Adjuvant therapies in breast cancer
In this series a GP interviews an expert to get first-hand information that goes beyond the textbook on a topic of current clinical interest
Exciting new treatment developments are improving outlook,
as Dr Murray Brunt explains to
Dr Roger Henderson
Practical points l
Tamoxifen remains the first-choice endocrine adjuvant therapy
Anastrozole works only in postmenopausal women
Radiotherapy now offers a large survival benefit –
up to 10 per cent
Capecitabine for metastatic disease should be supervised by a specialist oncologist
Mortality decreased by better management
There is a lot of coverage in the media about advances in the management of breast cancer – has the outlook changed for patients in recent years?
Yes, it has changed a great deal. The chance of dying from breast cancer is now approximately half when compared with 1989.
Advances are made by many small improvements, which together add up to a large step forward.
An improvement in survival with a new therapy is usually in the range of 2-5 per cent, so a number of these advances, when taken sequentially, translate into a large difference. The incidence and mortality from breast cancer in the UK increased for much of the second half of the 20th century.
However, despite a continued increase in incidence, since 1989 the mortality has progressively decreased.
Though screening has played a part – which some authors still dispute – a major component is due to improved management of both early and advanced breast cancer.
Are there patients for whom tamoxifen isn't indicated, and is there just one standard dose?
Tamoxifen remains a very important adjuvant therapy and plays a much bigger role than in 1989. However, one might believe from media reports that it no longer has a role in adjuvant therapy – it has, and remains the first-choice endocrine adjuvant therapy here. If tamoxifen is contraindicated, aromatase inhibitors are used for post-menopausal patients and ovarian ablation for pre-menopausal women.
We also now know tamoxifen only has a role if the cancer is oestrogen and/or progesterone receptor positive. For patients with receptor negative tumours there is no known advantage.
We now use tamoxifen for at least five years, which is better than a shorter duration (two years was previously standard), but studies are ongoing to see if more than five years of therapy is even better.
There are also studies, not yet fully reported, looking at switching to an aromatase inhibitor after two to three years or at five years.
The ATAC study has already shown that a combination of tamoxifen with anastrozole is not better than either drug on its own, but is showing an encouraging trend favouring anastrozole. Mature results of this British-led study will emerge in the next few years and are eagerly awaited.
Remember – 20mg is the standard dose of tamoxifen and more is not better. I have a few patients on 10mg a day who cannot tolerate 20mg, but this is not common.
For patients who tolerate tamoxifen poorly, particularly due to vasomotor side-effects, it is worth looking at the brand. Some patients have few symptoms on a particular brand.
A revolution in radiotherapy
Radiotherapy is another treatment that has been around
for a long time. Are there any developments related to
Yes, it is the most exciting time I have known in almost 20 years in the specialty. I used to show a slide in lectures explaining that while radiotherapy had a large benefit on local recurrence in the breast, it didn't alter survival. Though the initial worldwide overviews supported this, the slide hit the bin some time ago.
The survival benefit seen in the first 10 years was counteracted by increased cardiac mortality between 15 and 30 years after treatment. With modern radiotherapy the heart is spared entirely or to a large extent.
When radiotherapy is given to the intact breast after a wide local excision of the primary there is now a survival benefit of 4-5 per cent.
For patients with 10 or more nodes involved, radiotherapy given to the chest wall post-mastectomy can confer a survival benefit of 10 per cent or more. This is an unusually large benefit from an adjuvant therapy.
On the technical side, radiotherapy is undergoing a revolution. We now use CT planning for many treatments and this is beginning to happen for breast cancer as the three-dimensional information obtained is a considerable advance.
With breast cancer we should start to see significantly reduced morbidity to the lung and heart and further improvements in breast cosmesis and post-radiation discomfort. There are also a number of new breast radiotherapy trials due to start within the next year or two, all looking at refining what we are currently doing.
Could anastrozole replace tamoxifen?
Is anastrozole appropriate for first-line treatment, and do women have to be post-menopausal? Are there alternatives?
Aromatase inhibitors only work in post-menopausal women. There are three in common usage – anastrozole, letrozole and exemestane. They prevent peripheral conversion of androgens into oestrogens, thus abolishing the already low levels of oestrogen in post-menopausal women.
In pre-menopausal women the production of oestrogen from the ovaries continues unaffected by aromatase inhibitors.
