What is the purpose of the IBIS-II DCIS part of the study?

This study has been set up to investigate which of the two drugs, tamoxifen or anastrozole, is most effective at preventing local recurrence or a second breast cancer after completion of your surgery for ductal carcinoma in-situ. We will be investigating how well these drugs are tolerated. This is a randomised, double blind, double dummy study, which means that you will have an equal chance of receiving either drug. The reason for this is because we do not know whether anastrozole is more or less effective than tamoxifen. The study is double blind in order to reduce any bias when it comes to reporting or recording side effects. Neither you nor your local co-ordinator will know which treatment group you are randomised to.

Currently we do not know exactly how successful tamoxifen is in preventing local recurrence or a second breast cancer. The American DCIS study claims a significant reduction in breast cancer incidence but the UK DCIS (study) shows only a moderate benefit and it is too early to establish whether there will also be an effect on deaths. We need to look closely at the type of woman who may benefit most from taking tamoxifen. We do know, however, that tamoxifen is not the sole candidate for use in preventing local recurrence or a second breast cancer. A new group of drugs, known as aromatase inhibitors, have recently been shown to be effective in treating breast cancer and have few side effects. They are promising candidates for use in DCIS and we hope to provide important information about their value in this study as anastrozole is one of the drugs in this group.

Who can take part in the DCIS trial?

You can take part in the DCIS trial if you have been through the menopause and aged between 40-70 years with locally excised DCIS diagnosed in the last six months, in which there are tumour free margins of at least 1mm.

You will not be able to join if:

• Your DCIS is not oestrogen responsive (check with your doctor for further details)
• You have a history of blood clots
• You have had a previous stroke or transient ischaemic attack

You may not be able to join if:

• You have osteoporosis. An x-ray of your spine and a bone scan will be required to check that you do not have any early signs of osteoporosis. However, you may still be able to join the study if you are willing to take bisphosphonates (bone medication).
• You are using oestrogen-based hormone replacement therapy (HRT). You would have to change to an alternative non-hormonal treatment.

You should discuss these with your doctor before making your decision.

What will I have to do if I decide to join the DCIS trial?

If you decide to join the study, you will be randomly assigned to one of two groups (i.e. you have a 50/50 chance of being assigned to either group):

1. tamoxifen 20mg and anastrozole placebo
2. tamoxifen placebo and anastrozole 1mg

You will be asked to take two tablets every day for five years. The placebo tablets contain inactive substances. No one (apart from the sponsor) will know who is taking the tablets with the active ingredients. Tamoxifen and anastrozole look quite different from each other, which is why we need to have a placebo tablet for each of the active tablets and why the study is called 'double dummy'.

You will also be asked to provide a blood sample. This will be considered as a gift to Cancer Research UK and will be stored securely by the charity indefinitely. We do not know exactly what tests may be carried out in the future, but it is likely that some of these may be of a genetic nature. Your sample will be identified by a study number only, and any test results will not be available individually but will only be reported anonymously on a group basis. In order to protect you, the blood samples will be made completely anonymous before any genetic tests are performed. We would also like your permission for us to have access to any relevant tissue specimen should you have further investigations or operations. If you do not wish to do this you may still participate in the trial, but you should tick the appropriate 'No' boxes on the Consent form.

Will I have to go to the trial centre on a regular basis?

You will have check-ups every year and regular mammograms. If you decide to take part, your GP will be told that you are involved in the study and will be notified about any important findings.

A schedule of appointments at your local centre is below:

You may receive additional questionnaires from time to time requesting further relevant information, some perhaps even after active participation has been concluded.

Please note that you are always able to contact your research centre between your yearly appointments.

Unfortunately funding for the study is not sufficient to cover individual travel expenses for clinic visits. However, your local clinic may be able to make special arrangements for you.

What do I have to do once I am on the trial?

It is important that you take the medication regularly. This will be two tablets a day for five years. If you are already taking other medication you may take these tablets at the same time, otherwise you may take them at any time of the day. If you forget to take your tablets one day do not take two lots the next day, but just continue on the two a day regime for the five years. There are no dietary restrictions associated with this study. You will still be able to drive, drink and take part in any sport you wish to.

Taking part in the study should not have any major affect on your daily activities. However, if you are a blood donor, the Blood Transfusion Centre has advised us that women participating in this study should not give blood.

If you have life assurance or private medical insurance, you may need to inform the company about your involvement with the study, though this should not affect your status from their point of view. You may wish to discuss this with your own company before you decide whether to take part in the study or not.

You should inform any doctor or person treating you for a medical condition that you are involved with the study and you are taking tamoxifen or anastrozole. Remember, you will not know which one you are taking.

What are the drugs that are being tested?

