The ATLAS Study: Adjuvant Tamoxifen - Longer Against Shorter
ATLAS is an international, multi-centred study which was designed to evaluate the effects of greater than 5 years of tamoxifen versus cessation of therapy after about 5 years on total mortality in women with breast cancer.
ATLAS is coordinated in Australia & New Zealand by the ANZ Breast Cancer Trials Group (ANZBCTG)
Recruitment to ATLAS commenced in 1996 and closed in March 2005 and it is now in the follow-up phase, which will conclude in early 2010.
The conception of ATLAS
Approximately 1 million women worldwide are being treated with tamoxifen following breast cancer (35,000 women in Australia).
We know that with 5 years of tamoxifen the benefits are 30 times greater than the risks. So the current tendency is for adjuvant tamoxifen to be used for about 5 years in women following initial treatment for breast cancer. But there is uncertainty as to whether longer use would be more beneficial.
There are potential, serious adverse side effects of tamoxifen, which are:
There is insufficient, reliable data on the balance of the risk of these side effects and the net survival benefit with the longer treatment with tamoxifen. ATLAS will provide this data.
The establishing of ATLAS
ATLAS was set up as a ‘mega trial’ based on ISIS (International Studies of Infarct Survival).
The ISIS Collaborative Group of over 1000 hospitals worldwide randomised more than 100,000 myocardial infarction patients into their studies within just a few years. This was achieved by:
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addressing important therapeutic questions,
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basing eligibility on uncertainty of both the physician and the patient,
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streamlining the trial design,
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adopting very simple protocols.
As a result, tens of thousands unnecessary cardiac deaths are being avoided each year.
ATLAS is the world’s largest ever trial of cancer treatment.
There are 35 countries participating in ATLAS with approximately 450 centres (33 in Australia & New Zealand).
Aim of ATLAS (therapeutic question):
To establish whether the more prolonged treatment with tamoxifen carries a net therapeutic advantage in terms of recurrence free survival and/or overall survival compared with treatment for 5 years in women with breast cancer.
Patient Cohort (eligibility):
Is totally comprised of women who, with their doctors, were uncertain as to whether to prolong their tamoxifen treatment beyond 5 years.
ATLAS trial design
The ATLAS Study was designed to establish whether there is an improvement in recurrence free survival and/or survival with tamoxifen beyond the current treatment time of 5 years.
A reliable demonstration of just a small benefit with the prolonged use of tamoxifen could save the lives of thousands of women worldwide.
ATLAS will detect a difference of 2-3% in survival between the treatment group (those women who were randomly allocated to stay on tamoxifen following about 5 years of treatment) and the control group (those who were randomly allocated to stop tamoxifen).
The principal analysis will be of all cause mortality, which will be complemented by subsidiary analyses of death from specific causes, eg breast cancer, myocardial infarction. The analysis will be stratified by age, oestrogen receptor status and other prognostic factors recorded at the enrolment of the women. It will be an ‘intention to treat’ analysis, which means that it will detect any real difference between the trial arms in their effects on long term outcome.
ATLAS will determine the balance of risks versus benefits of greater than 5 years of tamoxifen through direct randomised comparison. Data will be collected on serious, unexpected side effects, which are considered attributable to tamoxifen, including vascular events and secondary primary cancers thereby contributing to the growing body of evidence on the longer-term side effects, both negative and positive, of tamoxifen.
ATLAS Protocol
There are no tests or extra visits required of the women who agreed to participate in ATLAS and every woman stays in the care of her treating physician.
Eligibility criteria for a woman to participate in ATLAS.
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History of early breast cancer.
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Clinically free of cancer at time of enrolment.
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Oestrogen Receptor (ER) status positive (must be ‘known’)*
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Had been taking tamoxifen for about 5 years.
For whom there was substantial uncertainty as whether or not to continue tamoxifen beyond that treatment time (ie. at this time the woman’s treating physician does not consider it in her medical interest that she should absolutely continue tamoxifen or absolutely cease it).
* emphasis was on randomising ER positive women to the study as tamoxifen treatment for women who have ER negative tumours is still a matter of research.
(87% of women diagnosed with early breast cancer are ER positive).
Ineligibility criteria.
A woman:
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who definitely wanted to either continue or stop her tamoxifen after taking it for about 5 years.
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whose primary treating physician considered her participation inappropriate or not in her best medical interest.
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who was being treated with tamoxifen for DCIS
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who was being followed on an IBSCG breast cancer research trial.
An eligible woman who agreed to participate in ATLAS had the approval of her physician, who documented her consent for her enrolment in the study. The woman’s physician provided the details of her breast cancer for her enrolment in ATLAS.
She was then randomly allocated to her further treatment for the study, to either stop tamoxifen after 5 years of treatment or continue it for a further 5 years.
Follow-up information is provided annually by her physician as to her current status for the duration of her participation in the study.
Any woman enrolled in ATLAS is free to discontinue her participation at any time.
ATLAS FOLLOW-UP PHASE:
ATLAS has randomised some 15,000 women and, in combination with aTTom (adjuvant Tamoxifen Treatment), the UK counterpart to ATLAS, and 3 other smaller trials that have already published their data, there are about 20,000 women with ER+/? disease so the ATLAS Trial Steering Committee endorsed closure to further recruitment to the study.
Long-term follow up in research studies such as ATLAS, is imperative.
The compliance of participants with the original, randomly-assigned treatment allocation is to be encouraged for the full duration of follow-up to protect the scientific integrity of ATLAS and the data collected on each woman.
A woman randomised to stop tamoxifen should stay stopped unless some particular reason to resume treatment is thought to have arisen. Likewise, a woman randomised to continue tamoxifen should keep taking it for the 5 additional years unless some particular reason to stop treatment is thought to have arisen. These women would be asked to continue to be followed-up in the study.
But, if a woman, with her physician, decides to change her randomly allocated treatment or switch to some other hormonal therapy she is free to do so, this is fully consistent with the ATLAS protocol, but she will also be asked to continue to be followed-up in the study.
Follow-up will be to 2010 and, even then, mortality follow-up to 2015 will be of further interest.
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