cancer and improving disease outcomes.



Page 18 of44

http://live-publications.nice.org.uk/evidence-tables#evidence-tables




The guideline states that the potential risks and benefits of 3–5 years of adjuvant bisphosphonate

treatment (plus vitamin D supplementation and adequate calcium intake) should be discussed with

relevant women.

Costs of bisphosphonates used most often in the meta-analysis

No cost-effectiveness studies were found considering bisphosphonates for preventing recurrence

and improving survival in people with early breast cancer.

Table 4 shows the costs of bisphosphonates at the dosages most commonly used in the EBCTCG

meta-analysis. The dosages shown do not represent the full range that can be used and they do not

imply therapeutic equivalence. Oral pamidronate is not included in the table because the meta-

analysis found it was ineffective and it is not currently available in the UK. Risedronate is not

included because relatively few women took this medicine in the trials in the meta-analysis.

The costs shown in the table are for the medicines only (excluding VAT) and do not include any local

procurement discounts or other costs incurred, such as dilution and administration, or any costs

associated with attendance for day case treatment. Calcium and vitamin D supplementation is

generally recommended when bisphosphonates are used, particularly if dietary intake is low; the

cost of this is not included in the table.

TTableable 4 Annual costs of bisphosphonates commonly used in the EBCT4 Annual costs of bisphosphonates commonly used in the EBCTCG meta-analysisCG meta-analysis

MedicineMedicine Usual dosageUsual dosage Cost per unit,Cost per unit,


Annual cost,Annual cost,


4 mg monthly for

3–5 years

£3.94b per vial £47.28IV zoledronic acid 4 mg/

100 ml

4 mg 6-monthly for

3–5 years

£3.94b per vial £7.88

Oral sodium clodronate

800 mg

1,600 mg daily for

2–3 years

£136.67c per

56 tablets

£1781.59

Oral ibandronic acid

50 mg

50 mg daily for 2 years £6.27c per 28 tablets £81.73



Page 19 of44

a The dosages shown reflect those most commonly used in the EBCTCG meta-analysis. They do

not represent the full range that can be used and do not imply therapeutic equivalenceb Average price paid in English NHS hospital trusts over the last 4 months of 2015 taken from

Drugs and pharmaceutical electronic market information; excluding VATc Costs taken from the Drug Tariff, April 2017; excluding VAT

It is unclear how many additional appointments and investigations will be required with

bisphosphonate treatment on top of those required for standard management of breast cancer. It is

also unclear what savings might be seen as a result of such treatment; for example, due to a

reduction in the need for dual energy X-ray absorptiometry (DEXA) scans in people taking breast

cancer treatments that are associated with osteoporosis (see the NICE guideline on early and

locally advanced breast cancer: diagnosis and treatment), or by reducing the number of people with

metastatic disease.

Current or estimated usage

Estimating the current usage off-label usage of bisphosphonates as adjuvant treatments for

preventing the recurrence of early breast cancer and improving survival is difficult because

bisphosphonates are used to treat various conditions. No information on prescribing adjuvant

bisphosphonates for early breast cancer was available at the time this evidence summary was

prepared.

Likely place in therapy

Local decision makers need to take safety, efficacy, cost and patient factors into account when

considering the likely place in therapy of adjuvant bisphosphonates for preventing recurrence and

improving survival in people with early breast cancer.

In the EBCTCG meta-analysis, in women with early breast cancer treated with adjuvant

bisphosphonates, there were small, borderline statistically significant reductions in distant

recurrence, bone recurrence and breast cancer mortality, but not breast cancer recurrence, at

10 years compared with control. No information is available on adjuvant bisphosphonates for

preventing recurrence or improving survival in men with early breast cancer.

When prespecified subgroup analyses according to menopausal status were undertaken, no

benefits were seen in premenopausal women, but the benefits were found to be higher than in the

general study population for postmenopausal women. At 10 years compared with control, the



Page 20 of44





absolute reductions in the risk of breast cancer death and bone recurrence in postmenopausal

women were 3.3% (14.7% compared with 18.0%; p=0.002; number needed to treat [NNT] 31) and

2.2% (6.6% compared with 8.8%; p=0.0002; NNT 46) respectively. Benefits appeared to be

independent of the type and dosage of bisphosphonate, the tumour characteristics and the use of

concomitant chemotherapy.

The CCO/ASCO guideline states that, although the EBCTCG meta-analysis found bisphosphonate

treatment reduced the risk of bone recurrence and subsequently improved survival in

postmenopausal women with early breast cancer, the absolute benefits were small compared with

control and may not result in a clinically meaningful effect. Nevertheless, a Lancet comment

accompanying the EBCTCG meta-analysis notes that the absolute reduction in the risk of dying of

breast cancer (3.3% at 10 years) seen in the meta-analysis is similar to the benefit seen with

anthracycline polychemotherapy versus nonanthracycline polychemotherapy.

The evidence is insufficient to determine precise subgroups of postmenopausal women who would

or would not benefit. The authors of the CCO/ASCO guideline consider that the benefits of

bisphosphonates might be less in women with low-risk cancers, which might be a factor in deciding

whether to use treatment, particularly when balanced against the risk of adverse events with

bisphosphonates. Similarly, when the European consensus guidance on adjuvant bisphosphonates

for early breast cancer was developed, although the panel agreed that data supported the use of

adjuvant bisphosphonates in postmenopausal (whether natural or induced) women, 58% of the

experts (14/24) suggested restricting use to women considered at intermediate- or high-risk of

recurrence of breast cancer rather than unselected use across all risk groups.

Several decision-making tools such as Adjuvant! Online, PREDICT and the Nottingham Prognostic

Index are available to help estimate the risk of recurrence and mortality, and the benefits of

standard adjuvant treatments based on various clinical parameters. According to the CCO/ASCO

guideline, similar parameters may be relevant when deciding whether or not bisphosphonates

should be used. If treatment with bisphosphonates is considered appropriate, it should be

discussed with each woman, taking their individual risk of recurrence and death into account and

balancing this against their risk of adverse effects from bisphosphonates.

The optimal choice, dosage and duration of bisphosphonate treatment for preventing recurrence

and improving survival in women with early breast cancer is unclear. Based on the available

evidence, the CCO/ASCO guideline generally recommends IV zoledronic acid (4 mg every 6 months

for 3–5 years) or oral clodronate (1,600 mg daily for 2–3 years) for postmenopausal women with

breast cancer deemed candidates for adjuvant bisphosphonate therapy (in addition to standard

breast cancer treatments). The European consensus guideline also recommends 6-monthly IV



Page 21 of44

https://www.nice.org.uk/Glossary?letter=N

http://thelancet.com/journals/lancet/article/PIIS0140-6736(15)61163-1/fulltext

zoledronic acid or daily oral clodronate first-line for preventing metastases and improving disease

outcomes in postmenopausal women with early breast cancer. There is less evidence to support the

use of monthly IV zoledronic acid and daily oral ibandronic acid, and little or no evidence to support

the use of risedronate and alendronic acid.

Different adverse effect profiles, frequency and route of administration, and cost may affect the

choice of treatment. Adverse effects vary among bisphosphonates. Oral bisphosphonates such as

clodronate are more likely to cause gastrointestinal adverse effects than IV bisphosphonates and

some people may find them difficult to swallow. Nevertheless, some people may prefer oral

medication because a hospital visit is not required. Zoledronic acid is administered intravenously

and, it may be easier for some people to adhere to 6-monthly IV treatment, rather than daily oral

treatment. Zoledronic acid infusion can cause an acute response resulting in flu-like symptoms.

More serious, less common adverse events associated with bisphosphonates include serious

oesophageal reactions, osteonecrosis of the jaw, atypical stress fractures and renal impairment.

The MHRA has issued guidance on preventing and managing these.

The annual cost of zoledronic acid given at the dosages generally used in the meta-analysis ranges

from around £8 to £47 (excluding VAT), not including any local procurement discounts or other

costs incurred, such as dilution and administration, standard supportive therapy (such as calcium

and vitamin D), or any costs associated with attendance for day case treatment. Clodronate costs

around £1780 per year and ibandronic acid costs around £80 per year (excluding VAT).

Information for the public about medicinesInformation for the public about medicines

Evidence summaries provide an overview of the best evidence that is available about specific

medicines. They also give general information about the condition that the medicine might be

prescribed for, how the medicine is used, how it works, and what the aim of treatment is.

Evidence summaries aim to help healthcare professionals and patients decide whether medicines

are safe to use and if they are likely to work well, especially when there isn't another suitable

medicine that has a licence for the condition. They don't contain recommendations from NICE on

whether the medicine should be used.

Information about licensing of medicines

In the UK, medicines need to have a licence before they can be widely used. To get a licence, the

manufacturer of the medicine has to provide evidence that shows that the medicine works well

enough and is safe enough to be used for a specific condition and for a specific group of patients,



Page 22 of44


and that they can manufacture the medicine to the required quality. Evidence summaries explain

whether a medicine has a licence, and if it does what the licence covers.

There is more information about licensing of medicines on NHS Choices.

Medicines can be prescribed if they don't have a licence (unlicensed) or for 'off-label' use. Off-label

means that the person prescribing the medicine wants to use it in a different way than that stated

in its licence. This could mean using the medicine for a different condition or a different group of

patients, or it could mean a change in the dose or that the medicine is taken in a different way. If a

healthcare professional wants to prescribe an unlicensed medicine, or a licensed medicine off-label,

they must follow their professional guide, for example for doctors the General Medical Council's

good practice guidelines. These include giving information about the treatment and discussing the

possible benefits and harms so that the person has enough information to decide whether or not to

have the treatment. This is called giving informed consent.

Questions that might be useful to ask about medicines

Why am I being offered this medicine?

Why am I being offered a medicine that is unlicensed or is being used off-label?

What does the treatment involve?

What are the benefits I might get?

How good are my chances of getting those benefits?

Could having the treatment make me feel worse?

Are there other treatments I could try?

What are the risks of the treatment?

Are the risks minor or serious? How likely are they to happen?

What could happen if I don't have the treatment?

ReleRelevance to other NICE progrvance to other NICE programmesammes

The use of adjuvant bisphosphonates for preventing recurrence and improving survival in early

breast cancer is not appropriate for referral for a NICE technology appraisal and is not currently

planned into any other work programme.



