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Early and Locally Advanced Breast Cancer: Diagnosis and Treatment National Institute for Health and Clinical Excellence Guideline 2009

2009; Elsevier BV; Volume: 21; Issue: 3 Linguagem: Inglês

10.1016/j.clon.2008.12.008

1433-2981

John Yarnold,

HER2/EGFR in Cancer Research

It is that time again; National Institute for Health and Clinical Excellence (NICE) guidelines on early and locally advanced breast cancer. There is a moment of unease as the document is scanned for daft suggestions and recommendations that overturn habits of a lifetime, but I admit to being a strong supporter of NICE. It attracts a bad press, but we would be in a proper mess without it, and statism is back in fashion, in any case. So, here is a whistle-stop tour, following roughly the same itinerary as the guidance published on February 25th 2009 at http://www.nice.org.uk/Guidance/CG/Wave9/10#keydocs. The first recommendation is for magnetic resonance imaging in all invasive lobular cancers if breast-conserving surgery is being considered, the rationale being accurate preoperative diagnosis of multifocal, multicentric and bilateral disease. We can expect more mastectomies, some necessary, others not. The second is for pretreatment ultrasound evaluation of the axilla in all patients with early stage disease, with image-guided sampling if the appearances are abnormal. The surgical section specifies that duct carcinoma in situ requires a minimum 2 mm excision margin after breast-conserving surgery, and while we are discussing duct carcinoma in situ, the document states that adjuvant tamoxifen should not be offered. All patients with oestrogen receptor-positive early invasive breast cancer should be treated with primary surgery irrespective of age, rather than with primary hormone therapy alone unless significant co-morbidity precludes surgery. The familiar guidance on sentinel node biopsy is there too, and the document confirms we should be auditing axillary recurrence rates. There is nothing contentious here. At the multidisciplinary team meeting, we need to ensure that the results of ER and HER2 testing are available, the latter assessment presenting a considerable challenge for many of us. The use of Adjuvant! Online is official to support estimations of prognosis and benefit of adjuvant treatment. I refer to Adjuvant! Online a lot, but bad treatment decisions can be made unless I take account of the underlying assumptions and evidence described in the online documentation. Admittedly an extreme example, a 80-year-old patient with minor co-morbidities and pT1G3ER-pN+(4-9)M0 invasive breast cancer is estimated by Adjuvant! Online to gain a 10% absolute survival benefit at 10 years after a third-generation cytotoxic regimen, such as FEC-T. No-one would think of giving this, of course, but lesser errors of judgement can easily be made. When taxanes are prescribed for younger node-positive patients, NICE says docetaxel, not paclitaxel, should be used. In any case, cytotoxic therapy or radiotherapy should be started within 31 days of completing surgery. Adjuvant ovarian suppression should not be offered to premenopausal women with ER-positive early invasive disease who are treated with tamoxifen and, if indicated, chemotherapy. On the other hand, adjuvant ovarian suppression should be offered in addition to tamoxifen to those premenopausal women with ER-positive early invasive breast cancer who are offered chemotherapy but choose not to have it. In postmenopausal women with oestrogen receptor-positive tumours (progesterone receptor status is no longer required) there is the familiar menu of endocrine options. NICE recommends that patients who are 'not good risk' (not defined in the guideline) should be offered an aromatase inhibitor right from the start. Exemestane or anastrozole, instead of tamoxifen, should be offered to postmenopausal women with ER-positive early invasive disease who are not low risk and who have been treated with tamoxifen for 2–3 years. In those with lymph node-positive disease treated with tamoxifen for 5 years, additional treatment with the letrozole for 2–3 years is recommended. This sounds a sensible approach, and a definite improvement on last year's consultation document. By the way, DEXA scans are needed if women have treatment-induced menopause, when starting ovarian suppression therapy or if adjuvant aromatase inhibitors are introduced, and bisphosphonates should be offered for treatment-induced bone loss according to published algorithms. What about radiotherapy? NICE confirms that adjuvant radiotherapy should be offered to patients with duct carcinoma in situ after excision with minimum 2 mm margins, with a discussion of potential benefits and risks. The guidance also says breast radiotherapy should be offered to all patients with early invasive breast cancer after breast-conserving surgery with clear microscopic excision margins. This is appropriate, but local tumour relapse risk after breast-conservation surgery fell to low levels over the last decade, for example to 3.5% at 5 years in the 4451 women entered between 1998 and 2002 in the UK START radiotherapy fractionation trials [1Forbes J.F. Cuzick J. Buzdar A. Howell A. Tobias J.S. Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial.Lancet Oncol. 2008; 9: 45-53Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar, 2Bentzen S.M. Agrawal R.K. Aird E.G. et al.The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial.Lancet Oncol. 2008; 9: 331-341Abstract Full Text Full Text PDF PubMed Scopus (890) Google Scholar, 3Bentzen S.M. Agrawal R.K. Aird E.G. et al.The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial.Lancet. 2008; 371: 1098-1107Abstract Full Text Full Text PDF PubMed Scopus (952) Google Scholar]. This rate is quite a bit lower than the 10% rate of ipsilateral tumour relapse predicted when the trial was designed in the mid-1990s. The 10-year ipsilateral local relapse rate in the START cohort is likely to be about 5%, and if we apply the hazard rate (0.7) for radiotherapy effect generated by the 2005 systematic overview by the Early Breast Cancer Trialists' Collaborative Group, it is unlikely this rate would be much higher than 15% without radiotherapy [4Mannino M. Yarnold J.R. Local relapse rates are falling after breast conserving surgery and systemic therapy for early breast cancer: can radiotherapy ever be safely withheld?.Radiother Oncol. 2009 Jan; 90: 14-22Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar]. Selective avoidance of radiotherapy in several thousand low risk patients defined by patient age, tumour size and oestrogen receptor looks like an obvious research priority. Returning to the guidelines, the document states that radiotherapy should be offered to patients with early invasive breast cancer post-mastectomy, chest wall radiotherapy if they are at high risk (not defined) of local recurrence, including those with four or more positive axillary nodes or involved resection margins. The document confirms that patients with early invasive breast cancer and intermediate risk of local relapse should be considered for the SUPREMO trial testing postoperative radiotherapy. Lymphatic radiotherapy recommendations offer no surprises; none should be given if axillary sentinel node biopsy or four-node sample is negative. Axillary radiotherapy is only indicated if sentinel node biopsy is positive and axillary lymph node dissection is not possible or incomplete, for example, due to inoperable nodal disease. Radiotherapy to the supraclavicular fossa is only recommended in patients with four or more positive axillary nodes, but should be offered in patients with one to three positive nodes if they have other poor prognostic factors, e.g. T3 and/or histological grade 3 tumours. No subgroups are identified to whom the internal mammary chain should be irradiated. NICE recommends 40 Gy in 15 fractions as standard practice for patients with early invasive breast cancer receiving external beam radiotherapy after breast-conserving surgery or mastectomy. The documentation does not refer to lymphatic radiotherapy, but assuming accurate technique and dosimetry, 40 Gy in 15 fractions is safe and effective. It is gentler on the brachial plexus than 50 Gy in 25 fractions. Applying the linear quadratic model and assuming an alpha/beta value of 2 Gy, 40 Gy in 15 fractions is equivalent to 47 Gy in 2.0 Gy fractions. It is notable that NICE identifies trials of hypofractionation, partial breast radiotherapy and newer radiotherapy techniques as high priorities. The UK breast cancer trials portfolio is tackling these issues, and although half the UK centres are actively involved, this should provide a powerful incentive for others to join in, not least because it offers access to the expertise of the quality assurance team to upgrade local protocols. There are many other things to pick and choose from, but one item is guidance on the management of menopausal symptoms. Tibolone or progesterones are not recommended, and selective serotonin re-uptake inhibitors (paroxetine and fluoxetine) should not be used in women taking tamoxifen, as they accelerate its breakdown in the liver. Soy, red clover, black cohosh, vitamin E and magnetic devices are not recommended either, so that leaves clonidine, venlafaxine and gabapentine. Let us finish by looking at follow-up. NICE says patients should have the choice of how further follow-up is undertaken, including primary, secondary or shared care. Patient choice is a wonderful thing, but it will lead to a real patchwork of practice within a single breast clinic. Either way, women should have a written care plan (dates for review of adjuvant therapy, surveillance mammography, contact points for referral to specialist care and support services) and a named healthcare professional. Annual mammography for 5 years is recommended for patients with early invasive disease or DCIS. In young women, annual examinations continue until women enter the NHS Breast Screening Programme, after which it can be adjusted according to risk. All in all, this is a very good document, and those who have contributed are to be congratulated.