Tamoxifen

Tamoxifen is a drug which has been used for over 30 years to treat breast cancer. It works by blocking the action of the female hormone oestrogen in breast cancer cells. Normal female sex hormones such as oestrogen can encourage breast cancer cells to grow in some women. Both pre and postmenopausal women have oestrogen present in their bodies. Tamoxifen will not stop the natural production of oestrogen but it will stop breast cancer cells from using it. More than 2 million women with breast cancer throughout the world have taken tamoxifen - over 40,000 of them in clinical trials. The progress of these women has been followed for up to twenty years, and is still continuing. Most women in these trials have reported few or no side effects.

We know that tamoxifen has major benefits for women who have had surgery for breast cancer. Previous research has shown that if taken for up to five years, tamoxifen can:

• Reduce the risk of breast cancer returning by more than one-third
• Reduce breast cancer deaths by nearly one-quarter
• Reduce the risk of developing cancer in the other breast by nearly half

In 1999 an American study reported on the use of tamoxifen as an adjuvant agent in DCIS and showed a 37% reduction of recurrence. However, so far a UK DCIS study has only found a 17% reduction.

Tamoxifen may also help with other health problems. The drug reduces the level of fats (cholesterol) that can 'fur up' blood vessels. One study showed that tamoxifen halved the rate of fatal heart attacks in postmenopausal women, but other studies have not found an effect.

The drug also reduces the rate of bone loss (osteoporosis) in the spine after the menopause. Recent evidence from the American prevention study showed a one-third reduction in fractures of the wrist, hip and spine.

Anastrozole

Anastrozole is a drug that is being used to treat breast cancer. It works by blocking the production of oestrogen by interfering with an enzyme called aromatase. Therefore it is called an aromatase inhibitor. In postmenopausal women, oestrogens are produced primarily from the conversion of other hormones through the aromatase enzyme complex in peripheral tissues, e.g. fatty tissue. Anastrozole prevents this happening, thus reducing the amount of oestrogen in the body. This reduction has been shown to produce a beneficial effect in women with breast cancer. It cannot block oestrogen produced by the ovaries, so can only be used in postmenopausal women.

Until recently its use as an adjuvant in early breast cancer has been restricted to clinical trials, but it has now been licensed for use in the adjuvant setting in several countries.

What are the alternatives for diagnosis or treatment?

You may prefer not to go into the trial but simply take tamoxifen. Alternatively you may wish to have no additional treatment but rely on surgery and radiotherapy. It is important to discuss these issues with your doctors. You will be given time to read about and consider the trial and other options available.

What are the side effects of any treatment received when taking part?

There is a great deal of information about the possible side-effects of taking tamoxifen for up to five years, but less is known about anastrozole, as it is a much newer drug. However, there are now over 550,000 total women years of use and our knowledge of side effects is developing all the time.

The most common side effects for both drugs are menopausal type symptoms and these can reappear in women who have already been through the change. With tamoxifen these usually present as hot flushes and changes in vaginal bleeding and secretions. This occurs in about 10% of postmenopausal women. Similar effects are found with anastrozole but they are less fully documented. Most of these side effects may also be related to normal hormonal changes.

There are also some very rare but potentially serious side effects: Several research studies have suggested an increased risk of cancer of the lining of the womb (endometrial cancer) in post-menopausal women taking tamoxifen. This is a rare form of cancer and available evidence suggests that the normal risk of 4 women in every 10,000 each year developing the disease is increased to 8-12 per 10,000 per year as a result of taking tamoxifen. Most cases of endometrial cancer are detected early and can be treated by removal of the womb (hysterectomy) and fortunately this is usually completely successful. However, late-stage or high-grade tumours have been seen very rarely.

Any unusual vaginal bleeding should be reported to your GP without delay. This could be due to a number of causes, but your doctor will check whether it could be endometrial cancer so that any necessary treatment can be carried out as early as possible.

Tamoxifen has also been reported to increase the risk of blood clots. This is rare but can occasionally have serious consequences. Women at high risk of blood clots should not participate in this study.

Eye problems have occasionally been reported in women taking tamoxifen. Recent research has shown that tamoxifen can cause a slight increase in the development of cataracts. A very rare eye complication - tamoxifen retinopathy - can cause impaired eyesight, but this usually disappears when treatment is stopped. If you do take part in the study, tell your GP about any changes in your eyesight as soon as they occur. Studies to date have not found that any other cancers are associated with the use of tamoxifen.

Anastrozole is a drug being used to treat breast cancer and has been found to be at least as effective as tamoxifen, but with fewer side effects. It is well tolerated generally, but has only been used in the treatment of breast cancer for 7 years. Reported adverse events have usually been mild to moderate with only a few withdrawals from treatment due to undesirable events. Because it reduces oestrogen levels the side effects are very similar to post-menopausal symptoms. These include hot flushes, vaginal dryness and hair thinning. Anastrozole may also be associated with gastrointestinal disturbances (anorexia, nausea, vomiting and diarrhoea), bone pain, weakness, sleepiness, headache or rash.