Page 23 of44

http://www.nhs.uk/Conditions/Medicinesinfo/Pages/Safetyissues.aspx


NICE has issued the following guidance relating to early breast cancer:

Early and locally advanced breast cancer: diagnosis and treatment (2009) NICE guideline

CG80, currently being updated

Improving outcomes in breast cancer (2002) NICE guideline CSG1

Hormonal therapies for the adjuvant treatment of early oestrogen-receptor-positive breast

cancer (2006) NICE technology appraisal guidance 112

Axxent electronic brachytherapy system for early stage breast cancer (2016) NICE medtech

innovation briefing 76

Gene expression profiling and expanded immunohistochemistry tests for guiding adjuvant

chemotherapy decisions in early breast cancer management: MammaPrint, Oncotype DX,

IHC4 and Mammostrat (2013) NICE diagnostics guidance 10.

A NICE interactive flowchart on early and locally advanced breast cancer and a quality standard on

breast cancer (2011; updated 2016) are also available.

The following NICE guidance relates to licensed indications for bisphosphonates:

Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary

prevention of osteoporotic fragility fractures in postmenopausal women (2008) NICE

technology appraisal guidance 160

Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for

the secondary prevention of osteoporotic fragility fractures in postmenopausal women (2008)

NICE technology appraisal guidance 161.

As well as guidance, NICE produces advice publications which do not constitute formal NICE

guidance but critically appraise the evidence to help decision-making. These include:

Early and metastatic HER2-positive breast cancer: subcutaneous trastuzumab (2013) NICE

evidence summary ESNM13.

ReferencesReferences

Brufsky A and Mathew A (2015) Bisphosphonates, bone, and breast cancer recurrence. Lancet 386:

1319–20



Page 24 of44


https://www.nice.org.uk/guidance/indevelopment/gid-ng10016

http://www.nice.org.uk/guidance/csg1

http://www.nice.org.uk/guidance/ta112


https://www.nice.org.uk/advice/mib76

http://www.nice.org.uk/guidance/dg10



https://pathways.nice.org.uk/pathways/early-and-locally-advanced-breast-cancer

http://www.nice.org.uk/guidance/qs12





https://www.nice.org.uk/advice/esnm13/chapter/Relevance-to-NICE-guidance-programmes


Coleman R, Cameron D, Dodwell D et al. (2014) Adjuvant zoledronic acid in patients with early

breast cancer: Final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3

trial. Lancet Oncology 15(9): 997–1006

Dhesy-Thind S, Fletcher GG, Blanchette PS et al (2017) Use of Adjuvant Bisphosphonates and

Other Bone-Modifying Agents in Breast Cancer: A Cancer Care Ontario and American Society of

Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology 35: 2062–81

Early Breast Cancer Trialists' Collaborative Group (2015) Adjuvant bisphosphonate treatment in

early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 386:

1353–61

Gnant M, Mlineritsch B, Stoeger H et al. (2015) Zoledronic acid combined with adjuvant endocrine

therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early

breast cancer: Final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12.

Annals of Oncology 26(2): 313–20

Gralow J, Barlow WE, Alexander HG et al. (2015) Phase III Trial of Bisphosphonates as Adjuvant

Therapy in Primary Breast Cancer: SWOG/Alliance/ECOG-ACRIN/NCIC Clinical Trials Group/

NRG Oncology Study S0307. Journal of Clinical Oncology 33 (suppl; abstr 503)

Hadji P, Coleman RE, Wilson C et al. (2016) Adjuvant bisphosphonates in early breast cancer:

consensus guidance for clinical practice from a European Panel. Annals of Oncology 27(3): 379–90

Jacobs C, Amir E, Paterson A et al. (2015) Are adjuvant bisphosphonates now standard of care of

women with early stage breast cancer? A debate from the Canadian Bone and the Oncologist New

Updates meeting. Journal of Bone Oncology 4(2): 54–8

Tierney JF, Vale C, Riley R, Smith CT, Stewart L, Clarke M, et al. (2015) Individual participant data

(IPD) meta-analyses of randomised controlled trials: guidance on their use. PLoS Med 12(7):

e1001855

Wong MHF, Stockler MR and Pavlakis N. Bisphosphonates and other bone agents for breast cancer.

Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD003474. DOI: 10.1002/

14651858.CD003474.pub3



Page 25 of44












http://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.503







http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001855


http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003474.pub3/abstract

Evidence tablesEvidence tables

TTable 5 Early Breast Cancer Table 5 Early Breast Cancer Trialists' Collaborrialists' Collaborativative Group (EBCTe Group (EBCTCG) (2015)CG) (2015)

StudyStudy

referencereference

EBCTCG (2015) Adjuvant bisphosphonate treatment in early breast cancer:

meta-analyses of individual patient data from randomised trials. Lancet 386:

1353–61

UniqueUnique

identifieridentifier

Not applicable

Study typeStudy type Meta-analysis of individual participant data from 26 RCTs

Aim of theAim of the

studystudy

To clarify whether adjuvant bisphosphonates reduce the risk of breast cancer

recurring, breast cancer mortality, and of bone and other metastases. Also,

whether menopausal status affects efficacy in women with early breast

cancer

Study datesStudy dates Trials were eligible if they began before 2008. Information on individual

participants was sought between 2012 and 2014

SettingSetting The trials in the meta-analysis were undertaken worldwide, including the

USA, the UK and many other European countries

Number ofNumber of

participantsparticipants

18,766 women (25% aged below 45 years, 36% aged 45–54 years, 34% aged

55–69 years and 6% aged 70 years or over; 33% premenopausal, 4%

perimenopausal and 63% postmenopausal)

PPopulationopulation Women with early breast cancer (not defined)

InclusionInclusion

criteriacriteria

No additional inclusion criteria were reported

ExExclusionclusion

criteriacriteria

No exclusion criteria were reported

IntervIntervention(s)ention(s) Adjuvant bisphosphonate treatment (mainly zoledronic acid 50%, clodronate

27% and ibandronic acid 16%)

ComparComparator(s)ator(s) Control group with no bisphosphonate treatment (open label or placebo)

LLength ofength of

follow-upfollow-up

Median follow-up was 5.6 woman-years (IQR 3.7 to 8.0 years). Mean

scheduled treatment duration was 3.4 years and 97% of participants were in

trials of 2–5 years' treatment



Page 26 of44



http://www.nice.org.uk/Glossary?letter=M

Primary outcomes:

any recurrence of breast cancer (distant, locoregional or new primary in

the contralateral breast)

distant recurrence (ignoring any previous locoregional or contralateral

recurrence) and

breast cancer mortality

Secondary outcomes:a

all-cause mortality

death without recurrence

bone recurrence as the first distant recurrence (with or without

concurrent other recurrence)

other first (extraskeletal) distant recurrence (with all analyses of distant

recurrence ignoring any previous locoregional or contralateral recurrence)

locoregional recurrence as first event (ipsilateral breast, chest wall, or

locoregional lymph nodes)

contralateral new primary breast cancer as first event, and

any bone fractures

Prespecified primary subgroup investigations included site of first distant

recurrence (bone or other site), menopausal status (or, if menopausal status

was unavailable, years of age [ less than 45 years, 54–54 years, 55 years or

more]), and class of bisphosphonate (clodronate or aminobisphosphonate)

OutcomesOutcomes

Safety outcomes:b

Non-fatal adverse events such as ischaemic heart disease, stroke and

osteonecrosis of the jaw

Source ofSource of

fundingfunding

Funding for individual trials was chiefly from manufacturers. Funding for this

analysis was from Cancer Research UK and the UK Medical Research Council.

Clinical Trial Service Unit staff policy excludes honoraria or consultancy fees

for any member of the EBCTCG



Page 27 of44

Did the review address a clearly focused question? Yes

Did the authors look for the right type of papers? Yes

Do you think all the important, relevant studies were included? Yesd

Did the review's authors do enough to assess the quality of the

included studies?

Uncleare

If the results of the review have been combined, was it

reasonable to do so?

Yes

What are the overall results of the review? See table 6

How precise are the results? See table 6

Can the results be applied to the local population? Yes

Were all important outcomes considered? Yesf

OvOvererall risk ofall risk of

bias/qualitybias/quality

assessmentassessment

(CASP

systematic

review

checklist and

checklist for

IPD meta-

analysesc)

Are the benefits worth the harms and costs? See key

points

StudyStudy

limitationslimitations

Information on how trials were identified, assessment of trial quality, and

citations for excluded and included papers were not reported

Little or no information is available for some commonly used

bisphosphonates, such as risedronate and alendronic acid

Limited information is available comparing different bisphosphonates, or

different dosages of bisphosphonates

No information is available on managing breast cancer in men

Safety and quality of life outcome data are not reported

Combining the data for all bisphosphonates in the meta-analysis was

controversial, as was including small trials not designed to measure the

outcomes of interest and performing a meta-analysis of subgroups (CCO/

ASCO and Jacobs C et al. 2015)



Page 28 of44

http://live-publications.nice.org.uk/results-tables#results-tables

http://www.casp-uk.net/casp-tools-checklists







http://live-publications.nice.org.uk/key-points#key-points

http://live-publications.nice.org.uk/key-points#key-points




CommentsComments a Results for many of these outcomes are not reported in this evidence

summary. See the published paper for more detailsb Although data were collected, results for safety outcomes are not reported

in the paperc Checklist for IPD meta-analyses of RCTs from Tierney et al. 2015d A systematic review appears to have been undertaken but the methods of

identifying trials, seeking collaboration, data collection, collation, checking,

and presentation have not been fully reported, apart from to note these were

undertaken as in previous EBCTCG reports. A protocol of the methods for this

particular study is not reported. Individual participant data were not obtained

for 6 of the 32 completed RCTs that recorded recurrence data, but these

included only 525 women and would have been unlikely to change the

outcomes of the meta-analysise No assessment of quality or risk of bias of the individual trials is reported,

including randomisation, allocation concealment, blinding and adjudication of

outcomes. It is unclear whether or not the integrity of the IPD meta-analysis

was checkedf Outcomes and analyses were prespecified, although detailed methods of

analyses were not reported (for example, methods for checking

heterogeneity, and whether 1- or 2-stage IPD meta-analyses were

performed). Safety outcomes were not reported for the study population;

however, the adverse effect profile of bisphosphonates is well-established

AbbreAbbreviations:viations: EBCTCG, Early Breast Cancer Trialists' Collaborative Group; IQR, interquartile

range; IPD, individual participant meta-analysis; RCT, randomised controlled trial

Results tablesResults tables

TTable 6 Early Breast Cancer Table 6 Early Breast Cancer Trialists' Collaborrialists' Collaborativative Group (EBCTe Group (EBCTCG) (2015)CG) (2015)

