SOUTH EAST LONDON CANCER NETWORK BREAST TUMOUR WORKING GROUP GUIDELINES

Transcription

1 SOUTH EAST LONDON CANCER NETWORK BREAST TUMOUR WORKING GROUP GUIDELINES

2 1. INTRODUCTION 2. Diagnostic Assessment 3. Radiotherapy 4. Systemic Therapy 5. Survivorship guidelines CONTENTS INTRODUCTION The South East London Cancer Network (SELCN) Breast Tumour Working Group (TWG) is a multidisciplinary group of specialist clinicians and nurses, supporting services personnel, network management personnel and service users/patient representatives from the boroughs of Bexley, Bromley, Camberwell, Greenwich, Lambeth, Lewisham and Southwark covered by The Guys and St Thomas Hospitals Foundation Trust, Kings College Hospital Foundation Trust and The South London Healthcare Trust (comprising of the Princess Royal University Hospital, Queen Elizabeth Hospital and Queen Mary s Hospital). The guidelines are developed by the group to ensure that care throughout the region conforms to best practice in the UK and worldwide. The group meets 4 times a year and the guidelines are reviewed annually to ensure they are updated with emerging evidence and changes in practice. The guidelines come from all the different therapy groups treatment breast cancer. The whole TWG is to be complimented on their effort in producing these guidelines and I am proud to chair such a group of dedicated professionals. Mr Jonathan Roberts Chairman SELCN Breast TWG

3 Diagnostic Guidelines 1: Referral 1.1 Referral from primary care to breast clinic QI1 Patients with the following symptoms or signs should be referred for assessment. All patients referred to the breast clinic should receive an appointment within two weeks of the date of receipt of the referral. Symptoms suggestive of urgent attention are denoted as U, and symptoms considered non-urgent but still requiring an appointment within two weeks are denoted as NU. (Please note that family history referrals and cosmetic referrals are excluded from the two week wait pathway.) 1.2 Lump, lumpiness, change in texture Discrete lump in any woman 30 years and older that persists after next period or presents after menopause (U) At any age: Discrete hard lump with fixation +/- skin tethering/dimpling/altered contour (U) A lump that enlarges (U) A persistent focal area of lumpiness or focal change in breast texture (U) Progressive change in breast size with signs of oedema (U) Skin distortion (U) Previous history of breast cancer with a new lump or suspicious symptoms (U) Under 30 years: A lump that does not meet above criteria (NU) Male patients: Over 50 years with unilateral firm subareolar mass +/- nipple discharge or associated skin changes (U) 1.3 Nipple symptoms

4 Spontaneous unilateral blood stained nipple discharge (U) Unilateral nipple eczema or nipple change that does not respond to topical treatment (U)

5 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS Recent nipple retraction or distortion (U) Women who can be managed at least initially by GP: Women under 50 years who have nipple discharge that is from multiple ducts or is intermittent and is neither blood stained nor troublesome (NU) Male patients: Over 50 years with unilateral firm subareolar mass +/- nipple discharge or associated skin changes (U) 1.4 Breast Pain Patient with minor/moderate degree of breast pain with no discrete palpable abnormality, when initial treatment fails and/or with unexplained persistent symptoms (NU) 1.5 Axillary lump (in absence of clinical breast abnormality) Persistent unexplained axillary swelling (U) 1.6 Communication Role of the GP The general practitioner plays a fundamental role in supporting the management of symptomatic breast patients. They are supported in their decision to refer (and to re-refer where necessary) by the existence of national guidelines. General practitioners are well placed to support the patient through the referral process, by providing choice and information, and also through any subsequent treatment phases by providing ongoing holistic support. They are often seen as the first port of call by the patient. Presentation of the patient with new breast symptoms In the initial consultation the GP should assess the patient with a view to referral to a symptomatic breast clinic. The GP may find that the patient has normal or benign changes that do not require referral and, at this point, they should give reassurance supported with the appropriate literature. All patients should be aware of present breast screening processes and informed not to await their next screening appointment if they develop symptoms.

6 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS Referral to clinic Once the patient is referred to the breast clinic, clear communication between professionals is vital at this point to ensure that all relevant information regarding the patient is relayed to the clinic prior to the patient s clinic attendance. The patient should receive written and/or verbal information regarding the symptomatic breast clinic. This information should include waiting times for an appointment and the likely process that will occur during the clinic (see Appendix A). This information may be sent out with the appointment letter and should ideally also include information on length of visit. The patient should also be provided with guidance for obtaining further information. Patients should be reminded of the importance of keeping their appointment.

7 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS 2: Assessment 2.1 Assessment The diagnostic assessment of patients with breast symptoms is based on the Multidisciplinary Triple Diagnostic Method: A. Clinical assessment B. Imaging assessment C. Needle biopsy The tests used in an individual case will be determined by the presenting symptom(s), the clinical findings and the age of the patient. The assessment clinic should be organised so that all appropriate tests can be carried out during the same clinic attendance. Use of the Triple Diagnostic Method will enable a diagnosis to be established in the majority of patients and diagnostic surgical excision should be rarely required. QI2 The delayed diagnosis of cancers after Triple Assessment in women who present with symptoms and are subsequently diagnosed with cancer is approximately 0.2%. Patients in whom the Triple Assessment is negative should be advised to seek advice from their GP if they remain concerned or if there is a change in symptoms or signs. The breast imaging facilities should include x-ray mammography and high frequency ultrasound with probes suitable for breast imaging (12 MHz or more). Digital mammography is preferred to film screen mammography particularly for women below 50 years and for those with dense breast tissue. The technical quality of mammography should be equivalent to that in the NHS Breast Screening Programme (NHSBSP). Breast imaging facilities should be integrated with, or be within reasonable distance of, the breast clinic for patient convenience and efficient service delivery.

8 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS Breast MRI does not form part of the initial imaging assessment of patients in the symptomatic breast clinic. It may, however, be useful in the further investigation of some breast lesions and in the evaluation of patients with confirmed breast cancer. MRI should be carried out according to local policy agreed by the multidisciplinary team. There should be clear administrative links between breast imaging and the breast clinic in order to ensure: efficient service delivery best use of resources clear and rapid communication for clinic scheduling, exchange of information and results of tests The clinical assessment and appropriate imaging and needle biopsy should be carried out during the same clinic appointment. Communication Assessment All staff should possess appropriate communication skills for both communicating with patients and ensuring consistent communication with all health professionals involved in the patient s care. Healthcare professionals should assess women during the diagnostic process (i.e. ascertain the patient s understanding of the situation and expectations) to intervene accordingly as patients own appraisals of their illnesses will affect their understanding of their situation and the diagnostic process, and their psychological well-being. The patient should be given clear information, that meets their individual needs, at each stage of the diagnostic process and made aware of the availability of, and contact details for, their breast care nurse. For patients who undergo needle biopsy, both written and verbal information should be provided, for those who wish, regarding the likely diagnosis and outcome of the biopsy. All patients who undergo needle biopsy should be provided with a definite appointment or other agreed arrangement for communication of the biopsy result, within five working days. A discussion between the patient and a clinician who has been involved with the assessment of the patient should occur prior to leaving clinic. This is to inform the patient of the likely outcome of the biopsy result in light of the clinical examination and imaging findings. If these are felt likely to be malignant a breast care nurse should be present at that consultation where possible.

9 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS

10 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS Patients should be advised of when they may receive their diagnosis i.e. know at what point they will receive their diagnosis, so they can arrange to be accompanied by family/friend if they wish. Patients who perceive themselves to have a high risk of breast cancer may continue to feel distressed following a benign diagnosis so it is important to accurately address these (mis)perceptions at the initial consultation. The results of Triple Assessment should be discussed at a multidisciplinary meeting for all women who undergo needle biopsy. The results of each element of the Triple Assessment should be considered in order to ensure a correct diagnosis and appropriate further management. If there is discordance between the results, further assessment, if necessary including repeat biopsy, should be considered (see section 3). Outcome of assessment Results should be given by an appropriately trained senior clinician who has experience and training in breaking bad news. The patient should be given their results in the presence of a breast care nurse and any relative/carer/friend of the patient that they wish to have at the consultation. Communicating the diagnosis takes time and it should be ensured that sufficient time and support is provided for this and that it takes place in an appropriate setting. Written information and supportive literature may be appropriate for the patient and their carers or family at this point. The format and language of written information should always be appropriate and easily understood and information and support should always be tailored to meet the needs of the individual. GPs should be informed of a diagnosis of cancer within 24 hours including details of test results and the care plan. GPs should be informed if the patient does not have a diagnosis of cancer within 10 working days. Patients with benign/normal results: Patients should be given appropriate reassurance and an explanation of their symptoms. Literature to support this verbal conversation may be useful. Patients who have an equivocal result or require repeats: Patients should have a face to face consultation to clearly discuss the need for further tests and possible outcomes, and a simple care plan put together. Clear explanation should be given of why further tests may be needed.

11 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS Patients who have a breast cancer diagnosis: Around the time of diagnosis approximately half of all cancer patients experience levels of distress that may adversely affect their quality of life, whilst around one third report significant levels of anxiety and/or depression. Clear routes of referral to specialist support services should be in place for any patient identified as needing further support beyond that provided by specialist nurses, e.g. clinical psychology referral. Role of the Breast Care Nurse The Breast Care Nurse (BCN) (Cancer Nurse Specialist) can play a vital role in improving the experience for patients with breast disease throughout all stages of the patient journey starting from the referral from the GP. As well as providing information, they are able to carry out a range of technical and emotional functions, with a coordination role in providing continuity of care throughout the patient pathway whether this involves a benign or a cancer diagnosis. The BCN works as part of the integrated multidisciplinary team with engagement in appropriate what if conversations. The BCN may be required to support and advise patient families and carers. They will have the relevant skills to carry out this role and have undertaken an advanced communication skills course. A. Clinical assessment All patients who attend the symptomatic breast clinic should have a clinical consultation and physical breast examination carried out by a suitably trained member of the multidisciplinary team. This may be a nurse practitioner, radiographer, radiologist, breast clinician or surgeon. The consultation is aimed at establishing the nature, site and duration of the patient s symptoms and gathering other relevant history, e.g. past history of breast disease or investigation, date of last mammogram, participation in breast screening, family history, history of HRT. It can be helpful to ask the patient to complete a questionnaire at the time of attendance at the clinic (see Appendix B for an example of questions in a patient questionnaire). The physical examination should establish the nature and site of any abnormalities found either on visual inspection or palpation of the breast. In particular, the physical examination should establish whether there is a discrete lump present or an area of textural change. The findings of the clinical examination should be correlated with the area of concern found by the patient or referring doctor.

12 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS The physical examination should include an assessment of the axillary and supraclavicular nodes. The results of physical examination should be recorded clearly using a diagram to indicate the site and extent of any lesions found. The level of suspicion for malignancy should be recorded using the 1-5 scale: P1 = normal P2 = benign P3 = uncertain P4 = suspicious P5 = malignant B. Imaging assessment Appropriate imaging should be carried out by suitably trained members of the multidisciplinary team e.g. radiologist, radiographer, breast clinician, nurse, surgeon. Ultrasound is the imaging method of choice for the majority of women aged < 40 years and during pregnancy and lactation. X-ray mammography is used in the investigation of women aged = > 40 years with the addition of ultrasound when indicated. X-ray mammography is not indicated for the majority of patients aged < 40 years. X-ray mammography should be carried out in patients aged years with clinically suspicious or malignant findings (P4, P5) and should be considered in patients with clinically indeterminate lesions (P3) if ultrasound is normal. X-ray mammography should be carried out in all patients with proven malignancy even if aged < 40 years. Mammography should include MLO and CC views of each breast. Digital mammography is preferred to film screen mammography, particularly for women aged < 50 years and for those with dense breast tissue. If a suspicious abnormality is demonstrated on mammography, it may be helpful to further characterise the mammographic features using magnification or spot compression views. These should be carried out during the clinic as directed by the radiologist or the consultant radiographer in breast imaging.