Anastrozole does not appear to have some of the other side effects of tamoxifen, such as blood clots or endometrial cancer, but there is a concern about bone loss with long-term use, because anastrozole works by lowering oestrogen levels. For this reason we need to do a baseline bone density scan and x-ray of the spine on all women to identify those who may have osteoporosis. This is currently being studied in women with breast cancer and will also be investigated in our study. There are also concerns about the quality of life, in particular memory and concentration, associated with a long-term reduction in oestrogen levels and this will be monitored during the study.

If you suffer any of the side effects described above or any other symptoms you should report them. If you become in any way concerned, you should contact your local centre (Contact details can be found in section 20 of this document).

What are the possible disadvantages and risks of taking part?

In addition to potential side effects in the previous section, you should be aware of the following:

• There is lactose in both the placebo formulations and if you suffer from lactose intolerance you will not want to participate in the study.
• Your future insurance status for life insurance or private medical insurance may be affected by taking part in this study. If you have private medical insurance you should check with the company before agreeing to take part in the trial. You will need to do this to ensure that your participation will not affect your medical insurance.

Radiation Dose - As part of a safety check on your bones you will receive a baseline spinal x-ray and a Bone Mineral Density Scan. The total radiation from these investigations is roughly equivalent to about 3-4 months natural background radiation found in the UK . You will also have had a mammogram within the last years and this also carries a small dose of radiation, which is equivalent to about 2 months natural radiation.

What are the possible benefits of taking part?

• You will be offered annual follow up by one of many specialist breast care teams involved in the study. You will receive appropriate screening and checks, and any problems or concerns you may have will be discussed. You will be advised if any further investigations are necessary.
• You will receive up to date information from your Local IBIS Team on any new research findings.
• You will automatically become a member of a growing body of women who are playing a vital part in the future treatment and understanding of breast cancer.
• You will have a 50% chance of receiving either tamoxifen or anastrozole. Both of these treatments may reduce your risk of getting a recurrence of breast cancer.
• The information we get from this study may help us to treat future patients with breast cancer better.

What if new information becomes available?

Sometimes during the course of a research project, new information becomes available about the treatment/drug that is being studied. If this happens, your research doctor will tell you about it and discuss with you whether you want to continue in the study. If you decide to withdraw your research doctor will make arrangements for your care to continue. If you decide to continue in the study you will be asked to sign an updated consent form.

Also, on receiving new information your research doctor might consider it to be in your best interests to withdraw you from the study. He/she will explain the reasons and arrange for your care to continue.

An Independent Data Monitoring Committee will be over-seeing the study on a frequent basis and will ensure that any concerning issues are investigated and women are informed of any relevant new information as it becomes available. This patient information sheet and all other study literature will also be updated as and when new data becomes available.

What happens when the research study stops?

Recruitment to the study will continue for 4 years or until 4000 women are recruited. All women will be actively participating for five years and then will be followed up for a further five years by annual questionnaire. During all this time trial data will be regularly checked by the Independent Data Monitoring Committee and should important new information be discovered, women will be informed and advised appropriately. At this stage, we are asking women to maintain the double blind protection of the trial and not to request a codebreak unless this is essential for their future health.

We will unblind in the following circumstances:

1. Where the woman develops breast cancer
2. Where it is considered necessary by any clinician involved in her care

What if something goes wrong?

Compensation for any injury caused by taking part in this study will be in accordance with the guidelines of the Association of the British Pharmaceutical Industry (ABPI). Broadly speaking the ABPI guidelines recommend that 'the sponsor', without legal commitment, should compensate you without you having to prove that it is at fault. This applies in cases where it is likely that such injury, not previously warned about, results from giving either drug or any other procedure carried out in accordance with the protocol for the study. Your right at law to claim compensation for injury where you can prove negligence is not affected.

Will my taking part in this study be kept confidential?

If you consent to take part in the research any of your medical records may be inspected by the organisation sponsoring the research for purposes of analysing the results. These records may also be looked at by an independent auditing body and regulatory authorities to check that the study is being carried out correctly. Representatives from the ethics committee may also wish to review some of the data. Your name, however, will not be disclosed outside the hospital, GP surgery, Cancer Research UK or relevant NHS Registers.

What will happen to the results of the research study?

he study hopes to recruit the total number of volunteers over 4 years and each woman will take the study medication for 5 years. This means that it will be quite a long time before any results are available. However, an Independent Data Monitoring Committee will scrutinise data every 6 months and should important information come to light they will recommend that we inform all women included in the study.

Who is organising and funding the research?

Cancer Research UK are organising this research study and Queen Mary’s University of London are the sponsors.

All Recruiting Centres will be reimbursed for including women in this study.

Who has reviewed the study?

The study has been approved by the North West MREC (Main Research Ethics Committee) and your local ethics committee (LREC)

Contact for Further Information

If you have any questions about the study either contact your local centre or email the IBIS-II office: ibis@cancer.org.uk