BisphosphonatesBisphosphonates ControlControl AnalysisAnalysis

TTotal n=18,766otal n=18,766 n=9,856n=9,856 n=8,910n=8,910

Primary outcomesPrimary outcomes



Page 29 of44



https://www.nice.org.uk/Glossary?letter=A


Rate of recurrence of

breast cancer

16.3% at 5 years

24.9% at

10 years

17.4% at

5 years

25.9% at

10 years

Difference at 10 years 1.1% (95% CI

−0.7% to 2.9%), NSS

Rate ratio 0.94 (95% CI 0.87 to 1.01)

p=0.08, NSS

Rate of distant

recurrence

13.5% at 5 years

20.4% at

10 years

14.8% at

5 years

21.8% at

10 years


−0.3% to 3.1%), NSS

Rate ratio 0.92 (95% CI 0.85 to 0.99)

p=0.03

Rate of breast cancer

mortality

8.9% at 5 years

16.6% at

10 years

9.7% at

5 years

18.4% at

10 years


0.0% to 3.5%)

Rate ratio 0.91 (95% CI 0.83 to 0.99)

p=0.04

Selected secondary outcomeSelected secondary outcome

Bone recurrence 4.7% at 5 years

7.8% at 10 years

5.9% at

5 years

9.0% at

10 years


−0.1% to 2.3%), NSS

Rate ratio 0.83 (95% CI 0.73 to 0.94)

p=0.004

All-cause mortality 10.6% at 5 years

20.8% at

10 years

11.4% at

5 years

22.3% at

10 years


−0.36 to 3.56), NSS

Rate ratio 0.92, 95% CI 0.85 to 1.00,

p=0.06

Prespecified subgroup analyses in postmenopausal womenPrespecified subgroup analyses in postmenopausal women

TTotal n=11,767otal n=11,767 n=6,099n=6,099 n=5,668n=5,668

Rate of recurrence of

breast cancer

13.4% at 5 years

22.8% at

10 years

15.8% at

5 years

25.8% at

10 years


0.5% to 5.5%)

Rate ratio 0.86 (95% CI 0.78 to 0.94)

p=0.002

Rate of distant

recurrence

11.1% at 5 years

17.9% at

10 years

13.6% at

5 years

21.2% at

10 years


1.0% to 5.8%)

Rate ratio 0.82 (95% CI 0.74 to 0.91)

p=0.0003



Page 30 of44

Rate of breast cancer

mortality

7.5% at 5 years

14.7% at

10 years

8.7% at

5 years

18.0% at

10 years


0.8% to 5.7%)

Rate ratio 0.82 (95% CI 0.73 to 0.93)

p=0.002

Bone recurrence 3.6% at 5 years

6.6% at 10 years

5.4% at

5 years

8.8% at

10 years


0.6% to 3.8%)

Rate ratio 0.72 (95% CI 0.60 to 0.86)

p=0.0002

All-cause mortality 9.5% at 5 years

21.1% at

10 years

10.8% at

5 years

23.5% at

10 years


−0.64 to 5.24), NSS

Rate ratio 0.86, 95% CI 0.77 to 0.96,

p=0.005

Safety and tolerSafety and tolerability outcomesability outcomes

Although data on safety outcomes was collected, results are not reported in the paper. From

the data obtained, it was not possible to assess the incidence of osteonecrosis of the jaw

AbbreAbbreviations:viations: CI, confidence interval; NSS, not statistically significant; p, p value

ExExcluded studiescluded studies

Study referenceStudy reference Reason forReason for

eexxclusionclusion

Charehbili A, van de Ven S, Smit VT et al. (2014) Addition of zoledronic

acid to neoadjuvant chemotherapy does not enhance tumor response in

patients with HER2-negative stage II/III breast cancer: the NEOZOTAC

trial (BOOG 2010-01). Annals of oncology: official journal of the European

Society for Medical Oncology 25(5), 998–1004

Does not report

recurrence or

survival

Fasching PA, Jud SM, Hauschild M et al. (2014) FemZone trial: a

randomized phase II trial comparing neoadjuvant letrozole and zoledronic

acid with letrozole in primary breast cancer patients. BMC Cancer 14, 66

Does not report

recurrence or

survival, and was

terminated early



Page 31 of44

https://www.nice.org.uk/Glossary?letter=C

https://www.nice.org.uk/Glossary?letter=s

http://www.nice.org.uk/Glossary?letter=P

Gralow J, Barlow WE, Paterson AHG et al. (2014) SWOG S0307 phase III

trial of bisphosphonates as adjuvant therapy in primary breast cancer:

comparison of toxicities and patient-stated preference for oral versus

intravenous delivery. Journal of clinical oncology 32(15 suppl. 1)

Conference

abstract only

Hasegawa Y, Tanino H, Horiguchi J et al. (2015) Randomized controlled

trial of zoledronic acid plus chemotherapy versus chemotherapy alone as

neoadjuvant treatment of HER2-negative primary breast cancer (JONIE

Study). PLoS ONE 10(12), e0143643

Does not report

recurrence or

survival

Wong MHF, Stockler MR and Pavlakis N. Bisphosphonates and other bone

agents for breast cancer. Cochrane Database of Systematic Reviews 2012,

Issue 2. Art. No.: CD003474. DOI: 10.1002/14651858.CD003474.pub3

Meta-analysis

superseded by the

2015 EBCTCG

meta-analysis of

individual patient

data

Search strSearch strategyategy

Database: MedlineDatabase: Medline

Platform: Ovid

Version: 1946 to March wk 5 2017

Search date: 07/04/2017

Number of results retrieved: 88

Search strategy:

--------------------------------------------------------------------------------

1 exp Breast Neoplasms/ (257990)

2 ((breast* or mammary) adj4 (cancer* or carcinoma* or neoplasm* or tumour* or tumor* or

malignan*)).tw. (265230)

3 1 or 2 (321579)



Page 32 of44



4 exp Diphosphonates/ (23662)

5 (bisphosphonate* or diphosphonate*).tw. (15702)

6 (alenato or alend or alendronate or alendros or alovell or arendal or bifemelan or bifosa or

binosto or bonapex or defixal or dronal or endronax or eucalen or fixopan or fosalan or fosamax or

fosmin or fosval or marvil or maxibone or neobon or oncalst or onclast or osdron or osdronat or

oseotenk or osficar or oslene or osteofar or osteofos or osteopor or osteosan or osteovan or

osticalcin or porosal or teiroc or tibolene or voroste or alendronic or fosavance).tw. (3653)

7 (bondenza or bondronat or bondronate or boniva or bonviva or destara or iasibon or ibandronate

or ibandronic acid or quodixor).tw. (861)

8 (amidronate or aminohydroxypropanediphosphonic acid or aminohydroxypropyldiphosphonate

or aminohydroxypropylidene or aminohydroxypropylidene diphosphonate or

aminohydroxypropylidenebisphonic acid or aminohydroxypropylidenebisphosphonate or

aminohydroxypropylidenediphosphonate or aminomux or apd or aredia or aredronet or ostepam

or pamidrin or pamidro cell or pamidro-cell or pamidrocell or pamidromyl or pamidronat or

pamidronate or pamifos or paminject or pamipro or pamired or pamisol or pamitor or panolin or

panorin or ribodronat or texpami or pamidronic).tw. (6132)

9 (risedronate or actonel or atelvia or risedronic acid or benet or optinate or ribastamin or

risedronic).tw. (1469)

10 (clodronic or dichloromethanediphosphonic or bonefos or clodronate or

dichloromethanediphosphonate or dichloromethanediphosphonic acid or

dichloromethylenebisphosphonate or difosfonal or lodronat or lodronate or mebonat or ossiten or

ostac or clasteon or loron).tw. (1658)

11 (aclasta or orazol or reclast or zoledronate or zoledronic acid or zomera or zometa or

zerlinda).tw. (3236)

12 or/4-11 (32684)

13 3 and 12 (2666)

14 randomized controlled trial.pt. (458924)



Page 33 of44

15 randomized controlled trial/ (458924)

16 controlled clinical trial.pt. (93874)

17 random allocation/ (91968)

18 Placebos/ (34857)

19 clinical trial, phase ii/ or clinical trial, phase iii/ (42481)

20 14 or 15 or 16 or 17 or 18 or 19 (650823)

21 animals/ (6075139)

22 humans/ (16769359)

23 21 not 22 (4347891)

24 20 not 23 (593032)

25 13 and 24 (310)

26 limit 25 to english language (298)

27 (2011* or 2012* or 2013* or 2014* or "2015 *" or 2016* or 2017*).ed. (4299379)

28 26 and 27 (88)

Database: Medline in-processDatabase: Medline in-process

Platform: Ovid

Version: April 06 2017

Search date:07/04/2017




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Search strategy:

--------------------------------------------------------------------------------




3 1 or 2 (26137)























Page 35 of44




zerlinda).tw. (587)

12 or/4-11 (2965)

13 3 and 12 (287)

14 (random* or placebo* or control* or blind*).tw. (388933)

15 13 and 14 (72)


17 (2011* or 2012* or 2013* or 2014* or 2015* or 2016* or 2017*).ed. (1178222)

18 16 and 17 (33)

Database: Medline epubs ahead of printDatabase: Medline epubs ahead of print

Platform: Ovid

Version: April 06 2017

Search date:07/04/2017


Search Strategy:

--------------------------------------------------------------------------------






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3 1 or 2 (6061)
























zerlinda).tw. (83)

12 or/4-11 (423)

13 3 and 12 (44)



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14 (random* or placebo* or control* or blind*).tw. (71361)

15 13 and 14 (11)


Database: EmbaseDatabase: Embase

Platform: Ovid

Version: 1974 to 2017 Week 14



Search strategy:

--------------------------------------------------------------------------------

1 exp *breast cancer/ (264740)



3 1 or 2 (423305)

4 exp *bisphosphonic acid derivative/ (24597)









Page 38 of44

















zerlinda).tw. (7394)

12 or/4-11 (46725)

13 3 and 12 (4031)

14 exp Clinical Trials/ (283882)

15 Randomization/ (85535)

16 Placebo/ (335538)

17 Double Blind Procedure/ (142603)

18 Single Blind Procedure/ (30608)

19 Crossover Procedure/ (55966)



Page 39 of44

20 ((random* or control* or clinical*) adj3 (trial* or stud*)).tw. (1343860)

21 (random* adj3 allocat*).tw. (34967)

22 placebo*.tw. (255879)

23 ((singl* or doubl* or trebl* or tripl*) adj (blind* or mask*)).tw. (201355)

24 (crossover* or (cross adj over*)).tw. (88145)

25 or/14-24 (1809520)

26 nonhuman/ not human/ (3791464)

27 25 not 26 (1749048)

28 13 and 27 (1457)


30 (201104* or 201105* or 201106* or 201107* or 201108* or 201109* or 201110* or 201111*

or 201112* or 2012* or 2013* or 2014* or 2015* or 2016* or 2017*).dc. (9553388)

31 29 and 30 (694)

32 limit 31 to (conference abstract or conference paper or conference proceeding or "conference

review") (301)

33 31 not 32 (393)

Database: CochrDatabase: Cochrane Librane Library – incorporary – incorporating Cochrating Cochrane Database of Systematic Reane Database of Systematic Reviews (views (CDSR);CDSR);

DDARE; CENTRAL; HTARE; CENTRAL; HTA database; NHS EEDA database; NHS EED

Platform: Wiley

Version:

CDSR – 4 of 12 April 2017



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DARE – 2 of 4, April 2015 (legacy database)

CENTRAL – 3 of 12 March 2017

HTA – 4 of 4 October 2016

NHS EED – 2 of 4, April 2015 (legacy database)


Number of results retrieved: CDSR 2; DARE 10 CENTRAL 249 ; HTA 0 ; NHS EED 3.

