Advanced Breast Cancer: Diagnosis and Treatment. National Institute for Health and Clinical Excellence Guideline 2009 — An Opportunity Missed
Article Outline
Evidence-based medicine has dramatically improved clinical standards, and oncology is blessed with perhaps more evidence than any other medical discipline on which to formulate sensible management guidelines. It is thus a great shame that the National Institute for Health and Clinical Excellence (NICE) in their guidelines on the management of advanced breast cancer have missed the opportunity to provide guidelines that will improve the management of nearly 11 000 women who die of this disease every year.
The previous NICE guidance on the management of breast cancer built logically on the developments in organisation of services begun by the Calman-Hine Report and continued by the Cancer Plan 1, 2, 3. It is therefore disappointing that further developments in the organisation of services for metastatic disease have not been adequately considered. For instance, the multidisciplinary team approach to the management of early disease was introduced, albeit without a specific evidence base, but has been enormously helpful in ensuring more consistent, high-quality, protocol-based investigation and treatment. Almost certainly multidisciplinary team-based discussion of management in patients with advanced disease would do the same. Such an approach has been strongly advocated by Breast Cancer Care's report of the Secondary Breast Cancer Task Force [4]. This latter, very sensible and thought-provoking document also focuses on the importance of specialist nurse support for patients with advanced disease, which is lacking in many advanced breast cancer clinics. However, other than stating that mechanisms to promote continuity of care ‘might include the nomination of a person to take on the role of key worker for individual patients’, the NICE guidelines fail to clearly recommend this linchpin to high-quality, holistic care. Early breast cancer patients are very well supported by specialist nurses, but sadly those with advanced disease typically have little or no access to such expertise. The omission of this within the NICE document will probably make funding of business cases for the appointment of clinical nurse specialists in advanced disease more difficult to justify.
The guidelines specifically cover diagnosis and assessment, information and decision making, systemic disease modifying therapy, supportive care and management of complications. These are well illustrated in the quick reference guide that describes the patient pathways that relate to these aspects of care. However, some of the conclusions and recommendations are at odds with both outcomes from well-designed clinical trials and published studies, as well as expert opinion.
Clinical decision making in cancer depends on knowledge of the extent and biology of the disease, plus an understanding of the functional status of the patient in terms of haematological, biochemical, cardiac and overall performance status. Although the recommendations for radiological assessment are sound and the guidelines talk about patient-centred care, there is actually insufficient consideration given to assessing the patient's underlying cancer, associated co-morbidity, functional status and treatment wishes to allow the formulation of a holistic treatment plan. This results, as we will see later, in guidelines that recommend a very fixed strategy of sequential treatments that minimise therapeutic options, limit choice, and seem to give inadequate consideration to the individual circumstances of every patient.
There is increasing evidence to show that the biology of metastatic disease may be different to that of the primary tumour. Oestrogen receptor status may be lost resulting in endocrine resistance, and Her2 status may be considered negative by immunohistochemistry of fluorescence in situ hybridisation testing on the initial primary tumour, but, due to selection of more aggressive clones during the metastatic process, can dominate the appearance at the metastatic site [5]. Although re-biopsy may not be considered essential, it is completely inappropriate to state categorically that patients should not have a further biopsy to re-assess oestrogen receptor or Her2 status. Often this can be carried out simply, cheaply and quickly under local anaesthetic, and the information provided may transform the management plan for an individual patient.
The systemic therapy options for advanced breast cancer are numerous and changing rapidly as information on new drugs and combinations is reported. Effective, safe palliation requires careful assessment of the patient and discussion as to her (his) individual wishes and expectations in order to match the most appropriate treatment plan to the clinical situation. It is therefore foolish to dogmatically dictate the order in which chemotherapy should be given. The guidelines recommend first-line therapy with docetaxel (but perversely not paclitaxel) followed by capecitabine and vinorelbine. However, docetaxel is associated with considerable toxicity and indeed a well-described finite treatment-related mortality. There are a large number of patients with advanced breast cancer for whom many oncologists would strongly counsel against the use of single-agent docetaxel. These would include those who are frail, the elderly, those with extensive bone metastases and patients with impaired bone marrow or liver function for whom a gentler option would be preferred. Additionally, there are some patients for whom many oncologists would recommend single-agent paclitaxel, a previously NICE-approved treatment (NICE Technology Appraisal Guidance 108), perhaps given on a weekly schedule to provide similar palliation to single-agent docetaxel, but with considerably less toxicity. This is now apparently forbidden except in combination with gemcitabine.
