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 cancer 1 , the National Institute of Clinical Excellence (NICE) issued an Evidence Summary in 2017 2 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)
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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)
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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%)
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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.
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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.
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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
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
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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:
Provider Trust Approx.
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.
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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.
Provider Trust Approx.
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
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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
2 Early breast cancer (preventing recurrence and improving survival): adjuvant bisphosphonates Evidence summary Published: 25 July 2017 nice.org.uk/guidance/es15 ENC 03
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
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
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.
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]
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.
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.
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)
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%
Bisphosphonate 16·6%
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.
(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)
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
AllocationBisphosphonateControlRate ratio (95% CI) from (O–E)/V
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%
Bisphosphonate 20·6%
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
AllocationBisphosphonateControlRate ratio (95% CI) from (O–E)/V
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%
Bisphosphonate 14·7%
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.
Articles
www.thelancet.com Vol 386 October 3, 2015 1361
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
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.
Early breast cancer (preventing recurrence and improving survival): adjuvant bisphosphonates (ES15)
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
Early breast cancer (preventing recurrence and improving survival): adjuvant bisphosphonates (ES15)
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,
eexxcluding Vcluding VAATT
Annual cost,Annual cost,
eexxcluding Vcluding VAATT
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
Early breast cancer (preventing recurrence and improving survival): adjuvant bisphosphonates (ES15)
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
Early breast cancer (preventing recurrence and improving survival): adjuvant bisphosphonates (ES15)
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
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
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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
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 clodronate1600 mg daily vsplacebo for 3 years
Oral clodronate1600 mg daily vsplacebo for 3 years
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.
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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)
Figure 2. Summary of major adjuvant trials evaluating intravenous zoledronic acid in early breast cancer.
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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
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
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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.
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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.
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.
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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
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
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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.
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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]