Search strategy:

Search Name: Breast cancer and bisphosphonates

Date Run: 07/04/17 11:03:14.233

Description:

ID Search Hits

#1 MeSH descriptor: [Breast Neoplasms] explode all trees 10139

#2 (breast* or mammary) near/4 (cancer* or carcinoma* or neoplasm* or tumour* or tumor* or

malignan*):ti,ab,kw (Word variations have been searched) 23796

#3 #1 or #2 23796

#4 MeSH descriptor: [Diphosphonates] explode all trees 2157

#5 bisphosphonate* or diphosphonate*:ti,ab,kw (Word variations have been searched) 2120

#6 alenato or alend or alendronate or alendros or alovell or arendal or bifemelan or bifosa or






Page 41 of44

osticalcin or porosal or teiroc or tibolene or voroste or alendronic or fosavance:ti,ab,kw (Word

variations have been searched) 1084

#7 bondenza or bondronat or bondronate or boniva or bonviva or destara or iasibon or

ibandronate or ibandronic acid or quodixor:ti,ab,kw (Word variations have been searched) 326

#8 amidronate or aminohydroxypropanediphosphonic acid or aminohydroxypropyldiphosphonate






panorin or ribodronat or texpami or pamidronic:ti,ab,kw (Word variations have been searched) 676

#9 risedronate or actonel or atelvia or risedronic acid or benet or optinate or ribastamin or

risedronic:ti,ab,kw (Word variations have been searched) 454

#10 clodronic or dichloromethanediphosphonic or bonefos or clodronate or



ostac or clasteon or loron:ti,ab,kw (Word variations have been searched) 333

#11 aclasta or orazol or reclast or zoledronate or zoledronic acid or zomera or zometa or

zerlinda:ti,ab,kw (Word variations have been searched) 979

#12 {or #4-#11} 4101

#13 #3 and #12 Publication Year from 2011 to 2017 264

DeDevvelopment of this eelopment of this evidence summaryvidence summary

The evidence summaries: process guide (2017) sets out the process NICE uses to select topics for

evidence summaries and details how the summaries are developed, quality assured and approved

for publication.

Expert advisers

Professor Robert Coleman, Department of Oncology and Metabolism, University of Sheffield.



Page 42 of44

https://www.nice.org.uk/process/pmg31/chapter/introduction

Dr John Graham, Consultant Oncologist & Trust Cancer Lead Clinician, Musgrove Park Hospital.

Professor Chris Holcombe, Oncoplastic Breast Surgeon, Royal Liverpool University Hospital.

Dr Karen McAdam, Consultant Medical Oncologist, Cambridge University Hospitals NHS

Foundation Trust.

Declarations of interest

Robert Coleman has previously received medical education fees for an unrelated topic from Eisai

and Astra Zeneca. His institution currently receives research funding from Amgen and Bayer and

has previously received research funding from Novartis. He has published extensively on this topic

(including practice guidelines, and advice to commissioners and the Breast Cancer Clinical

Reference Group), and contributed to the repurposing of drugs debate through his role as a Board

member for Breast Cancer Now.

John Graham is a Clinical Adviser for the National Guideline Alliance, Royal College of

Obstetricians & Gynaecologists, and the Vice Chair for NICE Guideline Updates Committee B. He is

the principal investigator for various ongoing clinical trials in prostate cancer and breast cancer, 3

of which are funded by Bayer Health Care and 8 of which are run via the National Cancer Research

Network, which is not pharmaceutical industry funded. He has received travel expenses from The

Conference Forum to attend the Immuno-Oncology 360 Conference.

Chris Holcombe has been paid to chair an Advisory Board for Genomic Health and lecture on

behalf of Roche. He has also accepted hospitality to attend a conference provided by the makers of

Braxon, an Acellular Dermal Matrix used in breast reconstruction.

Karen McAdam has received a speaker fee from Roche for a meeting on neoadjuvant

chemotherapy/anti HER2 therapy for early breast cancer. She previously sat on an advisory board

for Novartis and is now an advisory board member for the EISAI First Thoughts meetings.

About this eAbout this evidence summaryvidence summary

Evidence summaries provide a summary of the best available published evidence for selected

new medicines, unlicensed medicines or off-label use of licensed medicines.

The summaries assess the strengths and weaknesses of the best available evidence to inform

health professionals and commissioners' decision-making.

This summary is not NICE guidanceThis summary is not NICE guidance.



Page 43 of44

ISBN: 978-1-4731-2598-8



Page 44 of44

Adjuvant bisphosphonates in early breast cancer:consensus guidance for clinical practice from aEuropean PanelP. Hadji1,†, R. E. Coleman2*,†, C. Wilson2, T. J. Powles3, P. Clézardin4, M. Aapro5, L. Costa6,J.-J. Body7, C. Markopoulos8, D. Santini9, I. Diel10, A. Di Leo11, D. Cameron12, D. Dodwell13,I. Smith14, M. Gnant15, R. Gray16, N. Harbeck17, B. Thurlimann18, M. Untch19, J. Cortes20,M. Martin21, U.-S. Albert1, P.-F. Conte22, B. Ejlertsen23,24, J. Bergh25, M. Kaufmann26 & I. Holen21Department of Bone Oncology, Endocrinology and Reproductive Medicine, Philipps-University of Marburg, Frankfurt, Germany; 2Academic Unit of Clinical Oncology,Weston Park Hospital, University of Sheffield, Sheffield; 3Cancer Centre London, Wimbledon, UK; 4INSERM, Research Unit UMR403, University of Lyon, School of MedicineLyon-Est, Lyon, France; 5Breast Center of the Multidisciplinary Oncology Institute, Genolier, Switzerland; 6Hospital de Santa Maria & Lisbon School of Medicine, Institute ofMolecular Biology, Lisbon, Potugal; 7CHU Brugmann, Université Libre de Bruxelles (ULB), Brussels, Belgium; 8Medical School, National University of Athens, Athens,Greece; 9Medical Oncology, University Campus Bio-medico, Rome, Italy; 10Institute for Gynaecological Oncology, Centre for Comprehensive Gynecology, Mannheim,Germany; 11Sandro Pitigliani Medical Oncology Unit, Department of Oncology, Hospital of Prato, Prato, Italy; 12University of Edinburgh Cancer Research Centre, WesternGeneral Hospital, Edinburgh; 13Institute of Oncology, Bexley Wing, St James Hospital Leeds, Leeds; 14The Royal Marsden Hospital and Institute of Cancer Research,London, UK; 15Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; 16Clinical Trials and Epidemiological Unit,University of Oxford, Oxford, UK; 17Breast Center, Department of Obstetrics and Gynaecology, University of Munich, Munich, Germany; 18Kantonsspital St Gallen, BreastCenter, St Gallen, Switzerland; 19Interdisciplinary Breast Cancer Center HELIOS Klinikum Berlin-Buch Germany, Gynecologic Oncology and Obstetrics, Berlin, Germany;20Department of Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona; 21Department of Medical Oncology, Institute of Investigation Sanitaria Gregorio Marañón,University Complutense, Madrid, Spain; 22Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; 23Danish Breast CancerCooperative Group Statistical Center; 24Department of Oncology Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 25Karolinska Institute andUniversity Hospital, Stockholm, Sweden; 26Institute for Obstetrics and Gynaecology, Goethe University, Frankfurt, Germany

Received 16 October 2015; revised 21 November 2015; accepted 30 November 2015

Bisphosphonates have been studied in randomised trials in early breast cancer to investigate their ability to preventcancer treatment-induced bone loss (CTIBL) and reduce the risk of disease recurrence and metastasis. Treatment bene-fits have been reported but bisphosphonates do not currently have regulatory approval for either of these potential indica-tions. This consensus paper provides a review of the evidence and offers guidance to breast cancer clinicians on the useof bisphosphonates in early breast cancer. Using the nominal group methodology for consensus, a systematic review ofthe literature was augmented by a workshop held in October 2014 for breast cancer and bone specialists to present anddebate the available pre-clinical and clinical evidence for the use of adjuvant bisphosphonates. This was followed by aquestionnaire to all members of the writing committee to identify areas of consensus. The panel recommended thatbisphosphonates should be considered as part of routine clinical practice for the prevention of CTIBL in all patients with aT score of <−2.0 or ≥2 clinical risk factors for fracture. Compelling evidence from a meta-analysis of trial data of >18 000patients supports clinically significant benefits of bisphosphonates on the development of bone metastases and breastcancer mortality in post-menopausal women or those receiving ovarian suppression therapy. Therefore, the panel recom-mends that bisphosphonates (either intravenous zoledronic acid or oral clodronate) are considered as part of the adjuvantbreast cancer treatment in this population and the potential benefits and risks discussed with relevant patients.Key words: adjuvant, bisphosphonates, breast cancer, guidelines

introductionBisphosphonates have regulatory approval and are part of stand-ard care for the prevention and treatment of osteoporosis and

the prevention of skeletal related events associated with bonemetastases from metastatic solid tumours and multiplemyeloma [1]. Bisphosphonates have also been studied in rando-mised trials in the adjuvant setting of early breast cancer to in-vestigate their ability to prevent both cancer treatment-inducedbone loss (CTIBL) and reduce disease recurrence and metasta-ses. Bisphosphonates do not currently have regulatory approvalfor either of these indications. This consensus paper provides a

*Correspondence to: Prof. Robert E. Coleman, Academic Unit of Clinical Oncology,University of Sheffield, Weston Park Hospital, Whitham Road, Sheffield S10 2SJ, UK.Tel: +44-114-226-5000; E-mail: [email protected]

†Both authors contributed equally as joint first authors.

review

s

reviews Annals of Oncology 27: 379–390, 2016doi:10.1093/annonc/mdv617

Published online 17 December 2015

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved. For permissions, please email: [email protected].