It is true that there are very few trials comparing different sequences or ordering of the available treatments. However, lack of evidence should not lead to a dogmatic, simplistic approach, but recognise that there are many appropriate treatment options. Until we have more specific predictive factors for response and toxicity, it is reasonable to select from a range of approved treatments on the basis of clinical acumen and experience.
The management of Her2-positive breast cancer has been transformed by the development of Her2-targeted therapies. Trastuzumab improves survival in both the adjuvant and advanced disease settings. We do not have all the information we would like on the optimum use of such treatments, but the dogmatic recommendations for withdrawing treatment with trastuzumab for Her2-positive advanced breast cancer after progression on one line of therapy fly in the face of the evidence that was available to the committee when drawing up the guidance. There is randomised controlled trial evidence supporting the use of trastuzumab beyond progression outside the central nervous system [6]. Although this trial is relatively small and not yet fully published in a peer review journal, the data are widely known among the oncological community, and strongly support the use of trastuzumab beyond progression. Such a definitive recommendation to discontinue treatment is therefore illogical. On the other hand, there is a clear recommendation not to discontinue trastuzumab in the presence of central nervous system relapse. Although most breast oncologists would agree with this, this is not based on randomised trial evidence, but on an understanding of the pharmacology of trastuzumab and assumptions about the biological activity of the antibody.
The management of complications is a very important part of treating advanced breast cancer. In the context of bone metastases, sound advice is given on the use of bisphosphonates and involvement of an orthopaedic surgeon to assess patients at risk of long bone fracture. However, the guidelines focus too much on lymphoedema and fatigue, complications that are not necessarily related to advanced disease and for which there is little or no evidence-based management. Conversely, management of effusions, hypercalcaemia, pain and spinal cord compression is strangely ignored, despite the latter being the subject of a recent NICE review [7]. Recommendation 1.5.15 therefore completely ignores the very clear statement within the NICE guidance on spinal cord compression that recommends that all patients with vertebral metastases should be assessed by a spinal surgeon to pre-empt catastrophic spinal complications. There is also no cross-reference to the spinal cord compression guidance, which is regrettable.
The guidelines contain a number of research recommendations that have little resonance with the breast cancer community or the National Cancer Research Institute Breast Cancer Study Group, which oversees and develops the breast cancer National Institute for Health Research portfolio. In the main, the proposals are either superfluous (trastuzumab beyond progression), very unlikely to show any meaningful differences (sequencing of second and subsequent lines of endocrine treatments), or would have little or no chance of obtaining funding from the available grant giving bodies (clinical and cost-effectiveness of different sequences of chemotherapy). The research emphasis should be on the cost-effective integration of new disease and organ-targeted therapies, identification of predictive factors to allow tailoring of treatment to the individual patient, and optimising the organisation of care for metastatic disease to meet the needs of today's patient with advanced breast cancer.
I am quite sure the Guideline Development Group put considerable thought and effort into reviewing the evidence and developing the document. However, it is disappointing to see that only three oncologists are listed as being involved in the process. Furthermore, considerable expert feedback was provided through the usual sources, including the Royal College of Physicians, National Cancer Research Institute, Royal College of Radiologists, Joint Council for Clinical Oncology, and Association for Cancer Physicians. Little or no account of the feedback provided by experts in the field appears to have been taken. There must be a better process for producing fair and balanced guidelines than this. The final document is at odds in many areas of management with national guidance from elsewhere in the world and will do little to improve the standard of care for our patients. Clearly, an opportunity to do so has been missed!
References
- Improving outcomes in breast cancer – manual update. Cancer service guidance. Available from: www.nice.org.uk/csgbc2002;
- . A report by the expert advisory group on cancer to the Chief Medical Officers of England and Wales. Department of Health and Welsh Office; 1995;
- . A plan for investment. A plan for reform. Department of Health; 2000;
- Improving the care of people with metastatic breast cancer. Breast Cancer Care Secondary Breast Cancer Task Force Final Report. Available from: www.breastcancercare.org.uk/
- Changes in breast tumour receptor status with time: a prospective study assessing the impact of obtaining confirmatory biopsy at metastatic recurrence on patient management. J Clin Oncol. 2008;26:abstract 1052
- Capecitabine vs. capecitabine
+trastuzumab in patients with HER2-positive metastatic breast cancer progressing during trastuzumab treatment: the TBP phase III study (GBG 26/BIG 3–05). J Clin Oncol. 2008;26:abstract 1025 - Metastatic spinal cord compression. Diagnosis and management of adults at risk of and with metastatic spinal cord compression. NICE Clinical Guideline 75, 2008.
PII: S0936-6555(09)00109-5
doi:10.1016/j.clon.2009.03.008
© 2009 The Royal College of Radiologists. Published by Elsevier Inc. All rights reserved.