13 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS QI6a QI6b QI7 QI8c QI8a QI8b

14 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS The level of suspicion for malignancy should be recorded using the RCR Breast Group Classification U1-U5 and M1-M5: 1 = normal 2 = benign 3 = indeterminate/probably benign 4 = suspicious of malignancy 5 = highly suspicious of malignancy C. Needle biopsy (Needle core biopsy and fine needle aspiration) The clinical and imaging work up should be completed before needle biopsy (fine needle aspiration cytology (FNAC) or core biopsy) is performed. Breast needle biopsies should be performed under imaging guidance in order to achieve greatest accuracy and reduce the need for repeat procedures. Free hand core biopsy may be appropriate for cases of palpable, locally advanced breast cancer and cases in which the imaging is normal but there remains a suspicious localised clinical abnormality. Needle core biopsy is preferred rather than FNAC for most solid lesions and for lesions suspicious for cancer because of the higher sensitivity and specificity achieved in most centres and because of the importance of oncological information including tumour type, grade and receptor status obtained with histology. In units where appropriate expertise exists, FNAC is an acceptable alternative to needle core biopsy in the initial evaluation of symptomatic breast lesions and in patients presenting with a lump in the axilla alone with no known clinical abnormality of the breast. Centres using cytology should demonstrate appropriate sensitivity and specificity. Biopsy of lesions within or attached to skin can often be carried out using a 3mm or 4mm punch biopsy needle under local anaesthetic. This is particularly suitable for suspected Paget s disease of the nipple and local recurrences in the skin. Needle aspiration of clinically obvious cysts in patients with known recurrent cystic disease may be performed following initial clinical assessment. Appropriate imaging with mammography and ultrasound should still be carried out in such cases. Needle core biopsy and FNAC samples should be handled and reported (B1-5, C1-5) according to the Royal College of Pathologists tissue pathways guidance and NHSBSP/Royal College of Pathologists guidelines for non-operative diagnostic procedures and reporting.

15 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS One-stop assessment QI9 At one-stop assessment all the required elements of triple assessment are performed during a single visit. This provides: a basis for definitive diagnosis in the majority of patients reassurance with no need for further attendance in most patients with nonmalignant conditions information for multidisciplinary meeting (MDM) treatment planning prior to review of those diagnosed to have cancer Some patients do not require all the elements of triple assessment, as outlined below and defined in the Algorithms. This includes those with: resolved symptoms and no clinical abnormality clearly identified benign conditions with no other suspicious features found on clinical and imaging assessment such as: areas of benign breast change and diffuse nodularity without a dominant mass simple cysts whether aspirated or not breast pain non-bloody nipple discharge gynaecomastia One-stop breast assessments are generally more favourable for people without cancer as they go home without further waiting, knowing they do not have cancer. Generally, a same-day core biopsy reporting service is not practical. Expected turnaround time for pathology reporting of diagnostic needle core biopsy samples should be specified locally. Time is required during one-stop assessment for patients to raise questions and concerns (regardless of diagnostic outcome), and for these to be addressed promptly.

16 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS Breast lump, lumpiness, change in texture (Algorithm A) Assessment Both clinical and imaging assessment should be carried out for patients: with a persistent lump who remain concerned regarding the presence of a lump or localised change in the breast tissue Many patients attending for breast assessment with a possible lump will be found to be normal or to have clearly benign change e.g. cysts, and can be reassured and discharged following appropriate imaging. Clinical assessment History: the site, duration, associated pain, relationship to menstrual cycle and any recent change in the size of the lump should be established. Any previous history of breast lumps, relevant investigations or operations should be noted. Clinical examination: both breasts should be examined. The site, size and consistency of any lump or area of abnormal texture of the breast should be noted and correlated clearly with the site of symptoms noted by the patient and/or her doctor. The presence of any associated signs of malignancy such as skin tethering or nipple inversion should be sought. The axillary and the supraclavicular lymph nodes should be examined. Imaging QI10 All patients with a lump or localised change in texture should undergo appropriate imaging: Mammography and ultrasound for patients = > 40 years. Ultrasound for patients < 40 years with clinically benign or uncertain lesions (P2, P3). If ultrasound confirms normal, benign or probably benign findings, e.g. cyst or circumscribed solid lesion, mammography is unlikely to provide additional diagnostic information. Mammography should be performed in women below the age of 40 years for lesions which are suspicious on clinical or ultrasound criteria P4/5 or U4/5. Mammography should be considered in patients aged years with clinically indeterminate lesions (P3) in whom ultrasound is normal. Mammography may provide additional diagnostic information in the evaluation of some indeterminate U3 lesions.

17 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS Most solid breast lesions will require a needle biopsy to complete the triple diagnostic work up and to establish a diagnosis. Patients with ultrasound features categorised as U3-U5 should undergo needle biopsy. The following solid breast lesions may be safely diagnosed using clinical and imaging information and do not require needle biopsy. Presumed fibroadenoma For patients < 25 years a biopsy need not be performed if the following criteria are satisfied: ultrasound reveals a solid lesion which has benign ultrasound features (e.g. ellipsoid shape (wider than tall)), a well defined outline with smooth edges or fewer than four gentle lobulations. Presumed fat necrosis Clinical benign (P2) Imaging typical of fat necrosis U2 (+/- M1/M2) Presumed lipoma or hamartoma Clinically benign (P2) Imaging typical of a lipoma or hamartoma U2 (+/- M1/M2) If there is any doubt about the nature of the lesion or discrepancy between the clinical and imaging features, needle biopsy should be performed. Multiple lesions The lesions should be carefully assessed to establish whether they have the same morphological features and are likely to be due to the same histology. Multiple benign lesions U2 these are likely to be due to fibroadenomas and needle biopsy of one lesion (usually the presenting symptomatic lesion) is sufficient for diagnosis in a patient of 25 years or more. Multifocal malignancy it may be necessary to sample more than one of the lesions in order to establish disease extent and advise on appropriate surgical treatment.

18 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS Assessment of the axilla QI12 QI13 Ultrasound of the axilla should be carried out in all patients when malignancy is expected. If lymph nodes showing abnormal morphology on ultrasound are found, needle sampling should be carried out under ultrasound guidance. Lymph node sampling may be performed using FNAC or needle core biopsy (published studies have shown no significant differences in sensitivity or specificity). Outcome of assessment QI14 Following triple assessment, a definitive diagnosis of either benign/physiological changes or malignancy will be made in most patients. Where a definitive diagnosis is not established, repeat clinical assessment and needle biopsy should be considered. 2.4 Nipple symptoms Assessment Clinical assessment History: establish the duration, frequency, volume and colour of nipple discharge and particularly whether it occurs spontaneously or only on squeezing; whether bilateral; and whether there are any other associated breast symptoms particularly a lump or inflammation. Generally only single duct spontaneous discharges of genuine blood-stained, clear or serous colour need further evaluation; profuse bilateral milky discharges in non-pregnant patient may justify measuring serum prolactin. Note any history of nipple retraction or inversion, its duration and whether it is intermittent or permanent. Identify whether changes in nipple and areolar skin have been noticed such as bleeding or discharge from the skin, ulceration, and eczema. Clinical examination: in addition to normal breast examination, particular attention should be paid to trying to reproduce the discharge to determine whether it fits into the categories above. Recent unilateral nipple inversion is unlikely to be significant in the absence of any underlying palpable or mammographic abnormality, particularly if the inversion is correctable. Imaging Bilateral mammography in those >= 40. Ultrasound if any palpable abnormality.

19 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS Other investigations Nipple cytology is rarely of any value and must be treated with great caution after recent lactation. Dipstick testing for blood may eliminate those with dark brown discharges due to duct ectasia. Punch biopsy is indicated where Paget s disease is suspected and for any unexplained nipple eczema or ulceration. Outcome of assessment For persistent higher risk single duct discharge with no other identifiable abnormality, diagnostic retro-areolar open biopsy may be necessary. Occasionally duct disconnection may be indicated for benign but troublesome high volume discharge If Paget s disease is suspected but imaging and biopsy are benign, reassess and consider need for further biopsy Otherwise, refer back to GP with a summary of assessment and advice Verbal and written advice should be provided on the management of symptoms 2.5 Breast pain (Algorithm B) Assessment Clinical assessment History: establish the nature, duration and periodicity of pain; any other causative or related factors including injury, hormonal medication, lump or nipple discharge, features of infection and any recent treatment for this with antibiotics; current or recent breast feeding; and any features of referred breast pain from musculoskeletal conditions. Clinical examination: identify any focal clinical signs in the breast, lymph nodes and chest wall; look for signs of infection (pink or red discoloration of the skin with localised swelling and tenderness, and discharge from the nipple or skin); seek evidence of musculoskeletal disorders of the cervical and dorsal spine and shoulder. Identify any features of costochondritis (Tietze s Syndrome). Breast pain is a common symptom and if of short duration with no other clinical concern may be managed initially in a primary care setting.

20 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS Imaging When there are associated, or incidental, focal clinical signs in the breast (localised tenderness, nodularity, swelling or a lump) follow the lump imaging protocol (2.3). If infection or abscess is suspected an initial ultrasound scan should be performed and any fluid or pus aspirated and cultured. Breast pain alone is not an indication for imaging. Outcome of assessment Full clinical assessment and imaging as appropriate Verbal and written advice provided on the management of symptoms Referral back to GP with summary of assessment and advice Offer of review for severe or unremitting symptoms 2.6 Axillary lump (in absence of clinical breast abnormality) Assessment Clinical assessment In patients presenting with a lump in the axilla alone with no known clinical abnormality of the breast, information about the duration of symptoms, localised tenderness and other intercurrent illness or condition associated with more generalised lymphadenopathy should be obtained. Clinical examination should determine whether the lump is likely to be related to ectopic breast tissue, enlarged axillary nodes or skin related. A general physical examination should be performed if a systemic cause is suspected. Mammography may demonstrate an abnormality on the oblique view and ultrasound and core biopsy should be carried out where appropriate. Outcome of assessment If core biopsy demonstrates metastatic carcinoma and mammography is normal, MRI of the breast is indicated as well as more general screening for primaries elsewhere. Other investigations may be needed for abnormal core biopsy results such as for lymphoma, TB and sarcoidosis, along with appropriate clinical reassessment. Where no significant underlying abnormality is identified, refer back to GP with summary of assessment and advice.

21 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS 2.7 Women with breast implants Assessment Clinical assessment History: in women with breast implants symptoms may be incidental or related to the implant, including changes in texture, size or shape; following reconstructive surgery for previous breast cancer there may be concern about recurrence. Record the original reason for the implant (augmentation or reconstruction); the site, i.e. submuscular or subglandular; the nature of any associated reconstructive procedure e.g. latissimus dorsi flap; the date of surgery and type of implant used. If there are symptoms of pain or lump record details as under above protocols. Clinical examination: note any breast lump, swelling or distortion, and examine nodes. Assess the state of the implant: size, position, shape, and capsular contracture: Baker Grade I the breast is normally soft, and looks natural Baker Grade II the breast is a little firm, but appears natural Baker Grade III the breast is firm, and is beginning to appear distorted in shape Imaging Baker Grade IV the breast is hard, and has become quite distorted in shape For investigation of findings in the breast tissue: the protocols described above apply, to include ultrasound and mammography as indicated. Performing needle biopsy of any breast lesion under ultrasound guidance is advisable to reduce risk of damage to the implant. Mammography can be performed by compressing the breast in front of the implant, though it is not possible to achieve full imaging of the breast tissue. For investigation of integrity of implant: ultrasound scanning may identify possible disruption or leakage. MRI may be considered following MDM discussion in some circumstances to clarify suspicious new or recurrent breast lesions, to determine with more certainty if there is implant disruption, and to identify if there is intraor extra-capsular rupture.