Downloaded from https://academic.oup.com/annonc/article-abstract/27/3/379/2196531by SuUB Bremen useron 23 August 2018

review of the evidence and offers guidance on the use of bispho-sphonates in both these additional settings.

aimsTo provide guidance for the use of bisphosphonates in patientswith early breast cancer, focusing on CTIBL and the preventionof metastases.

methods

consensus meetingUsing the nominal group methodology for consensus [2] indi-vidual leading experts from European stakeholders in the clinic-al management of breast cancer (medical/clinical oncologists,gynaecologists, surgeons), and experts in pre-clinical bone re-search were asked to present their opinions on the predefinedaims of the consensus at a face-to-face meeting in October 2014.Following the presentations, a structured discussion was under-taken to collate individual expert opinions and review relevantpublished literature (identified as per ‘Data sources’ below).

consensus questionnaireFollowing the consensus meeting, a series of questions weredeveloped to consolidate expert opinions. Voting on each ques-tion was anonymous and in the format of ‘agreement’ or ‘dis-agreement’ (graded strong or slightly) or neutral if a panelmember felt there was insufficient evidence or he/she had insuffi-cient knowledge to support a recommendation. Questionnaireswere completed by 24/26 (90%) of experts and data was assessed.Detailed voting records for each question addressed to the panelare available in supplementary Appendix S1, available at Annalsof Oncology online.

data sourcesA systematic literature search was conducted using Pubmed andMedline databases from 1970 to 2014. In addition, the CochraneRegister of Controlled Trials and databases of ongoing and unpub-lished trials http://www.clinicaltrials.gov were searched. Conferenceproceedings from San Antonio Breast Cancer Symposium,European Society of Medical Oncology and American Society ofClinical Oncology (2000–2014) were reviewed. The key studies aresummarised in Figures 1 and 2. In addition, the panel had accessto the EBCTCGmeta-analysis findings before full publication.

cancer treatment-induced bone lossThe causes of bone loss in cancer patients and the functionalconsequences are multifactorial, occurring as a result of theanti-cancer therapies used to prevent tumour recurrence andpre-existing clinical risk factors for fracture (age, concurrentmedications, i.e. glucocorticoids, smoking status, low body massindex, family or personal history of fragility fracture, T score<−2.5) [1, 3]. The speed of CTIBL depends on the menopausalstatus of the patients in addition to the cancer treatmentreceived, and on average is more rapid than the natural rate ofbone loss that occurs in post-menopausal women [1, 4].

pre-menopausal womenPre-menopausal women have high circulating levels of ovariansecreted oestradiol and inhibins, which act directly on bone tomaintain bone mass [5]. However, accelerated bone loss in pre-menopausal women will occur if ovarian failure is induced by anti-cancer treatment, or if the effects of oestrogen on bone are inhibitedby selective oestrogen receptor modulators such as tamoxifen.

effects of chemotherapy. Chemotherapy probably does not have aclinically significant direct toxic effect on bone in women whomaintain menses [6]. Early bone loss has been observed duringchemotherapy, but this is likely due to the induction of menopause,high doses of glucocorticoids used as anti-emetics plus fatigue-related immobility, rather than the cytotoxic agents themselves [7].

effects of ovarian suppression. Loss or suppression of ovarianfunction from either chemotherapy or drugs affecting thehypothalamic–pituitary–gonadal axis such as GnRH/LHRHanalogues has been shown to cause rapid bone loss that persistsfor the duration of amenorrhoea [8]. In patients who receivechemotherapy and remain permanently amenorrhoeic, theindirect effects of chemotherapy on bone loss continue aftercessation of chemotherapy [9–11].In patients receiving GnRH analogues to suppress ovarian

function (OFS), accelerated bone loss occurs during treatmentbut there is recovery after treatment is stopped, especially inthose patients who resume menses [12, 13]. In the largest trial ofOFS with endocrine therapy in pre-menopausal women, bonemineral density (BMD) after 3 years was reduced by 11.3% and7.3% at the lumbar spine and trochanter, respectively. Seventy-five percent of patients’ regained menses after endocrine treat-ment stopped and BMD partially recovered (but did not reachbaseline levels) at both skeletal sites over the next 2 years [14].Moreover, bone loss in patients receiving anastrozole in additionto OFS was greater than that seen with tamoxifen plus OFS(−13.6% versus −9% at 3 years) [14]. The use of OFS and anaromatase inhibitor (AI) is likely to be increasing in routineclinical practice following a recent randomised trial showing sig-nificantly improved disease-free survival (DFS) in pre-meno-pausal women with high-risk disease treated with this endocrinestrategy compared with the current standard, tamoxifen [15].

effects of tamoxifen. Tamoxifen is the most commonly usedendocrine drug in pre-menopausal women with hormonereceptor-positive breast cancer, acting as an anti-oestrogen inbreast cancer cells but with effects in bone that are dependent uponprevailing oestrogen levels. In pre-menopausal women, where thebone microenvironment is rich in oestradiol, tamoxifen taken for 3years resulted in bone loss [16]. The effects of prolonged durationsof tamoxifen should be studied further, since pre-menopausalwomen with breast cancer may now be recommended to continuewith adjuvant tamoxifen for up to 10 years [17].

post-menopausal womenThere is no clear evidence for a direct effect of chemotherapy onbone loss in post-menopausal women. In addition, tamoxifenreduces fracture incidence compared with placebo in a low boneoestrogen environment [18] and thus does not contribute to

| Hadji et al. Volume 27 | No. 3 | March 2016

reviews Annals of Oncology


http://www.clinicaltrials.gov



endocrine therapy-related bone loss in this population. Themajor contributor to bone loss in a post-menopausal breastcancer population is the use of AIs.

bone effects of aromatase inhibitors. AIs improve diseaseoutcomes in comparison to tamoxifen but are associated withincreased fracture incidence [1]. These agents prevent the conversionof androgens to oestrogen by the aromatase enzyme, thereby rapidlyand dramatically reducing circulating serum oestadiol levels [19].This decline in oestradiol is associated with a 40% relative increase infracture rate compared with tamoxifen [20]. When compared withplacebo the excess fracture rate during AI therapy is less [21].Reassuringly, the bone loss induced by AI therapy appears topartially recover after completion of treatment [22, 23].

management of cancer treatment-induced bonelossManagement of the bone loss associated with cancer therapiesincludes both lifestyle recommendations and pharmacologicalintervention [24–26]. All patients at risk of bone loss should beadvised to take regular weight bearing exercise [27–29] andreduce smoking and alcohol consumption [3].Pharmacological intervention for patients at risk of bone loss

includes vitamin D supplementation (1000–2000 IU daily) as

many breast cancer patients are not replete with vitamin D [30].In addition, calcium supplementation (1000 mg daily) is recom-mended if dietary intake is inadequate. Anti-resorptive therapieshave been proven to be effective in preventing CTIBL, althoughtheir efficacy is influenced by menopausal status and the rate ofbone loss [1, 24–26].Current fracture risk assessment tools are based on data from

healthy post-menopausal women and do not adequately addressthe risks associated with treatments in younger pre-menopausalwomen. Guidelines from an UK expert panel [24] for pre-meno-pausal women with breast cancer have been published and dis-cussed in a recent review by Hadji et al. [26]. Recommendationsincluded informing patients of the risk of bone loss duringcancer therapy and consideration of the use of bisphosphonatesif the T score is <−2.0. However, how changes in BMD correlateto fracture risk needs further assessment since previous studiesin pre-menopausal women have used changes in either BMDor biochemical markers of bone resorption as surrogates forfracture risk [29].The evaluation of BMD and use of the WHO Fracture Risk

Assessment Tool (FRAX) in post-menopausal women providesa reliable estimate of fracture risk. However, FRAX does notinclude anti-cancer treatments as a specific risk factor, and somay underestimate risk [3, 31]. Published guidelines recommend

Trial population [ref]

Diel et al [61]

n = 302Stage I–IIIPremenopausal 36%Postmenopausal 64%ER+ve 75%ER–ve 25%DTC+ve bone marrow

n = 1069Stage I–IIIPremenopausal 50%Postmenopausal 50%ER+ve 64%ER–ve 36%

n = 299Stage II–IIIpremenopausal 48%postmenopausal 52%ER+ve 61%ER–ve 39%

n = 3323Stage I–IIIPremenopausal %Postmenopausal %ER+ve 78%ER–ve 22%

n = 2015Stage II–IIIPremenopausal 48%Postmenopausal 52%ER+ve 76%ER–ve 23%

n = 953Stage I–IIPremenopausal 67%Postmenopausal 33%ER+ve ~15%ER–ve ~60%

Oral clodronate1600 mg daily vsplacebo for 2 years


No significant difference in DFS (HR 1.03 95% Cl0.75–1.4 P = 0.86) or OS between groups.

No significant difference in DFS (HR 0.945 95% Cl 0.768–1.161 P = 0.589) or OS (HR1.04 95% Cl 0.763–1.419)P = 0.803 between groups. DFS was non significantlylonger in woman <40 and >60 years.

No significant difference in DFS between groups. Posthoc analysis in woman >60 years shown a significantlyimproved bone (HR 0.64 95% Cl 0.4–0.95 P = 0.047) andextraosseous (HR 0.63 95% Cl 0.43–0.91 P = 0.014)metasasis free survival for clodronate.

Increase in extraosseaous metasases (45% vs 32%) inclodronate group with increased risk of death (46% vs38%). In a sub group analysis postmenopausal womanwith ER+ve disease did not gain a negative effect fromclodronate.

Significantly reduced incidence of bone metastases (HR0.692 P = 0.043) and improved OS (HR 0.768 P = 0.048)for clodronate. Nb. in a sub group analysis,postmenopausal woman had the greatest diseaseoutcome benefit from clodronate



Oral pamidronate150 mg twice daily vsplacebo for 4 years

Oral ibandronate 50 mgdaily vs placebo for 2years

Significant reduction in the incidence of bonemetastases (P = 0.003) and improved survival (P = 0.001)for clodronate.

Powles et al [62]

Saarto et al [63]

Paterson et al [64](NSABP-B-34)

Von Minckwitzet al (GermanGAIN study)[65]

Kristensenet al [66]

Trial design Outcomes

Figure 1. Summary of major adjuvant trials evaluating oral bisphosphonates in early breast cancer.

