Condition category
Cancer
Date applied
12/10/2012
Date assigned
18/10/2012
Last edited
29/06/2015
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
We know from previous studies of many thousands of women with breast cancer that taking tamoxifen each day, for at least the first few years after surgery, reduces the risk of the breast cancer returning. Tamoxifen does this by interfering with the effect of the natural female hormones on the growth of any traces of breast cancer that may have remained. What is not known, though, is exactly how long women should carry on taking tamoxifen. Most women nowadays receive treatment for about five years, but it might be that 10 years of tamoxifen could be even better. This is why we are doing this study, called ATLAS, to help find out reliably which treatment duration is best in terms of reducing the risk of the breast cancer coming back, and improving long-term survival.

Who can participate?
Any woman with breast cancer (where the cancer has been removed by surgery) and who has been taking tamoxifen for some time, and where the woman and her doctor are uncertain whether she should keep on taking it for a few more years, or whether she should now stop.

What does the study involve?
The ATLAS collaboration aims to randomly allocate many thousands of women to one of two groups: one group stopping tamoxifen after some years of treatment and one group continuing for at least 5 extra years. Several hundred hospitals in many countries world-wide were invited to participate in ATLAS. After discussing the study with her doctor (and family/friends) a woman must sign an information and consent leaflet. Half of the women will be asked to continue taking tamoxifen for at least another five years (unless, later on, new evidence or some reason emerges why they should stop), and the other half will be asked to stop tamoxifen now and to stay off it (unless, later on, new evidence or some reason emerges why they should restart). No special tests or investigations are required to join the study and the woman's own doctor always remains responsible for her wellbeing. There is just a short annual follow-up form which asks for one line of information on the current status of each woman in the study. All information is treated in strict confidence and stored securely at the central study office in Oxford. No individual woman is identified in the study results.

What are the possible benefits and risks of participating?
We very much hope that taking tamoxifen for longer than a few years will provide extra protection against the breast cancer returning and as a result will save many extra lives, and that there will be enough extra benefit to outweigh any side-effects. We know that there is a small risk that tamoxifen will cause cancer of the lining of the womb (endometrium) - which, if caught early, can be successfully treated by hysterectomy. We also know, though, that a few years of tamoxifen has, so far, prevented many more breast cancers coming back than the few womb cancers it has caused. Tamoxifen might also increase the risk of an internal blood clot (thromboembolism), but this may well be counterbalanced by a reduction in the risk of having a heart attack because of the cholesterol-lowering effect of tamoxifen. It is only through studies like ATLAS that we will be able to estimate reliably the balance of benefits and risks of 10 years of tamoxifen compared with just 5 years, so that doctors can then ensure that they give their patients the optimal treatment as well as knowledgeably explaining how the benefits and risks balance out.

Where is the study run from?
ATLAS is coordinated by the University of Oxford's Clinical Trial Service Unit & Epidemiological Studies Unit, which has a very long history in conducting large international trials like this.

When is the study starting and how long is it expected to run for?
ATLAS started in 1995, completed recruitment of 15 262 women in March 2005, and all women had completed their 5 year trial treatment period by March 2010. Follow-up in ATLAS will continue until 2015 by which time, there should be clear answers on the main question being addressed.

Who is funding the study?
The study has received funding from Cancer Research UK, the UK Medical Research Council, the US Army Breast Cancer Research Program and the EU (Biomed Programme).

Who is the main contact?
Dr Christina Davies
christina.davies@ctsu.ox.ac.uk

Trial website

http://www.ctsu.ox.ac.uk/research/mega-trials/atlas/atlas-website

Contact information

Type

Scientific

Primary contact

Dr Christina Davies

ORCID ID

Contact details

Clinical Trial Service Unit and Epidemiological Studies Unit
Richard Doll Building
Old Road Campus
Roosevelt Drive
Oxford
OX3 7LF
United Kingdom
-
christina.davies@ctsu.ox.ac.uk

Additional identifiers

EudraCT number

2004-000735-29

ClinicalTrials.gov number

NCT00003016

Protocol/serial number

MHRA CTA: 21584/0002/001; EudraCT number: 2004-000735-29

Study information

Scientific title

An international randomised trial, involving tens of thousands of women, of 10 versus 5 years of adjuvant tamoxifen in the treatment of oestrogen receptor positive breast cancer, to assess the effects on relapse free and overall survival

Acronym

ATLAS

Study hypothesis

The worldwide randomised evidence now shows that 5 years of adjuvant tamoxifen, following the initial management of early breast cancer, greatly reduces the risk of relapse and improves long-term survival. Tamoxifen is now used by about 1 million women worldwide, avoiding about 20,000 deaths from breast cancer annually. However, there is substantial uncertainty as to whether more than 5 years of hormonal treatment produces even greater benefit. The fundamental aim of ATLAS is to assess reliably the benefits and risks (in terms of recurrence of the disease and long-term survival) of prolonging adjuvant tamoxifen by an extra 5 years in breast cancer patients who have already had about 5 years of treatment.