22 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS Outcome of assessment Full clinical assessment and imaging as appropriate Advice provided on the management of symptoms Referral back to GP with summary of assessment and advice Assessment of need for revisionary surgery Offer of review for severe or unremitting symptoms 2.8 Breast lumps in men Male breast cancer is rare (around 300 cases are diagnosed per year in the UK; around 46,000 cases are diagnosed in women each year), whereas gynaecomastia (benign enlargement of male breast tissue) is a very common finding in normal men, with peaks of around 60% at puberty and over 50 years. Numerous drugs and a variety of medical conditions including testicular tumours may be associated with gynaecomastia. Cancer is diagnosed in only about 1% of cases of male breast enlargement. Male breast cancer can be a distressing and difficult experience for both men and their families and appropriate support from the breast care nurse may be needed. Referral for further assessment is indicated in those with: clinical suspicion of malignancy no obvious physiological or drug cause unilateral lump persistent pain and swelling increased risk such as family history; Klinefelter s syndrome; androgen deficiency or oestrogen excess Assessment Clinical assessment QI4 History: in addition to the standard assessment of a breast lump, record any relevant history of prescribed, illicit or recreational drug use including alcohol consumption and (anabolic) steroids. Clinical examination: record findings in the breasts (P1-5) and nodal areas, examine the testicles for evidence of tumour, and note any evidence of chronic liver disease. Differentiate between true gynaecomastia with enlargement of glandular tissue and fatty male breast enlargement ( pseudogynaecomastia ) related to obesity. Identify features of feminisation and consider need for referral for an endocrine assessment.

23 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS Imaging QI5 QI6 Mammography and/or ultrasound scanning should be performed in men with unexplained or suspicious unilateral breast enlargement and the results recorded as M1-M5 and U1-U5 as appropriate. Imaging may also be used if there is clinical uncertainty in differentiating between true gynaecomastia and fatty breast enlargement. Testicular ultrasound scanning should be performed if there is any suspicious finding on testicular clinical examination, or raised αfp or βhcg. Blood tests Hormone profile (testosterone, oestradiol, prolactin, Luteinising Hormone, αfp, βhcg,), thyroid and liver function tests should be obtained in men with true gynaecomastia. Blood tests are not indicated in those with fatty breast enlargement, physiological pubertal or senile changes, identified drug cause, or clinically obvious cancer. QI15 Biopsy Needle core biopsy should be performed following imaging in those patients with uncertain or suspicious clinical or radiological findings (any one of P3-5, U3-5, M3-5). Fine needle aspiration is not to be recommended. Outcome of assessment Full clinical assessment, blood tests and imaging as appropriate Advice provided on the management of symptoms including medical therapy Assessment of need for referral for endocrine assessment Referral back to GP with summary of assessment and advice Assessment of need for surgery and in consideration of local PCT rules Offer of review for severe or unremitting symptoms Provision of appropriate patient support

24 BEST PRACTICE DIAGNOSTIC GUIDELINES FOR PATIENTS PRESENTING WITH BREAST SYMPTOMS 3: Multidisciplinary meeting 3.1 The Multidisciplinary Meeting (MDM) QI17 The purpose of the MDM is to ensure that patients who have undergone full triple assessment including needle biopsy receive the correct diagnosis and advice regarding management. All patients who undergo needle biopsy during assessment should be discussed. Patients in whom there is a discrepancy between the clinical findings and imaging should be discussed in order to decide whether further investigation should be undertaken. The results of each of the elements of the Triple Assessment should be discussed to ensure that there is concordance of the results when deciding on the final diagnosis and management. The outcome for most cases discussed at the MDM will either be a definitive diagnosis of cancer or benign disease. Treatment is planned for those patients with cancer according to National Guidelines. The majority of patients with benign disease can be discharged from the clinic. Further review and/or diagnostic intervention may be required following initial assessment for the following: discordance between elements of the Triple Assessment e.g. persistent suspicious clinical findings and normal imaging equivocal biopsy results e.g. B3, B4 core biopsy severe breast pain where assessment of treatment is required breast inflammation, infection, cellulitis, abscess nipple discharge if causing significant symptoms, for potential surgical intervention trauma Mondor s disease The MDM is an ideal forum in which to identify patients who can be offered the opportunity to take part in clinical trials.

25 Organisation of the MDM QI18 QI19 QI20 All key members of the MDM should be present in person or via video link to ensure full multidisciplinary discussion before the final result is communicated to the patient. The diagnostic MDM must include pathologist, radiologist or consultant radiographer in breast imaging, surgeon or breast clinician and breast care nurse. The lead clinician is responsible for accurate recording of the results of the MDM discussion and for ensuring that this is audited. A lead clinician should be appointed for the MDM to ensure that there is good interprofessional communication, that the key personnel required are in attendance and that this attendance is recorded.

26 26 MANAGEMENT OF NON-MALIGNANT CONDITIONS OF THE BREAST A. MASTALGIA Cyclical breast pain should be initially managed in primary care with reassurance, analgesics, evening primrose oil supplements and a good support bra. Failure to respond to these measures should be investigated in a breast unit. In cases of intractable pain, patients may be tried on anabolic steroids such as Danazol for a short period of 3 months. Tamoxifen is unlicensed for use in mastalgia but has shown to have greater efficacy than evening primrose oil or anabolic steroids and may be used for a short period of 3 months. B. BENIGN BREAST CHANGE Benign breast change is fairly common in premenopausal women. Reassurance and explanation is sufficient in majority of the women. Regular follow up is not recommended. C. BREAST CYST/S Simple cysts do not require intervention or follow up. If a residual lump is present following aspiration of a cyst or if the aspirate is blood stained, the fluid should be sent for cytology and a core biopsy also considered. If the

27 27 cytology and biopsy results are benign, no follow up is necessary. Biopsy is also indicated where there is suggestion of an intracystic lesion on ultrasound scan. D. FIBROADENOMA A Fibroadenoma is a benign condition. Majority will remain unchanged or static in terms of size. Some small lesions may even disappear. It is not necessary to remove a fibroadenoma. It is reasonable to remove a fibroadenoma if it has significantly increased in size or is causing pain. E. DUCT ECTASIA This may cause nipple discharge which sometimes may be blood stained. Where this is profuse and socially embarrassing, total excision of the ducts will provide permanent relief. F. PERIDUCTAL MASTITIS Periductal mastitis tends to occur in the younger women and can result in recurrent breast abscesses. Mammary fistula may also occur. The condition is strongly related to smoking. Breast abscesses should be treated by ultrasound guided drainage. The pus should be dilute with an infiltration of local anaesthetic plus saline to enable it to be aspirated completely. Repeated aspirations may be required. Surgical drainage is required exceptionally. The patient should be asked to stop smoking as recurrence is common amongst smokers. Mammary fistula will need to be excised surgically with the terminal duct lobular unit. This may be combined with total excision of the ducts. G.PAPILLOMA Majority of the intraduct papillomas are benign. However, because of the small incidence of malignant change in parts of the papilloma, excision is advised. The excision may be achieved by a Vacuum Assisted Biopsy (VACB) device or by surgery.

28 28 H.RADIAL SCARS Radial scars are benign entities that are seen on mammograms as distortion. Provided the lesion is sampled by a VACB and there is no atypia, surgical excision is not required. Surgical Management of Breast Cancer A. GENERAL PRINCIPLES The management of breast cancer should occur within a multidisciplinary team (MDT) Every case must be discussed in an MDM with the MDT prior to treatment being initiated A Breast Care Nurse Specialist must be present when the patient is given the results Staging tests are not necessary unless there are symptoms suggestive of metastatic disease or the tumour is locally advanced or in inflammatory breast cancer Where surgery is the first treatment, this should take place within 31 days of the diagnosis being made and at least 70% of the breast cases should be done as day case surgery The patients choice must always be respected Where the patient is eligible for a clinical trial, the trial should be fully explained to the patient including the eligibility criteria and randomisation B. SURGERY

29 29 Where feasible, surgery is the first treatment for breast cancer. SURGICAL TREATMENT OF THE BREAST CANCER: Majority of patients with breast cancer will be suitable for breast conservation. However, it is important to ensure that conservation surgery will leave the patient with an aesthetically acceptable breast. With the advent of oncoplastic surgery, the indications for mastectomy need to be considered according to the service available locally. Indications for mastectomy: Multifocal tumours whether invasive or non-invasive ( especially high grade DCIS) Extensive DCIS of high or intermediate grade- it is debateable whether low grade DCIS needs to be treated with a mastectomy Recurrent tumour is a previously treated breast Large tumour in a small breast- neoadjuvant chemotherapy may make breast conservation feasible in these cases Where radiotherapy may be contraindicated- excessive photosensitivity, vasculitis, severe pulmonary fibrosis, PATIENT CHOICE Breast conservation surgery Wide local excision Quadrantectomy Oncoplastic resection with partial breast reconstruction with volume displacement or replacement including therapeutic mammaplasty LIGACLIPS TO BE APPLIED TO THE CAVITY MARGINS IN ALL CASES SURGICAL MANAGEMENT OF THE AXILLA: In all cases where the axilla is clinically or radiological uninvolved, the axilla should be staged by sentinel node biopsy using the combined technique. Where for technical reasons radioisotope localisation is not possible, it is acceptable to carry out Patent Blue V guided 4 node sampling of the axilla

30 30 Where the axilla is involved, clearance to level 2 is the minimum acceptable standard. Presence of macroscopic disease at level 2 is an indication for level 3 clearance RECONSTRUCTIVE SURGERY ALL WOMEN FACING THE PROSPECT OF A MASTECTOMY SHOULD BE OFFERED RECONSTRUCTION AND COUNSELLED APPROPRIATELY A full and detailed explanation of the different options should be given with the pros and cons of each technique o Implant based reconstruction o Latissimus doris and implant o AUTOLOGOUS TISSUE TRANSFER PEDICLED FLAPS Extended LD flap Pedicled TRAM flap FREE FLAPS Free TRAM Muscle sparing TRAM DIEP FLAP SGAP FLAP

31 Radiotherapy after Breast Conserving Surgery and Axillary Node Clearance 1.1 Background: Radiotherapy to the whole breast is recommended following breast conserving surgery (BCS) as this is an established means of reducing the risk of local recurrence and compared with more extensive surgery it does not compromise survival [1,2,3]. 1.2 Recommendations: 1. Women who undergo BCS should be advised to have postoperative breast irradiation. Omission of radiation therapy after BCS increases the risk of local recurrence (20 year local recurrence rate 39% without radiation, 14% with radiation [1]). For women over the age of 65 there is a randomized control trial (PRIME 2) assessing whether radiotherapy can safely be omitted in low risk, node negative, ER positive invasive disease following BCS. 2. Contraindications to breast irradiation include: pregnancy, previous breast irradiation (including mantle irradiation for Hodgkin s disease) inability to lie flat or to abduct the arm Relative contraindications include: severe lung disease severe cardiac disease (left sided tumours) scleroderma / systemic lupus erythematosus (increased rates of acute and late radiation effects have been reported in patients with pre-existing collagen vascular disease [4,5]) The above patients should be discussed with the clinical oncologist in an MDM and if there is any doubt as to their suitability for radiotherapy they should be seen by the clinical oncologist prior to surgery. 3. A number of different fractionation schedules for breast irradiation have been used. Although the most common fractionation schedule used in clinical trials is 50 Gy in 25 fractions, 40Gy in 15 fractions is a widely used fractionation regime in the UK and the START trial has recently shown that 40Gy/15fractions is equivalent to 50Gy in 25 fractions both in terms of local control and cosmetic