Volume 27 | No. 3 | March 2016 doi:10.1093/annonc/mdv617 |

Annals of Oncology reviews


evaluation of BMD, fracture risk assessment and measurementof serum calcium, parathyroid hormone and 25-0H-vitamin Dlevels before and during AI therapy [24, 26, 32]. Anti-resorptivetherapy is recommended in patients with a baseline T score of<−2.0 or two or more clinical risk factors for fracture [1, 24, 25].In pre-menopausal women zoledronic acid, the most potent

available bisphosphonate has been shown at a dose of 4 mgevery 6 months to prevent the significant bone loss associatedwith goserelin + tamoxifen/anastrozole [14]. This schedule ofzoledronic acid has also been shown to prevent bone loss asso-ciated with ovarian failure due to chemotherapy [9, 33, 34].Other bisphosphonates have shown some ability to prevent themarked bone loss associated with ovarian suppression/failurebut do not have a sustained effect on BMD in this population[10, 11, 35]. Zoledronic acid in addition to calcium and vitaminD supplementation is therefore recommended to combat therapid bone loss in this clinical setting [1, 26].In post-menopausal women, the choice of bisphosphonate is

broader with evidence that ibandronate (150 mg oral monthly)[36], clodronate (1600 mg oral daily) [8], risedronate (35 mg oralweekly) [37], alendronate (70 mg oral weekly) [38] and zoledro-nic acid (4 mg i.v. 6 monthly) [39–41] all prevent the bone loss

associated with use of AIs. Although these trials were notdesigned for a fracture-prevention end point, data from the osteo-porosis setting have demonstrated a good correlation betweenBMD improvements and fracture prevention [1]. Recently, themore potent osteoclast inhibitor, denosumab, has been shown tohalve the incidence and significantly extend the time to first clin-ical fracture in post-menopausal women receiving AIs, irrespect-ive of baseline BMD [42].

toxicity and adherenceAlthough oral bisphosphonates are generally well tolerated, treat-ment adherence is reported to be poor, with up to 70% of patientsdiscontinuing treatment in the first year [43]. Intravenous bispho-sphonates avoid this issue but are associated with acute phasereactions and renal dysfunction [44] requiring renal monitoringand dose reductions for renal impairment. Osteonecrosis of thejaw (ONJ) is the most important adverse event associated withprolonged administration of potent inhibitors of bone resorption.ONJ is more common (incidence ∼1.3%) [45] when intravenousbisphosphonates are used monthly in the setting of advancedcancer but rare with less intensive use of intravenous

Trial population [ref]

AZURE [70]

n = 3360stage II/III

Premenopausal 45%Unknown menopausal 9.7%

<5 years since menopause 14.7%>5 years since menopause 31%

ER+ve 78.9%ER–ve 21%

ABCSG-12 [68]

n = 1803stage I/II

PremenopausalAll ER+ve

Zo-Fast [72]

n = 1060stage I–III

All PostmenopausalAll ER+ve

No significant difference betweengroups for DFS or OS. In women >5years postmenopausal thezoledronic acid group had a 25%relative risk reduction for invasiveDFS (HR 0.75 95% Cl 0.59–0.96P = 0.02) and risk of death by 26% (HR0.74 95% Cl 0.55–0.98 P = 0.04)

Relative risk reduction of 29% forDFS with zoledronic acid comparedto endocrine therapy alone (HR 0.7195% Cl 0.55–0.92). OS did not alterwith addition of zoledronic acid inoverall population. A significantbenefit for OS was seen in women>40 years (HR 0.57 95% Cl 0.33–0.99P = 0.042).

Patients who started zoledronic acidimmediately had a 34% relative riskdecrease for DFS (HR 0.66 95% Cl0.44–0.97 P = 0.0375). There was nodifference in OS. Women >60 years or>5 years postmenopausal had asignificantly improved OS withimmediate zoledronic acid (HR 0.5P = 0.0224)

Trial design Outcomes

Standard therapy (ST)

Goserelin 3.6 mg + tamoxifen 20 mg

Goserelin + tamoxifen + ZOL 4 mg Q6/12

Goserelin + anastrazole 1 mg

Goserelin + anastrazole + ZOL 4 mg Q6/12

Letrozole 2.5 mg + ZOL 4 mg Q6/12

Letrozole + delayed ZOL (started if; BMD Tscore <-2SD, Clinical fracture,

asymptomatic fracture at 36/12)

Standard therapy + ZOL 4 mg6 doses Q3-4/52, 8 doses Q3/12, 5 doses

Q6/12

VS

VS

VS

VS

VS

ZOL duration 5 years



Figure 2. Summary of major adjuvant trials evaluating intravenous zoledronic acid in early breast cancer.




bisphosphonates (6 monthly) or with oral bisphosphonates givenfor preservation of bone mass [46]. Nevertheless, before bispho-sphonates are initiated, it is recommended that patients undergoa dental examination and maintain good oral hygiene while ontreatment, avoiding invasive dental surgical procedures such asextractions or implant placement [1].

panel recommendations. The panel agreed that treatmentdecisions should take into account risk factors for fracture andmeasurement of BMD in all women receiving adjuvant therapy.Pre-menopausal women receiving OFS, especially when combinedwith an AI, were considered the highest priority for treatmentand pharmacological intervention was least relevant for pre-menopausal women on tamoxifen alone. The panel recommendedthat treatment is continued until the adjuvant breast cancertreatment programme is complete, taking note of BMD results, butnot continued indefinitely. Other than a preference for zoledronicacid in pre-menopausal women, there was variable preference onthe choice of agent in post-menopausal women. Although there isnot a specific license for bisphosphonate use in early breast cancer,the panel did not consider this a barrier to prescribing these agents(Table 1).

adjuvant use of bisphosphonates forprevention of metastases

pre-clinical and early phase clinical trial dataPre-clinical studies using in vivo model systems have evaluated theanti-cancer properties of bisphosphonates at various stages of breastcancer progression (Figure 3) and demonstrated an ability to:

• ‘prevent homing of tumour cells to bone’ using zoledronicacid [47], ibandronate [48] and olpadronate [49] administeredbefore tumour cell injection. In support of this, clinical studieshave shown that both zoledronic acid [50–52] and ibandro-nate [53] decrease the number of DTCs in bone marrow aspi-rates from breast cancer patients;

• ‘cause direct induction of tumour cell death in bone’ whencombined with chemotherapy in vivo [54];

• ‘maintain dormancy of tumour cells in bone’ with in vivostudies demonstrating that zoledronic acid [50] can preventproliferation of dormant tumour cells in bone followingincreased bone turnover secondary to ovariectomy [55];

• ‘inhibit release of growth factors from bone and interruption ofthe vicious cycle of bone metastasis’ with in vivo data showingthat bisphosphonates can slow tumour progression once bone

Table 1. Adjuvant bisphosphonate use to prevent osteoporosis and fracture

Areas of strong consensus (>80%)Should be considered in pre-menopausal women on ovarian suppression and an aromatase inhibitor

Agree 23 (16 + 7; 96%); Disagree 1 (0 + 1; 4%); Neutral/abstain 0 (0%);When used bisphosphonates should not be continued indefinitely

Agree 20 (11 + 9; 83%); Disagree 0 (0%); Neutral/abstain 4 (17%);Areas of modest consensus (60%–80%)a

Treatment should be based on fracture risk algorithms ± BMD resultsAgree 17 (8 + 9; 71%); Disagree 3 (2 + 1; 12%); Neutral/abstain 4 (17%);Should be considered in pre-menopausal women on ovarian suppression and tamoxifen

Agree 17 (9 + 8; 71%); Disagree 4 (0 + 4; 17%); Neutral/abstain 3 (12%);Zoledronic acid is the preferred agent for women receiving ovarian suppression

Agree 17 (6 + 11; 71%); Disagree 5 (1 + 1; 21%); Neutral/abstain 2 (8%);When used, bisphosphonates should be continued until the adjuvant treatment programme is complete

Agree 17 (6 + 11; 71%); Disagree 4 (1 + 3; 17%); Neutral/abstain 3 (13%);Bisphosphonates can be given in my health care system for this indication

Agree 17 (6 + 11; 71%); Disagree 3 (0 + 3; 12%); Neutral/abstain 4 (17%);Duration should depend on BMD results

Agree 14 (4 + 10; 58%); Disagree 5 (1 + 4; 21%); Neutral/abstain 5 (21%);Is not required in pre-menopausal women on tamoxifen alone

Agree 15 (5 + 10; 62%); Disagree 4 (2 + 2; 17%); Neutral/abstain 5 (21%);Areas of uncertainty or lack of consensusTreatment decisions should not be based on BMD results alone

Agree 12 (3 + 9; 50%); Disagree 9 (1 + 8; 37%); Neutral/abstain 3 (12%);Does not need to be considered in post-menopausal women on tamoxifen alone

Agree 11 (1 + 10; 46%); Disagree 8 (3 + 5; 33%); Neutral/abstain 5 (21%);Should be restricted to post-menopausal women receiving an AI

Agree 12 (0 + 12; 50%); Disagree 9 (7 + 2; 37%); Neutral/abstain 3 (12%);Any bisphosphonate can be used for post-menopausal women

Agree 13 (3 + 10; 54%); Disagree 9 (3 + 6; 37%); Neutral/abstain 2 (8%);Any bisphosphonate can be used for pre-menopausal women

Agree 9 (0 + 9; 37%); Disagree 9 (4 + 5; 37%); Neutral/abstain 6 (24%);

aNumber agreeing (strongly + slightly; %); number disagreeing (strongly + slightly; %).




metastases are formed [56–59], if used on a repeated scheduleand especially in combination with chemotherapy [60].