Exemestane is an irreversible inhibitor and has activity when used after failure of one of the other two. Anastrozole can be used first-line as adjuvant therapy only when tamoxifen is contraindicated; I would anticipate that it will replace tamoxifen under certain clinical conditions within a year or two, but further development of trial data is awaited.
Anastrozole can also be used as first-line hormone therapy of advanced breast cancer and appears to have a slightly higher efficacy than tamoxifen.
Does stilboestrol still have a role in the treatment of breast cancer?
This 'old-fashioned' hormone therapy does still have a place as third/fourth/fifth-line hormone therapy. It fell from grace with high doses giving a significant thrombotic risk, but a recent American study reminded us of its potential place, particularly when it is used after oestrogen antagonist therapy.
The theory is that it does 'the opposite' and attacks the cells growing despite oestrogen antagonist treatment. I have witnessed some spectacular responses in some of my patients.
There is a temporary production problem with stilboestrol, which should be overcome by March or April this year. The potential for thrombosis still exists and clinicians need to be aware of this. I use a dose of 5mg bd.
Does dose dense treatment work?
Moving on to chemotherapy, are current more toxic regimes worth the extra morbidity incurred?
I would say yes, but with appropriate tailoring of the therapy for each individual situation. Worldwide overviews have revealed, first, that CMF is of benefit and also that anthracycline combination chemotherapy is on average 4 per cent better than CMF. Some groups gain by much more than 4 per cent, and yet for a few patients CMF is still appropriate.
With more aggressive breast cancer, investigation is continuing into anthracycline and taxane-based combination regimes. Early results would suggest there may be further benefit over existing standard regimes but with extra toxicity – we are again waiting for results to mature. Breast cancer studies need at least five years' follow-up before good analysis can occur.
As well as investigating new chemotherapeutic agents and combinations, exciting information is emerging about dose dense treatment (more frequent chemotherapy doses). On the other hand, high-dose chemotherapy with bone marrow transplant rescue was in vogue in the mid-1990s, but as results matured it failed to live up to its early promise.
We do have to be wary of allowing enthusiasm and early reporting of studies which can be unduly optimistic.
What is capecitabine and who should have it?
Capecitabine is an oral cytotoxic agent. It is a precursor of 5-fluorouracil (5-FU), one of the oldest chemotherapy drugs. The enzyme (thymidine phosphorylase) involved in the final step of conversion to 5-FU is found in higher levels in some tumour tissue than in normal tissue.
Capecitabine is used in the management of metastatic disease either as monotherapy or with docetaxel. It has the advantage of being oral but has two particular dose-related effects, hand-foot syndrome (painful swelling of the hand or foot) and diarrhoea, both of which can lead to dose reduction or treatment cessation.
Capecitabine should only be supervised by an oncologist specialising in the management of patients with breast cancer.
What is the current role of trastuzumab, and what are its likely side-effects? Can it be given indefinitely?
Trastuzumab is a recombinant humanised monoclonal antibody that specifically targets the HER2 protein, which is overexpressed in about one in five breast cancers. It is used to treat metastatic breast cancer where that breast cancer overexpresses HER2.
I have found this one of the most exciting advances in breast cancer management over the last couple of decades – the results for many individual patients have been quite spectacular. I suspect that before too long we will use trastuzumab for life in patients overexpressing HER2 once they have been diagnosed with metastatic breast cancer. The question is going to be what to put with it or whether to use it as a single agent.
There is no information yet on the usage of trastuzumab in the adjuvant setting but there are ongoing studies with widespread international collaboration. Adjuvant usage might prove to be a significant development – time will tell.
As far as side-effects are concerned, trastuzumab is a winner when compared with a lot of therapies given by oncologists.
Cardiac dysfunction is occasional but appears to be reversible on ceasing therapy. It should usually be picked up before any clinical signs or symptoms are apparent with sequential monitoring of left ventricular ejection fraction.
Mild infusion-related reactions are sometimes seen, most commonly on the first infusion. Severe anaphylactic reaction can occur and 15 deaths were recorded among the first 25,000 patients to receive trastuzumab. I feel this rate of severe reaction is acceptable, however, given the metastatic state of the disease.
Overall, as an oncologist, I would say now is an extremely exciting and encouraging time to be involved in the care of breast cancer patients.
Roger Henderson is a GP in Newport, Shropshire
Murray Brunt is consultant oncologist, North Staffs Royal Infirmary