32 32 outcome [6]. We would therefore currently recommend the use of the shorter fractionation in all women irrespective of breast size or nodal irradiation [7]. 50Gy in 25 fractions may be used in patients with: connective tissue disease ( as radiotherapy can be discontinued in the 5 th week if patient develops a severe acute radiation reaction) very high risk of local recurrence heavily node positive or inflammatory breast cancer (as 50Gy in 25 fractions is a slightly higher total dose compared to 40Gy/15 fractions equivalent to 46-48Gy in 2Gy fractions) locally advanced breast cancer with no prior surgery 4. Patients with 4 or more axillary nodes containing metastatic disease should be offered supraclavicular fossa irradiation due to the high risk of nodal relapse. 5. Patients who have a confirmed cytological (C5) diagnosis of axillary lymph node involvement prior to neoadjuvant therapy should have an axillary clearance after it. The role of SNB in judging down-staging of the whole axilla as a predictor long-term axillary control is insufficiently proven to allow avoidance of axillary dissection surgery or to rely on axillary radiotherapy alone. 6. Patients who have any degree of lymph node involvement after neoadjuvant therapy should be offered supraclavicular fossa radiotherapy as the use of posttherapy axillary involved node numbers is unproven for risk assessment. 7. Absence of pathological node involvement after primary chemotherapy, where patients had clinically and/or cytologically positive axilla prior to therapy, is an unproven indicator of low risk of loco regional recurrence and management must be individualised based on pre-treatment clinical / imaging stage. 8. Additional irradiation to the lumpectomy site (boost irradiation) reduces local recurrence in women at high risk of local recurrence. Please see boost protocol 9. Patients must be made aware of the acute and late complications that can result from radiation therapy and the departmental side effect sheet should be discussed with them. 10. Breast irradiation should be started as soon as possible after surgery and not later than 12 weeks after, except for patients in whom radiation therapy is preceded by chemotherapy. However, the optimal interval between BCS and the start of irradiation has not been defined. 1.3 Summary:

33 33 1. Breast Irradiation Only Indications: following breast conserving surgery and node negative/1-3 nodes positive Dose: 40Gy/15# 2. Breast and Supraclavicular Fossa Irradiation Indications: following breast conserving surgery and 4 or more nodes positive Dose: 40Gy/15# AREA OF UNCERTAINTY- SCF irradiation in the 1-3 node positive group Grills et al [8] showed in a retrospective series (255 patients with 1-3 nodes and 80 with 4 nodes involved) that if a lymph node metastasis was 2cm or more in size, the risk of SCF relapse was 44% (median follow-up of 8.1 years) and on multivariate analysis, the only significant predictor of nodal relapse was the maximal size of the nodal metastasis. On the basis of this, some clinicians may wish to discuss SCF irradiation with patients who have 1-3 nodes positive with a nodal deposit measuring 2cm or more. Note: all patients will 1-3 nodes involved after neoadjuvant therapy should receive SCF radiotherapy. 3. Boosts please see section 4.0.

34 Radiotherapy Post Mastectomy and Axillary Node Clearance 2.1 Background: Post mastectomy radiotherapy, PMRT, (chest wall & regional lymph nodes) has been demonstrated in at least 18 randomized controls trials to improve loco-regional control particularly in node positive patients (1). Three of the more recent trials have also shown a survival benefit in node positive patients (2,3,4). Radiotherapy reduces the risk of loco-regional recurrence by two thirds and it is estimated that if vascular morbidity could be eliminated a 2-4% 20 year improvement in survival from radiotherapy might be achieved (1). In these trials patients with 4 or more nodes positive get the most benefit from PMRT. The benefit for patients with 1-3 nodes positive is less clear and these women should be given the opportunity of participating in a clinical trial (SUPREMO). 2.2 Recommendations: Chest Wall and SCF Irradiation (including post reconstruction) Indications: 1. Greater than 4 nodes positive post mastectomy and ANC 2. Patients who have any degree of lymph node involvement after neoadjuvant therapy should be offered chest wall and supraclavicular fossa radiotherapy as the use of post-therapy axillary involved node number is unproven for risk assessment. Note: Patients who have a confirmed cytological (C5) diagnosis of axillary lymph node involvement prior to neoadjuvant therapy should have an axillary clearance after it. The role of SNB in judging down staging of the whole axilla as a predictor long term axillary control is insufficiently proven to allow avoidance of axillary dissection surgery and reliance on axillary radiotherapy alone. Dose: 40Gy/15#

35 35 Use 1cm Bolus FIRST 7 fractions if skin involvement at presentation 50Gy in 25 fractions may be used in patients with: connective tissue disease ( as radiotherapy can be discontinued in the 5 th week if patient develops a severe acute radiation reaction) very high risk of local recurrence heavily node positive or inflammatory breast cancer (as 50Gy in 25 fractions is a slightly higher total dose compared to 40Gy/15 fractions equivalent to 46-48Gy in 2Gy fractions) AREA OF UNCERTAINTY- SCF irradiation in the 1-3 node positive group Grills et al (5) showed in a retrospective series (255 patients with 1-3 nodes and 80 with >/=4 nodes involved) that if a lymph node metastasis was 2cm or more in size, the risk of SCF relapse was 44% (median follow-up of 8.1 years) and on multivariate analysis, the only significant predictor of nodal relapse was the maximal size of the nodal metastasis. On the basis of this some clinicians may wish to discuss SCF irradiation with patients who have 1-3 nodes positive with a nodal deposit measuring 2cm or more. These patients will also be eligible for the SUPREMO TRIAL Chest wall irradiation only (including post reconstruction) Indications: 1. T3/T4 tumour stage (assessed prior to any neoadjuvant therapy) (who do not fall into category 1) 2. Discuss in patients who have 1-3 nodes positive (who have not had neoadjuvant therapy see above) especially in the presence of other risk factors (young age, Tumour>2cm, high grade, presence of LVI, ER negative ) as in this group in retrospective series (6,8) the risk of loco-regional relapse at 10 years is 20-30% and 2005 Oxford overview suggests a small survival advantage (but based on

36 36 old trials without up-to-date systemic therapy) OR ENTER INTO SUPREMO TRIAL. 3. Discuss in patients who are node negative with T2 tumours that are grade 3 with LVI as in retrospective series [7] the risk of loco-regional relapse at 10 years is 20% OR ENTER INTO SUPREMO TRIAL. (T2, N0 grade 3 tumours with no LVI are also eligible for SUPREMO the risk of LRR in this group is estimated as 13% & rises to 23% if no systemic treatment is given [7] - if patient refuses entry into SUPREMO then they will be offered standard treatment i.e. no radiotherapy) 4. Absence of pathological node involvement after primary chemotherapy, where patients had a clinically and/or cytologically positive axilla prior to therapy, is an unproven indicator of low risk of loco regional recurrence and management must be individualised based on pre-treatment clinical / imaging stage. Dose: 40Gy/15# Use 1cm Bolus FIRST 7 fractions if skin involvement at presentation 50Gy in 25 fractions may be used in patients with: connective tissue disease ( as radiotherapy can be discontinued in the 5 th week if patient develops a severe acute radiation reaction) very high risk of local recurrence heavily node positive or inflammatory breast cancer (as 50Gy in 25 fractions is a slightly higher total dose compared to 40Gy/15 fractions equivalent to 46-48Gy in 2Gy fractions)

37 Management for Stage III Breast Cancer The management of Stage III breast cancer requires a combined modality treatment approach involving surgery, radiotherapy and systemic therapy. 3.1 Staging All patients should have urgent staging investigations (1). These should include: FBC, Renal, Liver and Bone profiles CT scan of thorax and abdomen A bone scan TNM (tumor, node, metastasis) staging system: Classification Value Tx T0 Tis Tis(DCIS) Tis(LCIS) Tis(Paget's) T1 T1mic T1a T1b T1c T2 Definition Primary tumor cannot be assessed No evidence of primary tumour Carcinoma in situ Intraductal Carcinoma in situ Lobular Carcinoma in situ Paget's disease of the nipple with no tumor Tumor 2 cm or less in its greatest dimension Microinvasion 0.1 cm or less in greatest dimension Tumor more than 0.1 cm but not more than 0.5 cm in its greatest dimension Tumor more than 0.5 cm but not more than 1.0 cm in its greatest dimension Tumor more than 1.0 cm but not more than 2.0 cm in its greatest dimension Tumor more than 2.0 cm but not more than 5.0 cm in its greatest dimension

38 38 T3 T4 Tumor more than 5 cm in its greatest dimension Tumor of any size with direct extension to (a) chest wall or (b) skin as described below: T4a T4b T4c T4d Extension to chest wall Oedema (including peau d'orange) or ulceration of the breast skin, or satellite skin nodules confined to the same breast Both T4a and T4b Inflammatory breast cancer Nx N0 N1 N2 N3 Mx M0 M1 Regional lymph nodes cannot be assessed. no regional lymph node metastasis metastasis to movable regional axillary lymph nodes on the same side as the affected breast Metastasis to fixed regional axillary lymph nodes or metastasis to the internal mammary lymph nodes, on the same side as the affected breast. metastasis to supraclavicular lymph nodes or infraclavicular lymph nodes or metastasis to the internal mammary lymph nodes with metastasis to the axillary lymph nodes clinical information about spread of cancer to other body sites is not available at the time the cancer pathology report is written No distant metastases Distant metastases present (e.g. to bone, brain or lung)

39 Systemic therapy: chemotherapy Operable tumours Patients with operable stage IIIA disease are at high risk of development of distant metastases and should be offered adjuvant/neoadjuvant chemotherapy (see adjuvant systemic therapy guidelines). If breast conserving surgery cannot be attempted or breast size indicates wide excision is likely to be associated with involved margins, neoadjuvant systemic therapy should be offered if the MDM feels this will raise the chance of breast conservation. (3, 4) In women who have primary modified radical mastectomy adjuvant systemic therapy and radiation therapy should be guided by definitive pathological stage, grade, and hormone and HER2 receptor status (please see neo-adjuvant chemotherapy and post-mastectomy radiotherapy guidelines). Adjuvant endocrine therapy should follow chemotherapy. In women who are suitable for primary systemic therapy, to attempt breast conservation neoadjuvant chemotherapy should currently be considered the optimal choice in women fit to receive it. In women who are fit enough to receive taxane based chemotherapy, this is considered the optimal choice as it is associated with optimal response and thus tumour de-bulking to achieve breast conservation(5). It is also associated with improved survival in one randomised study(3, 4). The most usual regimen would be AC X 4 followed by docetaxel X 4 (5). If this is not suitable FEC X 6 cycles should be considered. Patients with HER2 +ve disease should receive Herceptin concomitant with the taxane component of the regimen. (Please see adjuvant systemic therapy guidelines for regimen details). Progression of disease on AC chemotherapy should lead to change to docetaxel for a total of 6-8 cycles of chemotherapy with close observation for progression leading to urgent surgical review. Progression on docetaxel should precipitate urgent surgical review. Post menopausal patients with ER +ve tumours but not fit to receive chemotherapy should receive neoadjuvant endocrine therapy. (see below) Inoperable tumours