These pre-clinical data showing an anti-tumour effect of bispho-sphonates provided scientific rational for the subsequent rando-mised, controlled clinical trials.

adjuvant clinical trials of bisphosphonatesto prevent metastasesThree randomised breast cancer trials initiated in the 1990sassessed the use of the oral bisphosphonate clodronate in add-ition to standard adjuvant therapy. The results were inconsistentwith two trials reporting a reduction in bone recurrence andimproved overall survival (OS) [61, 62], whereas the third sug-gested an adverse effect of clodronate with an increase in extra-osseous metastases [63] (Figure 1). Subsequent adjuvant trialswere performed that recruited larger numbers of patients toreceive oral bisphosphonates (NSABP-B34 with clodronate [64];German GAIN study with ibandronate [65] and the Danishcollaborative trial with pamidronate [66]) or the more potentintravenous bisphosphonate zoledronic acid (AZURE [67] andABCSG-12 [68]; Figure 2). It was the results of these subsequentclinical trials that first identified a probable link betweenimproved DFS outcomes with zoledronic acid in patients withlow levels of female hormones at initiation of adjuvant therapy(discussed below). In addition, pre-clinical data supported thehypothesis that adjuvant bisphosphonates can prevent metasta-ses and improve disease outcomes in the presence of low levelsof both female and male hormones. An in vivo study evaluatedthe effects of zoledronic acid on the growth of DTCs inbone comparing ovariectomised (OVX) mice (modelling post-menopausal disease) and sham-operated mice (modelling pre-menopausal disease). The number of detectable tumours inbone was only reduced by zoledronic acid treatment in OVX

animals, with no effect in sham-operated animals [55]. Thesedata have been further supported by the same group using aprostate cancer model, with the ability of DTCs in bone toform detectable tumours inhibited by zoledronic acid only incastrated mice, not sham-operated [56]. The molecular mechan-isms driving this differential effect of the drugs according to pre-vailing hormone levels remains an active area of research.

adjuvant clinical trials of bisphosphonatesdemonstrating the influence of menopausal statuson DFS outcomesThe ABCSG-12 trial results were thought provoking. Although pri-marily a trial to evaluate different endocrine strategies includingovarian suppression with goserelin plus either tamoxifen or letro-zole for good prognosis ER+ve pre-menopausal breast cancer, the2 × 2 randomisation including 6 monthly zoledronic acid orcontrol enabled evaluation of this bisphosphonate on disease out-comes. After 94.4 months median follow-up, relative risks ofdisease progression [hazard ratio (HR) = 0.77; 95% confidenceinterval (CI) 0.60–0.99; P = 0.042] and of death (HR = 0.66; 95%CI 0.43–1.02; P = 0.064) remain reduced by zoledronic acid [69].Shortly after publication of the initial findings from ABCSG-12

[68], the first results from the AZURE trial were announced. Inthis larger study, including both pre- and post-menopausalwomen with ER+ or ER− breast cancers, no improvements ineither DFS or OS were seen [70]. However, women with estab-lished menopause at study entry (>5 years since last menses) didappear to benefit, leading to the hypothesis that the benefits of ad-juvant bisphosphonates are (largely) restricted to women withlow levels of reproductive hormones, achieved either throughnatural menopause or ovarian suppression therapy. The NSABP-B34 [64] and GAIN trials [65] also failed to demonstrate a signifi-cant benefit with bisphosphonates in the overall population.However, both studies suggested benefits of bisphosphonates in

Figure 3. Potential effects of BPs in bone metastases.




older patients (NSABP-B-34 over the age of 50; GAIN over theage of 60) providing further support to the hypothesis.Several other trials evaluating zoledronic acid primarily as a

bone protector during AI treatment of post-menopausal breastcancer also investigated the effects of bisphosphonate use ondisease outcomes [40, 71, 72]. The largest of these (ZO-FAST)[71] reported fewer recurrences in women receiving immediatebone protection with zoledronic acid compared with the controlarm where the bisphosphonate was only introduced monthsor years later if there were changes in BMD or a fracture thatwarranted intervention.The improvement in disease outcomes in both the zoledro-

nic acid and oral clodronate trials were predominantly andmost consistently mediated by a reduction in bone metastasesas the first distant metastatic site. The AZURE trial alsoreported different effects of zoledronic acid on extra-skeletalrecurrence by menopausal status with benefit in post-meno-pausal women and an adverse impact on relapse outside bonein women who were pre-menopausal at study entry [67].However, this heterogeneity of response outside bone has notbeen observed in other trials.

meta-analysis of adjuvant bisphosphonate trial data. Severalselective, study level meta-analyses have been published suggestinga benefit in disease outcomes across adjuvant bisphosphonatetrials with a variety of agents [41]. One of these specificallyestimated the benefit in post-menopausal women and reported asignificant improvement in DFS (HR = 0.82; 95% CI 0.74–0.92,P≤ 0.001) [73]. These data supported the notion that adjuvant

bisphosphonates are likely to be most effective when there are lowlevels of female reproductive hormones due to natural/chemicalmenopause and helped trigger a more detailed meta-analysis.To investigate the available evidence in a more robust and

precise fashion, the Early Breast Cancer Trials CollaborativeGroup (EBCTCG) has conducted a formal individual patient datameta-analysis of data from 18 766 women involved in 26 rando-mised trials of adjuvant bisphosphonates for early breast cancer[74]. The majority of these patients received either oral clodronate1600 mg daily or i.v. zoledronic acid 4 mg every 6 months ormore frequent dosing as per the AZURE schedule [67]. 3453 and2106 breast cancer recurrences and deaths were reported, respect-ively. For the entire population, bisphosphonates did reduce thenumber of patients with first distant recurrence in bone(RR = 0.83; 95% CI 0.73–0.94, 2P = 0.004), but had less cleareffects on time to any breast cancer recurrence (RR = 0.94; 95%CI 0.87–1.01, 2P = 0.08), distant recurrence (RR = 0.92; 95% CI0.85–0.99, 2P = 0.03) or breast cancer mortality (RR = 0.91; 95%CI 0.83–0.99, 2P = 0.04). However, in post-menopausal women(n = 11 767), bisphosphonates not only improved recurrence inbone (RR = 0.72; 95% CI 0.60–0.86, 2P = 0.002) but also overallbreast cancer recurrence (RR = 0.86; 95% CI 0.78–0.94,2P = 0.002), distant recurrence at any site (RR = 0.82; 95% CI0.73–0.92, 2P = 0.003) and breast cancer mortality (RR = 0.82;95% CI 0.73–0.93, 2P = 0.002). Bisphosphonates did not appearto modify any disease outcomes in pre-menopausal women witha borderline significance test for heterogeneity by menopausalstatus (2P = 0.06). These results were maintained in a sensitivityanalysis where the hypothesis generating trials (ABCSG-12 and

*If not clinicallyassessable i.e.hysterectomy/IUD then ensureserum FSH is inpostmenopausalrange. Ensurepatient is notreceivingconcurrenttherapies thatcan affect theHPG axis.

6Include vitaminD 1000-2000 IUand calcium1000 mg daily.

Age ≥55

Yes

Yes

No

No

Natural amennorhoea for ≥ 12months*

Menstrual period within past 12 months

Adjuvant treatment plan includes GnRH analogue

Prescribe a BP6

Prescribe a BP6

Prescribe a BP6 for the durationof GnRH analogue.

Assess fracture risk and use BPs accordingto CTIBL guidelines. Council patient that BPsdo not affect survival outcomes when used inthis context.

Figure 4. Selection of patients suitable for adjuvant bisphosphonates to prevent metastases.




AZURE) were omitted; without these trials post-menopausalwomen continuing to show benefit across key recurrence andsurvival end points.The risk reductions for relapse and mortality in post-meno-

pausal women treated with bisphosphonates were similar irre-spective of ER status or grade of the primary tumour, axillarylymph node involvement and use/non-use of chemotherapy,suggesting that menopausal status should be the main criterionfor selection of patients for adjuvant bisphosphonates to preventmetastases.The data also suggest that menopausal status at the initiation of

adjuvant bisphosphonates is important. If this were not so, benefitwould also be expected in women rendered post-menopausal byadjuvant chemotherapy. However, with the exception of womenreceiving ovarian suppression therapy at the start of adjuvantbisphosphonates, neither the AZURE data nor the meta-analysiscould identify a subset of pre-menopausal women, for examplethose aged >45 years who have a very high likelihood of developinga chemotherapy induced menopause, who derived benefit fromadjuvant bisphosphonates. This indicates the initial interaction

between bisphosphonates and endocrine/paracrine factors in thebone microenvironment differentially influences the survival oftumour cells already disseminated into the bone/ bone marrowmicroenvironment at diagnosis (reviewed in Wilson et al. [75]).

patient selection, choice of agent, dose and duration of therapy.A clinical definition of ‘post-menopausal’ status, based on thewidely accepted WHO definition (the permanent cessation ofmenstruation determined retrospectively after 12 months ofamenorrhoea without any other pathological or physiologicalcause) [76], could be utilised in selecting patients for adjuvantbisphosphonates (see Figure 4). Biochemical classification ofmenopausal status based on serum FSH levels in the post-menopausal range before initiation of treatment may be of usein patients whose clinical status is unknown, e.g. due tohysterectomy or intrauterine devices. For those women who arenot post-menopausal, bisphosphonates could be considered iftreatment with GnRH/LHRH analogues is planned as part ofadjuvant therapy, and continued for the duration of the ovariansuppression.

Table 2. Adjuvant bisphosphonates to prevent metastases in early breast cancer

Areas of strong consensus (>80%)Should be considered because the data are conclusive

Agree 20 (17 + 3; 83%); Disagree 2 (1 + 1; 8%); Neutral/abstain 2 (8%);Should be considered in post-menopausal women

Agree 22 (14 + 8; 92%); Disagree 1 (0 + 1; 4%); Neutral/abstain 1 (4%);Should not be considered in pre-menopausal women

Agree 21 (17 + 4; 87%); Disagree 1 (0 + 1; 4%); Neutral/abstain 2 (8%);Should be considered in pre-menopausal women receiving ovarian suppression therapy

Agree 22 (11 + 11; 92%); Disagree 1 (0 + 1; 4%); Neutral/abstain 1 (4%);Zoledronic acid or oral clodronate are the agents of choice

Agree 21 (16 + 5; 87%); Disagree 0 (0 + 0; 0%); Neutral/abstain 3 (12%);Areas of modest consensus (60–80%)a

Should not be considered for all women with early breast cancerAgree 19 (14 + 5; 79%); Disagree 3 (1 + 2; 12%); Neutral/abstain 2 (8%);Should be considered even though there is no regulatory approval for their use in this setting

Agree 18 (15 + 3; 75%); Disagree 3 (1 + 2; 12%); Neutral/abstain 3 (12%);When used, 6 monthly zoledronic acid is preferred to more intensive regimens

Agree 17 (12 + 6; 75%); Disagree 2 (1 + 1; 8%); Neutral/abstain 4 (17%);Can be given in my health care system as an off-label treatment based on a locally or nationally defined protocol or treatment guidance

Agree 15 (8 + 7; 62%); Disagree 6 (3 + 3; 25%); Neutral/abstain 3 (12%);Any bisphosphonate can be used

Agree 3 (1 + 2; 12%); Disagree 15 (5 + 10; 62%); Neutral/abstain 6 (25%);Should be considered in women with ER−ve early breast cancer

Agree 15 (8 + 7; 62%); Disagree 5 (2 + 3; 21%); Neutral/abstain 4 (17%);When used, bisphosphonate should be administered for 3–5 years

Agree 15 (8 + 7; 62%); Disagree 4 (1 + 3; 17%); Neutral/abstain 5 (21%);Areas of uncertainty of lack of consensus

Should only be considered in post-menopausal women considered at intermediate or high risk of recurrenceAgree 14 (7 + 7; 58%); Disagree 7 (2 + 5; 29%); Neutral/abstain 3 (12%);Should only be considered in post-menopausal women with node-positive breast cancer

Agree 7 (5 + 2; 29%); Disagree 12 (5 + 5; 50%); Neutral/abstain 5 (21%);Weekly oral alendronate or risedronate should not be used

Agree 12 (7 + 5; 50%); Disagree 4 (0 + 4; 17%); Neutral/abstain 8 (33%);A patient on weekly oral alendronate or risedronate should be changed to zoledronic acid or clodronate

Agree 13 (8 + 5; 54%); Disagree 5 (0 + 5; 21%); Neutral/abstain 6 (25%);

aNumber agreeing (strongly + slightly; %); number disagreeing (strongly + slightly; %).