Ethics approval

Oxford Tropical Research Ethics Committee, 06/01/2003, ref: 035-02

Study design

International multicentre randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Screening

Patient information sheet

Patient information sheet can be found at http://www.ctsu.ox.ac.uk/research/mega-trials/atlas/atlas-protocol (see pages 11-14)

Condition

Operable, oestrogen receptor positive breast cancer already trated with ~5 years of adjuvant tamoxifen

Intervention

Random allocation was either to stop tamoxifen immediately, using no placebo tablets and restarting endocrine therapy only if a definite indication was thought to have emerged, or to continue tamoxifen for another 5 years (total 10 years), stopping before then, or changing to another endocrine therapy, only if a definite contra-indication was thought to have emerged. The tamoxifen regimen used both before and during the trial treatment period was almost always 20 mg/day oral Nolvadex. (In countries where continuing up to or beyond 5 years was not affordable for many patients, ATLAS supplied free Nolvadex to enable a woman to receive 5 years of tamoxifen prior to enrolment in ATLAS and for the full 5-year post-randomisation period.) All other aspects of patient management were at the doctor's discretion.

Intervention type

Drug

Phase

Not Applicable

Drug names

Tamoxifen

Primary outcome measures

1. Recurrence (loco-regional, contralateral or distant)
2. Breast cancer mortality

Secondary outcome measures

1. Overall mortality
2. Various first events before recurrence:
2.1. Cancer incidence (particularly uterine, including endometrial)
2.2. Hospital admissions for particular reasons (particularly uterine or vascular)
2.3. Cause-specific mortality

Overall trial start date

01/03/1995

Overall trial end date

01/12/2015

Reason abandoned

Eligibility

Participant inclusion criteria

Women were eligible for randomisation if:
1. They had had early breast cancer (in which, by definition, all detected disease could be removed surgically)
2. They had subsequently been on adjuvant tamoxifen for several years and were still on it (or had stopped only recently, and could therefore resume treatment without much interruption)
3. They still appeared clinically free of disease (with any local recurrence removed and no distant recurrence ever detected)
4. Long-term follow-up appeared practicable; and, fundamentally,
5. Substantial uncertainty was shared by the woman and her doctor about whether to stop tamoxifen or to continue for several more years, so compliance with random allocation to stop or to continue both seemed likely. There were no restrictions on age, type of initial surgery or histology, hormone receptor status, nodal status or what other treatments had also been given.

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

10,000-20,000: 15, 262 women were randomised in ATLAS in total

Participant exclusion criteria

Any perceived contraindications to continuing tamoxifen precluded entry. These were specified not by the ATLAS protocol but by the judgment of the responsible clinician. However, the protocol suggested as possible contraindications to tamoxifen continuation (and hence to trial entry):
1. Intended or actual pregnancy or breast feeding
2. Retinopathy
3. Need for coagulation therapy
4. Significant endometrial hyperplasia
5. Any other serious toxicity thought to be due to tamoxifen
6. Negligibly low risk of breast cancer death
7. Presence of another major life-threatening disease

Recruitment start date

01/03/1995

Recruitment end date

01/03/2005

Locations

Countries of recruitment

Argentina, Australia, Belarus, Belgium, Brazil, Chile, China, Colombia, Croatia, Cuba, Czech Republic, Egypt, Estonia, France, Greece, Hong Kong, India, Iran, Ireland, Israel, Italy, Japan, Latvia, Lithuania, Mexico, Netherlands, New Zealand, Oman, Paraguay, Poland, Portugal, Russian Federation, South Africa, Spain, Taiwan, Tunisia, Turkey, United Kingdom, United States of America

Trial participating centre

Clinical Trial Service Unit and Epidemiological Studies Unit
Oxford
OX3 7LF
United Kingdom

Sponsor information

Organisation

University of Oxford (UK)

Sponsor details

University Offices
Wellington Square
Oxford
OX1 2JD
United Kingdom
-
richard.liwicki@admin.ox.ac.uk

Sponsor type

University/education

Website

http://www.ox.ac.uk/

Funders

Funder type

Charity

Funder name

Cancer Research UK

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Funder name

Medical Research Council (UK)

Alternative name(s)

MRC

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Funder name

AstraZeneca* (UK)

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

United Kingdom

Funder name

US Army Breast Cancer Research Program (USA)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

EU-Biomed (EU)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

*AstraZeneca had no involvement in the scientific design or management of ATLAS, which is sponsored by the University of Oxford, the host organisation of the Clinical Trial Service Unit and Epidemiological Studies Unit (the international coordinating centre of ATLAS).

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2013 results in http://www.ncbi.nlm.nih.gov/pubmed/23219286

Publication citations

  1. Results

    Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Medeiros Alencar VH, Badran A, Bonfill X, Bradbury J, Clarke M, Collins R, Davis SR, Delmestri A, Forbes JF, Haddad P, Hou MF, Inbar M, Khaled H, Kielanowska J, Kwan WH, Mathew BS, Mittra I, Müller B, Nicolucci A, Peralta O, Pernas F, Petruzelka L, Pienkowski T, Radhika R, Rajan B, Rubach MT, Tort S, Urrútia G, Valentini M, Wang Y, Peto R, , Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial., Lancet, 2013, 381, 9869, 805-816, doi: 10.1016/S0140-6736(12)61963-1.

Additional files

Editorial Notes