40 40 Patients with stage IIIB or IIIC disease, including those with inflammatory breast cancer and those with isolated ipsilateral internal mammary or supraclavicular lymph-node involvement, should be treated with primary chemotherapy followed by loco regional management to include both mastectomy (where possible) and loco regional radiation (see below). Patients should meet a Clinical Oncologist at initial visit or at least within the first two cycles of chemotherapy. In women who are fit enough to receive taxane based chemotherapy (with Herceptin in HER2 +ve cases), this is considered the optimal choice as it is associated with optimal response and thus tumour de-bulking before loco-regional therapy as discussed above. (Please see neo-adjuvant systemic therapy guidelines) Progression of disease at any point should precipitate urgent both senior surgical and oncology review to consider relative merits of a change of chemotherapy or urgent locoregional therapy. Even in the setting of response the patient should be reviewed by a senior breast surgeon and clinical oncologist at the time of the final treatment cycle to plan locoregional therapy. 3.3 Systemic therapy: hormonal therapy Women with Stage III breast cancer are at high risk of distant recurrence and should always be considered, where appropriate, for adjuvant or neo-adjuvant chemotherapy. (See systemic therapy guidelines) Women with both operable and inoperable tumours that are hormone receptor positive should receive either adjuvant or neoadjuvant endocrine therapy. After completion of chemotherapy and surgery 5 years of tamoxifen should be recommended to women who were premenopausal prior to chemotherapy. The additional use of an LHRH agonist may be considered as discussed (See systemic therapy guidelines)

41 41 Postmenopausal women whose tumours are ER+ve should receive 5 years of an aromatase inhibitor (Anastrazole or Letrozole) after completion of chemotherapy (see adjuvant endocrine therapy guidelines). Postmenopausal women not fit enough for neoadjuvant chemotherapy should be considered for neoadjuvant endocrine therapy with an aromatase inhibitor (Anastrazole or Letrozole)(6, 7). 3.4 Radiotherapy to the chest wall / breast reconstruction site / nodal areas Operable tumours - chest wall / breast reconstruction site Patients with stage IIIA disease should receive both definitive surgery and locoregional radiotherapy if feasible. Those who are deemed to by the MDM to be unsuitable for attempts at breast conservation may be managed by mastectomy followed by chemotherapy and locoregional radiotherapy, or chemotherapy first followed by MRM and locoregional radiotherapy. Breast-conserving surgery and radiotherapy with axillary clearance may be considered after neoadjuvant chemotherapy in patients presenting with T3 N1 disease. Final margins of excision must be microscopically clear of tumour by at least 2mm or re-excision or MRM be considered. Radiotherapy should be delivered to the chest wall or conserved breast in all Stage IIIA patients (see post mastectomy radiotherapy guideline). NB. Patients receiving neo-adjuvant chemotherapy for Stage I / II breast cancer then treated by mastectomy with T2 tumours of <5cm that are also node negative by USS +/- FNAC on pre-chemotherapy imaging and pathologically node negative at axillary surgery, will not usually require chest wall radiotherapy Operable tumours - Lymph node areas Patients who have a confirmed cytological (C5) diagnosis of axillary lymph node involvement prior to neoadjuvant therapy should have an axillary

42 42 clearance after it. The role of SNB in judging down staging of the whole axilla as a predictor long term axillary control is insufficiently proven to allow avoidance of axillary dissection surgery or to rely on axillary radiotherapy alone. Radiotherapy to the supraclavicular fossa should generally be delivered in stage III breast cancer. Exceptions are those who have <4 pathologically involved axillary nodes at axillary clearance and did not receive neoadjuvant therapy (see Regional Nodal Radiation guidelines). Absence of pathological node involvement after primary chemotherapy, where patients had clinically and/or cytologically positive axilla prior to therapy, is an unproven indicator of low risk of locoregional recurrence in an otherwise high risk population and should not guide recommendations with regard radiotherapy. The role of internal mammary chain (IMC) irradiation is unclear and should not be performed outside a clinical trial Inoperable tumours Patients unsuitable for neoadjuvant systemic therapy or inoperable despite it. These patients should be considered for radical radiation therapy to the breast supraclavicular fossa and axilla guided by original CT staging data (and repeat CT Neck and thorax if progression) Radiotherapy should be CT simulated and delivered using 6MV photons with bolus to the breast skin for at least half of the treatment fractions (bolus through out over areas of continued skin involvement) A three phase shrinking field technique should be considered. Phase I to whole breast tangents and regional nodes 50Gy in 25 fractions / 5 weeks A posterior axilla field should be considered in women where there is macroscopic disease in the axilla or the dose in the axillary canal is <85% of the prescribed dose. In this circumstance a maximum total dose should not exceed 55 Gy in 25 fractions at any point in the SCF/axilla. Phase II reduced whole breast tangents to all original disease (with rib sparing if possible) 10Gy in 5 fractions. Axilla or SCF electron boost Phase II if palpable residual nodal disease at start of radiotherapy.

43 43 Phase III breast electron boost to area of macroscopic residual disease marked at start of radiotherapy Gy in 3-5 fractions. Mastectomy should be re-considered if the tumour becomes operable >/= to 6 weeks after radiotherapy(1, 8). Tumours operable after neoadjuvant systemic therapy Patients with stage IIIB disease who become operable should then undergo modified radical mastectomy and locoregional radiation to the chest wall and SCF(1, 8, 9). The locoregional management of patients with stage IIIC or true inflammatory breast cancer should be individualized. Analysis of SEER and other data indicates that, despite advanced stage, long term survival is achieved in many patients with modern therapy(10, 11). Local control is thus an important issue. If the tumour becomes operable, modified radical mastectomy should discussed to optimise lifetime locoregional control and minimise complications from high dose radiotherapy (1, 8, 12-14). This should be followed by chest wall and SCF radiotherapy(9, 11). If mastectomy is declined macroscopic tumour should, where possible, be resected and axillary dissection be performed(15, 16). This should be followed promptly by radiotherapy to the breast and SCF. 3.5 Breast Reconstructive Surgery and Radiotherapy in Stage III breast cancer Patients with stage III breast cancer having mastectomy should be carefully counselled about breast reconstructive options early in the course of therapy. Immediate breast reconstruction has the potential to significantly delay adjuvant therapies in women at high risk of micro-metastatic disease and locoregional recurrence but if delay does not occur then recurrence outcomes appear acceptable(17). Women with inflammatory breast cancer or T4 disease should be discouraged from immediate reconstruction particularly with skin sparing techniques. If delayed

44 44 reconstruction is unacceptable then chemotherapy and adjuvant pre-operative radiation therapy should precede mastectomy and immediate reconstruction. If, despite understanding a potentially increased risk of recurrence, a woman wishes immediate reconstruction her onco-plastic surgeon should be informed of the need for subsequent radiation therapy as they may wish to avoid an implant based reconstructions with associated increased risk of implant capsulitis (18). Radiotherapy should commence as soon as possible after post-operative healing.

45 Guidelines on the Use of Boost Radiotherapy to the Breast Tumour Bed (SELCN Breast TWG) 4.1 Localisation of the target volume, treatment technique and beam quality Network Guidelines now state that the wide local excision cavity should be marked with pairs of ligaclips at the medial, lateral, superior, inferior and deep cavity edges. The anterior edge of the cavity should also be marked with clips if the surgical scar is not located above the tumour bed. The number and position of clips should be documented in the operation note. Absence of clips should be noted and the consultant surgeon informed. The tumour bed clinical target volume (CTV) includes the volume enclosed by the clips and any changes in surrounding tissue architecture on CT felt to be target. The CTV should be increased if the surgical margins are less than 5mm. An anisotropic margin of 5mm in the direction of the close surgical margins should be added. A further margin is also necessary if there are no clips marking the excision cavity. This will be on an individual patient basis and should be a rare occurrence. The CTV should be modified if the volume produced is felt to be clinically inappropriately large and could potentially increase the risk of late normal tissue complications. The planning target volume (PTV) includes the tumour bed CTV plus a uniform 5mm margin. It must be confirmed that a clinically marked boost is correctly localised to treat the tumour bed as described in the boost simulation protocol. The PTV for the boost should be treated with electrons that must be prescribed to the 100% isodose or Dmax to conform to ICRU recommendations. An additional 1cm margin is added to the boost PTV to account for electron beam penumbra. 4.2 Eligibility for a tumour bed boost and dose fractionation The recommendation for a boost should take into account the individual s risk of local recurrence in the tumour bed and the risk of late normal tissue complications added by the boost irradiation. These might be greater for shallow breast tissue over ribs, heart and in the cosmetically more significant upper medial quadrant.

46 46 The following recommendations are made based on a risk based assessment. For women recommended a boost, those at high or moderate risk of local recurrence are given 16Gy in 8 daily fractions and those at lower risk 10Gy in 5 daily fractions, regardless of the breast tangential field schedule. 4.3 High Recurrence Risk Women of 40 years of age or younger should have a boost : Age under 40 is the strongest independent risk factor for local recurrence after 50Gy in 25 fractions, at rates of 20% at 5 years and approaching 30% at 8 years. An additional dose of 16Gy in 8 fractions to the tumour bed reduces recurrence rate to 10% at 5 years 1. Tumour involving resection margins (all age groups): All women who have microscopic tumour present at a resection margin, and where re-excision or mastectomy is declined, should be considered for a boost. The recommended boost dose for this High Risk group is 16Gy in 8 daily fractions Moderate Recurrence Risk Women of years of age: Women in this age group, taken overall, still appear to gain from an electron boost of 16Gy in 8 fractions in the 2006 update of the EORTC trial The relative reductions in risk of recurrence are the same regardless of age. The absolute benefits are lower than in women under 40 yrs of age 3. The recommended boost dose for this Moderate Risk group is 16Gy in 8 daily fractions 1 For those at higher risk of late effects or poor cosmesis 10 Gy in 5 fractions may be used. 4.5 Lower Recurrence Risk Women of 60 years of age and older: Women in this age group, taken overall, have a 5 year local recurrence risk of <5% after whole breast radiotherapy alone and gained no significant benefit from a tumour bed boost in the first analysis of the EORTC boost vs. no boost trial. 1 The most

47 47 recent update of the trial suggests that women over 60 yrs may safely avoid an additional radiotherapy boost 3. A boost could be considered for the sub-group of women in this age group with two or more of the following adverse features: margins of <5mm (but not involving resection margin - involved margins = high risk). A tumour that is palpable at presentation 1 PgR ve tumour Grade 3 LVI +ve lack of systemic adjuvant therapy As the absolute benefits are likely to be more modest, the risk of late toxicity and effects on cosmesis should be considered carefully in those with upper medial quadrant tumours, shallow breast tissue and tumours overlying heart. In view of the more modest benefits in this lower risk group a boost dose of 10Gy in 5 daily fractions 2,is recommended to reduce the likelihood of late toxicity.

48 Radiotherapy Referral: 5.1 Consent This is completed following the Radiotherapy Department s guidelines, Consent in Radiotherapy PM 2.031, using Department of Health consent forms and GSTFT information booklets. 5.2 Radiotherapy Request A Radiotherapy Request form is completed in full (either electronically or a paper copy), signed and handed in to the Activations team. 6.0 Radiotherapy Planning 6.1 Position & Immobilisation All patients are to be planned and treated using the SinMed Breast Board unless otherwise stated by the referring Practitioner in line with departmental protocol PT CT Scanning for Breast Patients. 6.2 CT Planning Scan Patients are scanned according to PT CT Scanning for Breast Patients. 6.3 Delineation of Target Volumes Although all breast and chest wall radiotherapy with or without nodal fields is planned in 3 dimensions using 3D CT imaging, the classical GTV, CTV and PTV is not used in the same way as for other tumour sites. For breast radiotherapy, the GTV could be described as the whole breast with a 0.5-1cm margin for the CTV excluding skin and chest wall. An additional 1cm margin could be added for the PTV. However for breast, chest wall and nodal radiotherapy we continue to define fields as detailed below.