The meta-analysis was unable to demonstrate any importantdifference in disease outcome by type of bisphosphonate (aminoversus non-amino), with the outcomes in the clodronate trials atleast as good as those achieved with the more potent aminobi-sphosphonates. Additional data in support of this comes from therecently reported SWOG trial that showed no difference in DFSoutcomes following 3 years of adjuvant clodronate, ibandronateand zoledronic acid [77]. The meta-analysis also found the intensetreatment schedules of zoledronic acid, as used in AZURE, were ofsimilar efficacy to the less intensive schedules of zoledronic acid6 monthly or daily oral clodronate or ibandronate. There are nodirect comparisons of duration of bisphosphonate treatmentalthough the SUCCESS trial (NCT02181101) comparing 3 or5 years of zoledronic acid treatment will help address this. In themeta-analysis, treatment benefits appeared early but there wereinsufficient data from trials of short-term (<2 years) adjuvantbisphosphonate use to recommend short durations of therapywith most of the data supporting treatment for 3–5 years.Neither alendronate nor risedronate have been adequately

evaluated in randomised adjuvant clinical trials. A retrospectivereview of over 20 000 women treated with osteoporosis doses oforal alendronate, risedronate or etidronate, either following abreast cancer diagnosis or started before and continued after diag-nosis suggested that exposure to these agents reduced the risk ofrelapse and improved survival [78]. However, despite their estab-lished role in the prevention of osteoporosis, there are insufficientdata to recommend their use for metastasis prevention.

panel recommendations. There was strong consensus that thedata supported the use of adjuvant bisphosphonates in post-

menopausal (whether natural or induced) women, with someexperts (58%) suggesting further restriction to those considered atintermediate or high risk of recurrence rather than unselected useacross all risk groups. There was consensus that a lack of regulatoryapproval for bisphosphonates in this setting should not precludetheir use, with the majority indicating they could administeradjuvant bisphosphonates in their health care system as an off-label treatment based on a locally or nationally defined protocol ortreatment guideline. The Panel was in agreement that either dailyoral clodronate or i.v. zoledronic acid (Q6 monthly) are thepreferred agents for metastasis prevention and recommended thatthe potential risks and benefits of adjuvant bone targetedtreatment for 3–5 years alongside vitamin D supplementation andadequate calcium intake should be discussed with relevant patients(Table 2). With these regimens, the risk of ONJ is <1%.

summary of treatment recommendationsThe overall consensus was that bisphosphonates should be usedas part of routine clinical practice in the adjuvant managementof CTIBL in ‘at risk’ patients and in the prevention of metastasesin patients with low levels of female sex hormones (seeFigure 5). Ongoing adjuvant trials of the osteoclast inhibitordenosumab (ABCSG 18 and D-CARE) will provide further in-formation on the clinical role of mechanistically different adju-vant bone targeted treatments.

acknowledgementsWe thank Janet Horseman at the Cancer Clinical Trials Unit,Weston Park Hospital, Sheffield, UK, for her assistance withdata management.

Prevention of CTIBL

Prevention of metastases and improving disease outcomes

Premenopausal women not receiving adjuvant ovarian suppression

Premenopausal women on adjuvant ovarian suppression

Postmenopausal women at low risk of recurrence

Postmenopausal women at intermediate or high risk of recurrence

– Chemotherapy unlikely to have a direct affect on bone– Tamoxifen induces bone loss – long term effects need to be established– Assessment of fracture risk should include BMD assessment– Consider BPs if T score £2.0

– Chemotherapy unlikely to have a direct affect on bone– Tamoxifen reduces fracture risk– Als induce bone loss– Assessment of fracture risk should include FRAX assessment and BMD assessment– Ensure adequate calcium and vitamin D intake– Consider BPs if T score £2.0 or ≥2 clinic risk factors for fracture– BPs can include alendronate (70 mg PO weekly), risedronate (35 mg PO weekly), ibandronate (150 mg PO monthly), zoledronic acid (4 mg IV Q6 months), clodronate (1600 mg PO daily) (I,A)

– BPs should be considered to prevent CTIBL and metastases (I,A)– Recommended BP is zoledronic acid (4 mg IV Q6 months) or clodronate (1600 mg PO daily) (I,A)– BPs should be initiated at the start of adjuvant therapy (II,A)– Duration of BP treatment should not exceed duration of ovarian suppression unless indicated for low T score (3–5 years) (II,A)

– BPs should be considered to prevent metastases irrespective of fracture risk (I,A)– Recommended BPs are zoledronic acid (4 mg IV Q6 months) or clodronate (1600 mg PO daily) (I,A) alongside vitamin D supplementation and adequate calcium intake– BPs should be initiated at the start of adjuvant therapy (II,A)– Duration of BP treatment should be 3–5 years and only continued after 5 years if indicated by fracture risk (II,A)

Figure 5. Summary of key clinical points and levels of evidence for adjuvant BP treatment recommendations.




fundingThe consensus meeting received financial support from theBANSS Foundation, a non-profit body based in Biedenkopf ander Lahn, Germany. No pharmaceutical support was receivedfor this work.

disclosureREC has provided expert testimony on behalf of Novartis concern-ing litigation in cases of osteonecrosis of the jaw and receivedresearch grants from Amgen, Bayer and Celgene. MA has been aconsultant for and received honoraria for lectures at symposia forAbraxis, Amgen, Astellas, Bayer Schering, BMS, CAris LifeScience,Celgene, Cephalon, Eisai, Ferring, GEnomicHealth, GSK, Helsinn,Hospira, Ipsen, Orthobiotech, Novartis, Merck, Merck Serono,Pfizer, Piere Fabre, Roche, Sandoz, Teva, Vifor. PH has given lec-tures for Novartis and Amgen. LC has received speaker fees and re-search grants from Amgen and Novartis. CW has received speakerfees from Amgen. BT owns stock in Novartis and Amgen andhas received honoraria from Roche. JC has received consultancyfees from Roche, Celgene and speaker fees from Roche, Celgene,Novartis and Eisai. CM has received research grants fromAstraZeneka (AZ). ADL has received consultant fees from Roche,AZ, Pfizer and Novartis and conducted research funded by AZ andPfizer. MG has received research grants from Sanofi-Aventis,Novartis, Roche, GlaxoSmithKline, Pfeizer, Smith Medical andconsultancy from AZ, Novartis and Acceisiors and speaker fees fromAmgen, Novartis, GlaxoSmithKline, AZ, Roche. DC has received re-search grants from Amgen, Novartis and Roche. MM has receivedspeaker fees and research funding from Novartis. BE has receivedresearch funding from Novartis, Amgen, Roche and Nanostring.All remaining authors have declared no conflicts of interest.

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Annals of Oncology 27: 390–397, 2016doi:10.1093/annonc/mdv616

Published online 17 December 2015

Rituximab and risk of second primary malignancies inpatients with non-Hodgkin lymphoma: a systematicreview andmeta-analysisI. Fleury1, S. Chevret2,3, M. Pfreundschuh4, G. Salles5, B. Coiffier5, M. H. J. van Oers6,C. Gisselbrecht1, E. Zucca7,8, M. Herold9, M. Ghielmini7,8 & C. Thieblemont1,10*Departments of 1Hemato-oncology, 2Biostatistics, APHP, Saint-Louis hospital, Paris; 3ECSTRA Team, UMR 1153, Inserm Paris Diderot University Paris, Paris, France;4Internal Medicine, Universitätsklinikum des Saarlandes, Homburg, Germany; 5Hospices civils de Lyon, Pierre-Bénite, France; 6Department of Hematology, AcademischMedisch Centrum, Amsterdam, The Netherlands; 7Oncology Institute of Southern Switzerland, IOSI, Ospedale San Giovanni, Bellinzona; 8Swiss Group for Clinical CancerResearch-SAKK, Berne, Switzerland; 9Onkologisches Zentrum, HELIOS Klinikum, Erfurt, Germany; 10Paris Diderot University, Sorbonne Paris Cité, Paris, France

Received 29 September 2015; revised 21 November 2015; accepted 30 November 2015

Background: Addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy improves response rates andsurvival in patients with B-cell non-Hodgkin lymphoma (NHL). However, rituximab induces a transient B-cell depletionand a dose-dependent T-cell inactivation that could impair T-cell immunosurveillance. The impact of rituximab on secondprimary malignancy (SPM) risk remains unclear so far. We thus carried out a systematic review to compare SPM riskamong patients treated or not with rituximab.Patients and methods: We retrieved trials from MEDLINE and EMBASE and updated data presented at AmericanSociety of Hematology and American Society of Clinical Oncology meetings from 1998 to 2013. We selected randomized,controlled trials addressing newly or relapsed/progressive B-cell NHL in which randomization arms differed only fromrituximab administration. Two authors extracted data and assessed the study quality.Results: We analyzed nine trials involving 4621 patients. At a median follow-up of 73 months, a total of 169 SPMs wereobserved in patients randomized to rituximab compared with 165 SPMs in patients not randomized to rituximab(OR = 0.88; 95% CI 0.66–1.19). The proportion of females, histology subtypes, use of rituximab in first line or in mainten-ance did not influence SPM risk (P = 0.94, P = 0.80, P = 0.87, P = 0.87, respectively). Cumulative exposure through pro-longed administration in trials with rituximab maintenance did not contribute to an increased risk of SPM (P = 0.86).Conclusion: Our meta-analysis suggests no SPM predisposition among NHL survivors exposed to rituximab at amedian follow-up of 6 years.Key words: meta-analysis, non-Hodgkin lymphoma, rituximab, second primary malignancies, secondary cancers,randomized controlled trials

*Correspondence to: Dr Catherine Thieblemont, Service d’hémato-oncologie, HôpitalSaint-Louis, 1, avenue Claude Vellefaux, Paris 75010, France. Tel: +33-1-42-49-92-36;Fax: +33-1-42-49-99-41; E-mail: [email protected]


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Implementation of Adjuvant Bisphosphonates for Early