49 49 Breast tangential fields standard borders marked up at CT and reviewed: Superior: sternal notch Medial: midline Lateral: 1cm behind breast tissue (likely to be mid axillary line) Inferior: 1cm below breast tissue Using CT scan borders the fields are modified to cover PTV while minimising dose to organs at risk; <2cm lung distance ant to post throughout field length with consideration of total lung volume, <1cm heart distance for left sided radiotherapy. If border compromise is needed to achieve these normal tissue constraints, the border furthest from the tumour bed is altered first. Ideally all patients have surgical clips in their tumour bed to aid delineation and a marker on their surgical scar at CT. Chest wall tangential fields: as for breast tangents above. Use contralateral breast to aid localisation. Supraclavicular fossa +/- axillary radiotherapy. Similar principles apply. The classic GTV is the surra and infraclavicular fossa nodes with a 1cm margin for CTV and 1 cm margin for PTV. We plan these treatments with fields as defined below: Superior: cover clavicle with 1cm margin (except if clavicle lying very vertically making field very long towards chin etc) Inferior: matched to superior border of tangential field Medial: adjacent to the pedicles of the spinal vertebra checking on the axial scans to avoid spinal cord overlap Lateral: the edge of the chest wall where border meets ribs Lateral border extended if axilla to be included preferably using surgical axillary clips to mark extent of axillary surgery. 7.0 Selection of Optimal Plan and Normal Tissue Dose Constraints:

50 50 The plan is reveiewed in 3D with the aid of the dosimetrists and physicists. The PTV is covered to 95% with the Gmax of 107% or less as per ICRU definition. Unless stated by the clinician, the skin is not necessarily included in the 95% isodose. The anterior chest wall including pectoral muscle and ribs is included in the 95% to allow for set up variation and the patient breathing during radiotherapy. The organs at risk are: Lung: usually well within tolerance but the V20 is 20Gy Heart: shielded with MLC if >1cm distance unless compromises tumour bed coverage. 8.0 Dose Prescription: Site Prescription Considerations Breast Only Breast and SCF Chest Wall only (including post reconstruction) 40Gy in 15 prescribed to100% delivered over 19 to 22 days 40Gy in 15 prescribed to100% delivered over 19 to 22 days 40Gy in 15 prescribed to100% delivered over 19 to 22 days 1cm bolus FIRST 7 if skin involvement at presentation Chest Wall and SCF (including post reconstruction) Alternative fractionation for above, if any of considerations listed are met 40Gy in 15 prescribed to100% delivered over 19 to 22 days 50Gy in 25 prescribed to 100% and delivered over 33 to 36 days. 1cm bolus FIRST 7 if skin involvement at presentation If connective tissue disease present If very high risk of local recurrence (patient either heavily node positive or has inflammatory breast cancer) If locally advanced breast cancer with

51 51 Tumour Bed - boost Tumour Bed - boost 10Gy in 5 prescribed to 100% and delivered over 5 to 7 days 16Gy in 8 prescribed to 100% and delivered over 5 to 7 days no prior surgery Lower risk of local recurrence High or moderate risk of local recurrence 9.0 Treatment Verification A Radiographer led off-line portal imaging protocol managed by IMAGETrack is utilised within the department. For more information refer to the Breast Portal Imaging Protocol V or the Palliative Portal Imaging Protocol V Any radiographer assessing images must have completed the training package and been signed off to prove competency V

52 Patient Management during Radiotherapy: 10.1 On-treatment Review All patients should be seen during the 1st and last week of treatment and at least once by the Doctor. Patients should be offered a weekly review with the Treatment Review Radiographers in line with department protocol, Review Procedure for Patients Undergoing a Course of Radiotherapy PM Blood Monitoring Patients should only be monitored when it has been requested on the front of the treatment sheet by the prescribing doctor. For more information refer to PM Blood Monitoring of Patients Receiving Radiotherapy Treatment Interruptions Patients with breast cancer are classed as category 2 according to the Royal College of Radiologists; please refer to Patient Categories (PM 2.010). These patients should have no more than two treatment interruptions during their course of radiotherapy. Any further break in treatment should be managed according to Management of Unscheduled Treatment Interruptions (PM 2.051) Patient Follow Up: Patients are to be seen 6 to 8 weeks after the completion of radiotherapy. A follow up appointment will be made at the referring hospital with Consultant Clinical Oncologist Monitoring the Effectiveness of the Process: 12.1 Clinical Audit

53 53 Regular audit will be undertaken to monitor compliance with this protocol QRM Review A monthly review of incident reports and variance forms is undertaken and is presented in the Quality Review Meeting. References: References - Section 1: 1. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347: B / A 2. Early Breast Cancer Trialists' Collaborative Group: Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000;355: A / A 3. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347: B / A 4. Robertson JM, Clarke DH, Pevzner MM, Matter RC. Breast conservation therapy: severe breast fibrosis after radiation therapy in patients with collagen vascular disease. Cancer 1991;68(3): / B 5. Fleck R, McNeese MD, Ellerbroek NA, Hunter TA, Holmes FA. Consequences of breast irradiation in patients with pre-existing collagen vascular diseases. Int J Radiat Oncol Biol Phys 1989;17(4): / B 6. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised triallancet Mar 29;371(9618): B / A 7. Livsey JE, Magee B, Stewart AL, Swindell R. Axillary recurrence following conservative surgery and radiotherapy in early breast cancer. Clin Oncol (R Coll Radiol). 2000;12(5): B / B 8. Grills IS, Kestin LL, Goldstein N, Mitchell C, Martinez A, Ingold J, Vicini FA. Factors for regional nodal failure after breast-conserving therapy: regional nodal irradiation

54 54 reduces rate of axillary failure in patients with four or more positive lymph nodes. Int J Radiat Oncol Biol Phys Jul 1;56(3): A / B References - Section 2: 1. Early Breast Cancer Trialists' Collaborative Group: Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000;355: A / A 2. Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, et al. Postoperative radiotherapy in high-risk pre-menopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997;337: B / A 3. Ragaz J, Jackson SM, Le N, Plenderleith IH, Spinelli JJ, Basco VE, et al. Adjuvant radiotherapy and chemotherapy in node-positive pre-menopausal women with breast cancer. N Engl J Med 1997;337: B / A 4. Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, et al. Postoperative radiotherapy in high-risk postmenopausal breast cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group (DBCG) 82c randomised trial. Lancet 1999;353: B / A 5. Grills IS, Kestin LL, Goldstein N, Mitchell C, Martinez A, Ingold J, Vicini FA. Factors for regional nodal failure after breast-conserving therapy: regional nodal irradiation reduces rate of axillary failure in patients with four or more positive lymph nodes. Int J Radiat Oncol Biol Phys Jul 1;56(3): A / B 6. Wallgren A, Bonetti M, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, Holmberg SB, Lindtner J, Thurlimann B, Fey M, Werner ID, Forbes JF, Price K, Coates AS, Collins J; International Breast Cancer Study Group Trials I through VII. Factors for loco regional recurrence among breast cancer patients: results from International Breast Cancer Study Group Trials I through VII. J Clin Oncol Apr 1;21(7): B / A 7. Truong PT, Lesperance M, Culhaci A, Kader HA, Speers CH, Olivotto IA. Patient subsets with T1-T2, node-negative breast cancer at high loco regional recurrence risk after mastectomy. Int J Radiat Oncol Biol Phys May 1;62(1): A / B 8. Truong PT, Olivotto IA, Kader HA, Panades M, Speers CH, Berthelet E. Selecting breast cancer patients with T1-T2 tumours and one to three positive axillary nodes at high post-mastectomy loco regional recurrence risk for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys Apr 1;61(5): A / B

55 55 References - Section 3: 1. Giordano SH. Update on locally advanced breast cancer. Oncologist 2003;8(6): Singletary SE, Allred C, Ashley P, Bassett LW, Berry D, Bland KI, et al. Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 2002;20(17): IV / C 3. Hutcheon AW, Heys SD, Sarkar TK. Neoadjuvant docetaxel in locally advanced breast cancer. Breast Cancer Res Treat 2003;79 Suppl 1:S A /B 4. Smith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, et al. Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 2002;20(6): B / A 5. Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, et al. The effect on tumour response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2003;21(22): B / A 6. Dowsett M, Ebbs SR, Dixon JM, Skene A, Griffith C, Boeddinghaus I, et al. Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists. J Clin Oncol 2005;23(11): B / A 7. Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Janicke F, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB- 1- and/or ErbB-2-positive, oestrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 2001;19(18): B / A 8. Shenkier T, Weir L, Levine M, Olivotto I, Whelan T, Reyno L. Clinical practice guidelines for the care and treatment of breast cancer: 15. Treatment for women with stage III or locally advanced breast cancer. Cmaj 2004;170(6): IV / C 9. Huang EH, Tucker SL, Strom EA, McNeese MD, Kuerer HM, Buzdar AU, et al. Postmastectomy radiation improves local-regional control and survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and mastectomy. J Clin Oncol 2004;22(23): A / B 10. Anderson WF, Chu KC, Chang S. Inflammatory breast carcinoma and non inflammatory locally advanced breast carcinoma: distinct clinicopathologic entities? J Clin Oncol 2003;21(12): IV / C 11. Brito RA, Valero V, Buzdar AU, Booser DJ, Ames F, Strom E, et al. Long-term results of combined-modality therapy for locally advanced breast cancer with

56 56 ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Centre experience. J Clin Oncol 2001;19(3): A / B 12. Panades M, Olivotto IA, Speers CH, Shenkier T, Olivotto TA, Weir L, et al. Evolving treatment strategies for inflammatory breast cancer: a population-based survival analysis. J Clin Oncol 2005;23(9): A / B 13. Arriagada R, Mouriesse H, Rezvani A, Sarrazin D, Clark RM, DeBoer G, et al. Radiotherapy alone in breast cancer. Analysis of tumour and lymph node radiation doses and treatment-related complications. The experience of the Gustave-Roussy Institute and the Princess Margaret Hospital. Radiotherapy Oncol 1993;27(1): A / B 14. Arriagada R, Mouriesse H, Sarrazin D, Clark RM, Deboer G. Radiotherapy alone in breast cancer. I. Analysis of tumour parameters, tumour dose and local control: the experience of the Gustave-Roussy Institute and the Princess Margaret Hospital. Int J Radiat Oncol Biol Phys 1985;11(10): A / B 15. Chen AM, Meric-Bernstam F, Hunt KK, Thames HD, Oswald MJ, Outlaw ED, et al. Breast conservation after neoadjuvant chemotherapy: the MD Anderson cancer centre experience. J Clin Oncol 2004;22(12): A / B 16. Chen AM, Meric-Bernstam F, Hunt KK, Thames HD, Outlaw ED, Strom EA, et al. Breast conservation after neoadjuvant chemotherapy. Cancer 2005;103(4): A / B 17. Foster RD, Hansen SL, Esserman LJ, Hwang ES, Ewing C, Lane K, et al. Safety of immediate transverse rectus abdominis myocutaneous breast reconstruction for patients with locally advanced disease. Arch Surg 2005;140(2):196-8; discussion IV / C 18. Senkus-Konefka E, Welnicka-Jaskiewicz M, Jaskiewicz J, Jassem J. Radiotherapy for breast cancer in patients undergoing breast reconstruction or augmentation. Cancer Treat Rev 2004;30(8): B / B

57 57 Systemic Therapies 1. Adjuvant Systemic Therapy 1.1 Endocrine therapy Current recommendations from the Overview of Randomised trials shows that there is an absolute survival benefit of around 10% from adjuvant tamoxifen 20mg orally daily for 5 years in patients with oestrogen receptor (ER) positive invasive breast cancer. The proportional benefit is unaffected by nodal status, but the absolute benefit rises to about 13% in patients with node positive cancer, compared with about 5% in those with node negative disease. At 15 years there is a sustained 10% benefit for both recurrence and breast cancer mortality with 5 years of Tamoxifen (SABCS 2007) The overview shows minimal benefit or no benefit for patients whose tumours are ER negative. All pre-menopausal and post-menopausal women with invasive ER positive tumours should therefore be offered adjuvant endocrine therapy. The histopathology report of ER and PR status specifies the level of positivity on a 0-8 (Allred) scale. A score of 0 or 2 is considered negative. Patients with tumours which express any degree of ER positivity (scores of 3 or more) can be considered for endocrine treatment but if the level of positivity is very low the risks and benefits should be discussed with the patient. Timing of endocrine therapy Recent evidence suggests that the concurrent administration of chemotherapy and endocrine therapy is less effective than when they are given sequentially. In addition, there is evidence that concurrent administration (especially with tamoxifen) carries an increased risk of thromboembolism. For these reasons, if the patient is receiving adjuvant chemotherapy the endocrine therapy should only be started 2-3 weeks after completion of chemotherapy. Otherwise it should be started as soon after surgery as convenient. Endocrine therapy can be given concurrently with radiotherapy. Adjuvant aromatase inhibitors

58 58 In contrast to tamoxifen that acts as an anti-oestrogen at the oestrogen receptor site in the tumour, the aromatase inhibitors anastrozole, letrozole and exemestane act by inhibiting the aromatase enzyme which converts androgens to oestrogens in the peripheral tissues and adrenal glands of post-menopausal women and therefore switches off oestrogen production. Aromatase inhibitors should never be prescribed for pre-menopausal women. They may not be effective as premenopausal oestrogen levels are so much higher. Also, there is in vivo data to suggest ovarian hyperstimulation may occur due to the deprivation of oestrogen causing a negative feed-back loop with the hypothalamic-pituitary axis. The concurrent administration of HRT may entirely negate the effects of an aromatase inhibitor and is contra-indicated. The ATAC trial has shown a small but significant improvement in disease-free survival of 2.5% at 5 years and 4.1% at 9 years for ER positive post-menopausal patients receiving anastrozole 1mg orally daily compared with tamoxifen for 5 years. The subgroups deriving the greatest benefit were those with node negative tumours, who had no prior chemotherapy and the ER positive/pr negative receptor profile. Anastrozole was also associated with a lower incidence of side effects including hot flushes, vaginal bleeding and vaginal discharge. In addition, it was not associated with an increased incidence of uterine cancer or thromboembolism. It was however associated with an increased incidence of muscle-skeletal pains and fractures. There was a 55% increased risk of fracture on the anastrozole arm compared to tamoxifen but the risk is the same as in the tamoxifen arm once anastrozole treatment is discontinued. The BIG 1-98 trial has demonstrated a similar advantage for the use of adjuvant letrozole compared with tamoxifen. An absolute disease-free survival advantage at 26 months of 2.6% has increased to 2.9% at 56 months in favour of letrozole. The patient subgroups deriving the greatest benefit were those with node positive cancer who received prior chemotherapy. The response in those with PR positive tumours was the same as the PR negative tumours. The side effect profile for letrozole was similar to anastrozole. Cholesterol levels were measured prospectively and those on letrozole had mild elevations compared with those on tamoxifen. Letrozole also showed significant more grade 3-5 cardiac adverse events, mainly cardiac failure not fully explained by raised cholesterol but numbers were small. An update of the BIG 1-98 trial presented at the SABCS 2008 showed, at 71 months median follow up, no difference on disease-free survival between monotherapy with letrozole and the sequential treatment with letrozole followed by tamoxifen or tamoxifen followed by letrozole but there was a trend supporting the initial use of letrozole in patients at higher risk of relapse. The Intergroup Exemestane Study has also recently reported on the use of tamoxifen for 2-3 years and then a randomisation to either continuing tamoxifen to a total of 5 years or switching to exemestane to complete 5 years of endocrine therapy. Again, disease-free survival is improved in the sequential tamoxifen-exemestane group. In addition, when the ER positive/unknown population of the study were analysed separately overall survival was significantly improved for the sequential

59 59 tamoxifen-exemestane group (p=0.05). In the IES trial patients benefited irrespective of nodal status, receipt of previous chemotherapy or PR status. Three trials have investigated the role of anastrozole following 2-3 years of tamoxifen. The Italian Tamoxifen Anastrozole (ITA), Arimidex/Nolvadex 95 (ARNO95) and Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG 8) were combined for a meta-analysis which has shown a significant benefit in disease-free survival and overall survival for the sequential tamoxifen/anastrozole arm compared with tamoxifen alone. The MA-17 trial gave women with early breast cancer tamoxifen for 5 years. At this point they were randomised to either letrozole for 5 years or a placebo for 5 years. An update at ASCO 2004 showed that women with node-positive breast cancer diagnosis had a small but significant improvement in overall survival if they received tamoxifen followed by letrozole. On the basis of this letrozole was granted a UK license for use in node positive breast cancer within 3 months of completing 5 years of tamoxifen. A further update of MA 17 presented at SABCS 2009 showed disease-free survival benefit of 10% to 11% with extended letrozole therapy for both node-positive and node-negative women who were premenopausal at initial diagnosis. Summary of recommendations for adjuvant endocrine therapy NICE guidance was issued in November 2006 relating to adjuvant endocrine therapy for hormone receptor positive breast cancer in postmenopausal women. All women with an ER positive early breast cancer who are postmenopausal should be offered the option of tamoxifen and/or an aromatase inhibitor. The decision about treatment choice should be made by the woman and the responsible clinician after appropriate discussion and consideration of breast cancer risk factors and the potential side effects. Tamoxifen alone should no longer be considered the standard of care for these women. New guidelines issued in February 2009 state that an AI (anastrozole or letrozole) should be offered as initial therapy for this group of patients if they are not considered to be at low risk (10 years predictive survival of 93% or above on Nottingham Prognostic Index or Adjuvant! Online). Tamoxifen should be offered if AI is not tolerated or contraindicated. Ovarian suppression

60 60 Adjuvant ovarian ablation reduces the risk of breast cancer recurrence in pre-menopausal patients. Suppression of ovarian function (LHRH analogue goserelin) with or without tamoxifen for 2 years is at least as effective as CMF chemotherapy but the latter is rarely used now in pre-menopausal women with evidence of the superiority of anthracyclines. There is controversy as to whether this treatment is as effective as chemotherapy and also as to whether ovarian ablation in addition to chemotherapy and/or tamoxifen confers further benefit. A number of international trials are addressing these issues. Meanwhile such patients should have the evidence discussed with them in clinic. If the patient wishes to have ovarian suppression then the following options are available. LHRH agonists have the advantage of being reversible which is of benefit if the patient has intolerable menopausal symptoms or has a strong desire to become pregnant at a later date. 1 GnRH analogue goserelin given 4-weekly. In the adjuvant setting the recommendation is for 4-weekly injections for a period of 2 years. In the metastatic setting patient can switch to 12- weekly injections after 2 courses of 4-weekly injections. 2 Laparoscopic oophorectomy has the advantage of being a one-off procedure which avoids the need for regular medical treatments. There may be an additional benefit in likely BRCA carriers at risk of ovarian carcinoma. Meanwhile goserelin in addition to tamoxifen should be offered to women who maintain/regain menstruation within 6 months of completing chemotherapy in the following situations: 1 Younger women who are perceived to be at high risk of recurrence 2 Women who declined chemotherapy because of desire to maintain fertility. Goserelin in addition to tamoxifen should also be offered to women who decline recommended chemotherapy or when there is a small benefit from chemotherapy. Neo-adjuvant Endocrine therapy

61 61 Post menopausal women with large operable ER positive cancers are at moderate to high risk of systemic failure and, if fit, should be considered for both chemotherapy and endocrine therapy. Neoadjuvant chemotherapy should be considered followed by loco-regional treatment and then adjuvant endocrine therapy. Neo-adjuvant endocrine therapy is preferably given in the context of a trial. Outside of trials, current evidence suggest that neo-adjuvant letrozole is more effective than tamoxifen in terms of both clinical response and avoidance of mastectomy in post menopausal women with large ER positive tumours, otherwise requiring a mastectomy. Such patients should be offered a therapeutic trial of letrozole 2.5 mg orally prior to surgery. Normally, six months of neo-adjuvant endocrine therapy would be given providing the primary tumour is responding. Clinical response should be checked 2-4 weeks after starting therapy and then at 4 weekly intervals, preferably by the same clinician at each visit. These measurements should be recorded sequentially in the case notes. Response to endocrine therapy can be slow. Measurable disease progression (a 25% or grater increase in the product of the 2 longest perpendicular diameters of the tumour) is an indication to stop therapy and refer urgently to the surgical team. Women with ER positive breast cancers who refuse surgery or are unfit for surgery should also be offered letrozole. In exceptional circumstances it may be more appropriate to prescribe tamoxifen at the clinician s discretion. http// Management of symptoms of endocrine therapy Hot flushes According to NICE guidelines the selective serotonin re-uptake inhibitor antidepressants paroxetine and fluoxetine may be offered to women with breast cancer for relieving menopausal symptoms, particularly hot flushes, but not for those taking tamoxifen. Clonidine, venlafaxine and gabapentin should only be offered to treat hot flushes in women with breast cancer after they have been fully informed of the significant side effects. NB with exeption of clonidine, the medicines listed are not licensed for this indication and may not be stocked in all Acute Trusts in the network. The prescribing of treatments for unlicensed indications will require approval according to local trust policies. Do not offer HRT (including oestrogen/progestogen combination) routinely to women with menopausal symptoms and a history of breast cancer. HRT may, in exceptional cases, be offered to

62 62 women with severe menopausal symptoms and with whom the associated risks have been discussed. It may be acceptable with tamoxifen or in patients with ER negative tumours. As treatment is controversial it should be a consultant decision. Atrophic vaginitis Vaginal dryness can be treated with topical oestrogen creams or pessaries. Systemic spillover effect is likely to be very low and will probably not affect the efficacy of tamoxifen or the aromatase inhibitors. 1.2 Chemotherapy Summary of recommendations for patients not involved on clinical trials Neo-adjuvant setting: Patients should receive 4 cycles of EC followed by 4 cycles of Docetaxel. Adjuvant setting: Node negative patients should receive 6 cycles of FEC 75 (Epirubicin 75mg/m 2 ).

63 63 Node positive patients should be considered for taxanes (FEC 100 /Docetaxel) but if otherwise good prognostic factors/older-age group/significant co-morbidities 6 cycles of FEC 75 can be considered. Elderly patients with ER negative tumours should receive 6 cycles of FEC 75. Patients with HER2 positive tumours should receive trastuzumab concomitantly with taxanes in the neo-adjuvant and adjuvant settings. Consider continuing trastuzumab during adjuvant radiotherapy mainly for patients with right breast cancer and for patients at high risk of relapse. The Overview of randomized trials of polychemotherapy for early breast cancer shows an absolute 10-year survival benefit in women under 50 years old with node positive disease at around 11% and node negative disease 7%. The absolute survival benefit falls with age but statistically significant survival is still seen up to but not beyond the age of 70. There is a further survival benefit for chemotherapy over and above that achieved with tamoxifen in patients whose tumours are ER positive. The decision to offer chemotherapy is based on many factors including age, general clinical condition, prognostic factors for outcome and the patient s own wishes following informed discussion. Low Risk In this category, the absolute survival benefit for adjuvant chemotherapy is either unproven or so small as to be not clinically recommended. 1 Patients aged 70 or over Chemotherapy may need to be discussed with some patients over 70 with multiple poor risk factors but deemed fit for chemotherapy. This is always an MDTM/Consultant decision.

64 64 2 Patients with all of the following Tumour 2cm in diameter Oestrogen Receptor positive Grade 1 or 2 histology No lympho-vascular invasion Negative lymph nodes Moderate to High Risk Patients with any of the following are at sufficient risk to offer adjuvant chemotherapy on the basis of established survival benefits. For each patient the pros and cons of the treatment need to be discussed. As a general guideline, the greater the number of factors involved the greater the risk and the stronger the recommendation for chemotherapy. 1 Node positive disease 2 Oestrogen receptor negative 3 Lympho-vascular invasion present 4 Grade 3 histology 5 Tumour 2cm in diameter 6 Patients 35 years There has been increasing evidence regarding the use of taxanes as part of adjuvant treatment for women with high risk of relapse. NICE guidance from September 2006 stated that women with node positive breast cancer should be offered the option of being treated with a regimen containing taxane. The registration regimen for the Docetaxel in the adjuvant setting was TAC, but this is associated with considerable toxicity and has similar efficacy to a regimen of 3 cycles FEC 100 (Epirubicin 100mg/m 2 ) and 3 cycles of Docetaxel (100mg/m 2 ). Many UK cancer networks (including SELCN) have accepted 3 cycles FEC 100 followed by 3 cycles of Docetaxel as their standard of care for women with node positive breast cancer. However the UK TACT study (Lancet 2009 May 16; 373 (9676): ) which enrolled 4162 women with node positive or high-risk node negative operable breast cancer, showed no advantage for the addition of Docetaxel to standard anthracycline chemotherapy in any patient group.

65 65 Our general recommendation is for node negative patients to be treated with FEC75 and all node positive patients to be considered for taxanes (FEC 100 /Docetaxel). However there are circumstances where this advice might be modified. For example: 1. Patient has otherwise good prognostic factors/older-age group/significant co-morbidities therefore FEC 75 can be considered. 2. Adjuvant taxane is unlikely to add extra benefit for a one node positive patient with strongly ER positive Grade 1 invasive carcinoma. 3. Adjuvant taxane is likely to add extra benefit for a node negative patient with ER negative, HER2 positive Grade 3 invasive carcinoma. Timing of adjuvant chemotherapy Adjuvant chemotherapy is given before adjuvant radiotherapy and endocrine therapy. There is evidence of an increased risk of thrombo-embolism if chemotherapy is given concurrently with tamoxifen. Also, there is pre-clinical and clinical evidence of sequential chemotherapy and endocrine therapy being more effective than concurrent. Standard chemotherapy regimens The policy is to offer patients entry into adjuvant chemotherapy clinical trials wherever possible. Standard chemotherapy should be considered for those who do not wish to take part in a trial or who are ineligible for trial entry. FEC (60) 5 FU 600 mg/m 2 iv day 1 Epirubicin 60 mg/m 2 iv day 1 Cyclophosphamide 600 mg/m 2 iv day 1 21 day cycle for 6 to 8 cycles FEC (75) 5 FU 600 mg/m 2 iv day 1

66 66 Epirubicin 75 mg/m 2 iv day 1 Cyclophosphamide 600 mg/m 2 iv day 1 21 day cycle for 6 cycles FEC (100) 5 FU 500 mg/m 2 iv day 1 Epirubicin 100 mg/m 2 iv day 1 Cyclophosphamide 500 mg/m 2 iv day 1 21 day cycle for 3 cycles (followed by 3 cycles of Docetaxel for node positive) EC Epirubicin 90 mg/m 2 iv day 1 Cyclophosphamide 600 mg/m 2 iv day 1 21 day cycle for 4-6 cycles Epi-CMF Epirubicin 100 mg/m 2 iv day 1 21 day cycle for 4 cycles Followed by CMF (as below) for 4 cycles CMF Cyclophosphamide 100 mg/m 2 po days 1-14

67 67 Methotrexate 40 mg/m 2 iv days 1 and 8 5FU 600 mg/m 2 iv days 1 and 8 Folinic acid rescue 15 mg 6hrly x 6 doses po days 2 and 9 (start 24 hours post MXT) CMF alone is rarely used because of the compelling evidence suggesting the superiority of anthracycline-based regimens. It can be used if a patient does not wish to lose their hair, is frail or has significantly impaired cardiac function (LVEF 45%). Docetaxel Docetaxel 100 mg/m 2 iv day 1 Primary prophylaxis with GCSF, starting 24h post chemotherapy is recommended with Docetaxel 100 mg/m 2, e. g. pegfilgrastin Paclitaxel 175 mg/m2 iv day 1 21 day cycle for 4 cycles or 80 mg/m2 iv day 1 Weekly for 12 weeks Paclitaxel can be used as an alternative to Docetaxel typically for patients who are allergic to Docetaxel or when there is contraindication for high dose of steroids. TC

68 68 Docetaxel 75 mg/m 2 Cyclophosphamide 600 mg/m 2 21 day cycles for a total of 4 cycles For a small subgroup of patients with a low LVEF on echocardiography/muga where there is concern about the use of an anthracycline the TC regimen could be considered. For the up-to-date list of agreed chemotherapy regimens and the individual protocol details see the website Click on chemotherapy on the left hand side of the page (no password required) then oncology then breast, the protocols will then be listed. Each protocol describes the drugs and doses, the schedule of treatment, administration guidelines, extravasation and emetogenic potential, regular investigations required, common toxicities, drug interactions and guidance for management of common toxicities. Primary or Neo-adjuvant Chemotherapy Primary or Neo-adjuvant chemotherapy should be considered for 1 Patients with large tumours ( 3 cm) that would require a mastectomy 2 Patients with a central primary tumour less than 2 cm from the centre of the nipple 3 Patients with locally advanced breast cancer 4 Patients with tumours of >2 cm in a small volume breast where the MDM considers the tumour to be inoperable and operability may be achieved and/or the chance of breast conservation with optimum cosmesis can be significantly improved. The standard regimen is 4 cycles of EC followed by 4 cycles of Docetaxel. GCSF starting 24h post chemotherapy should be added to each cycle of Docetaxel 100 mg/m 2.

69 69 All patients receiving primary or neo-adjuvant chemotherapy should have assessments with breast ultrasound scan and, if possible, breast MRI before starting chemotherapy (baseline), following 3 cycles of EC (mid-treatment) and following completion of chemotherapy (end of treatment). Midtreatment scans should be reviewed at MDT meeting. MRI should not be performed if this was not performed prior to commencing chemotherapy. EC regimen maybe switched to Docetaxel after 3 cycles if there is no clinical and/or radiological response. Docetaxel may also be discontinued earlier and surgery brought forward if there is no clinical and/or radiological response HER2 positive patients should have cardiac assessment as per the United Kingdom National Cancer Research Institute recommendations (see below) and Trastuzumab should be added to Docetaxel prior to surgery and continued to complete a total of 18 cycles (standard regimen) or as appropriate if patient participating on a clinical trial. In brief, HER2 positive patients should have echocardiograms performed prior to commencing chemotherapy, following treatment with anthracyclins and at 4 and 8 months of trastuzumab treatment. End of treatment echocardiogram (12 months) should only be performed if a cardiac intervention was required during treatment. Patients receiving adjuvant trastuzumab only (following completion of chemotherapy) should have clinical reviews with blood tests and echocardiogram result on 4-monthly basis and a pro-active approach with ACE inhibitors should be adopted as per the UK National Cancer Research Institute recommendations (see below). General Procedure for prescription and administration of adjuvant/neo-adjuvant chemotherapy Obtain written informed consent from the patient. It is essential to discuss the need for contraception and conversely the risk of infertility/early menopause with all premenopausal patients (see later section on fertility). Check and record in the notes whether there is a history of, or strong risk factors for, cardiac disease. If present then consider ECG and Echo/MUGA assessment prior to administration of an anthracycline-containing regimen. All patients should have a full blood count, U & Es and LFTs prior to each cycle of chemotherapy.

70 70 Blood results and toxicity scores should be recorded. A bone scan, liver ultrasound and CXR (or CT scan if available) should be performed for women with 4 or more positive nodes prior to adjuvant chemotherapy. These tests should also be organized for patients due to receive neoadjuvant chemotherapy if they have palpable or radiologically involved ipsilateral axillary lymph nodes or locally advanced disease in the breast. The prescription of any chemotherapy must be protocol based and consultant led. If the consultant is temporarily unavailable then chemotherapy can be initiated by a specialist registrar providing this is protocol based and it is recorded in the notes that the consultant has been informed. Follow-up courses of chemotherapy initiated by a consultant can be prescribed by the SPR or clinical fellow. Record patient height and weight and calculate surface area. The patient s weight should be measured prior to each cycle of chemotherapy. However, the dose need not be altered unless there is at least a 10% change in the patient s weight from baseline. Surface area calculations are only accurate between m 2. For those patients with surface area above 2.0 m 2 it is suggested to cap at 2.0 m 2 except on special circumstances and this decision should be made by a consultant oncologist. Consider wig referral if alopecia is likely. Two cycles prior to completion of chemotherapy the patient should be reviewed to check, if appropriate, that a start date for radiotherapy is scheduled and, if appropriate, that a plan to commence endocrine therapy post chemotherapy has been finalized. Managing common chemotherapy-related toxicity It is essential to record toxicity after each cycle using grading system Leucopenia/Neutropenia G-CSF should not be routinely prescribed as primary prophylaxis except when Docetaxel 100mg/m 2 is being given.

71 71 Maintaining dose intensity is an important aim for early breast cancer chemotherapy. On day 1 of each new cycle treatment should be given if neutrophil count is 1.0 x 10 9 /l providing the patient is clinically well. If the neutrophil count is < 1.0 x 10 9 /l delay chemotherapy and repeat FBC on subsequent days. GCSF support (e.g. pegfilgrastim, lenograstim or filgrastim) should be considered for subsequent cycles. Taxanes have a more profound myelosuppressive effect and if there is persistent neutropenia then a dose reduction may be necessary. This should be a consultant decision. Refer to individual treatment protocols for further recommendations ( Click on the Chemotherapy button on the left hand side of the page (no password required) then click on oncology then breast, the protocols will be listed. Anaemia/thrombocytopenia Anaemia can occur, particularly after several cycles of treatment. Mild anaemia can be treated with ferrous sulphate (if due to iron deficiency). If the Hb falls below 8-10g/dl consider blood transfusion after discussion with the patient. Thrombocytopenia is rare. If the platelet count on day 1 is below 100 x 10 9 /L discuss with consultant before proceeding with chemotherapy Chemotherapy induced nausea and vomiting (CINV) CINV is a common side effect of anthracycline regimens and these patients routinely receive dexamethasone and 5HT3 receptor antagonist prophylaxis at the time of administration and for 3 days afterwards. If the patient experiences protracted CINV despite this then the addition of domperidone for a longer period of time may be helpful. Domperidone can be administered orally or rectally. In extreme cases it may be necessary to admit a patient to hospital for subcutaneous anti-emetic infusions at the same time as chemotherapy. Lorazepam should be considered for anticipatory nausea (at GSTT refer to CINV guidelines)

72 72 Alopecia If hair loss is occurring ensure that a wig referral has been made and advise the patient about minimal hair washing and avoidance of heat/chemical treatments to limit hair damage. Stomatitis Grade1 or 2 stomatitis should be treated with prophylactic mouth care for subsequent cycles. This consists of chlorhexidine, nystatin and sucralfate mouthwashes after each meal. Grade 3 or 4 stomatitis may require hospital admission for intravenous fluids, antimicrobials and analgesics. Subsequently, prophylactic mouth care should be given and a dose reduction discussed with the consultant. Disturbance of bowel function Diarrhoea can be treated with loperamide or codeine phosphate although infective causes should be considered. Constipation can also occur, most probably due to the use of anti-emetics such as 5- Hydroxytryptamine 3 (5 HT3) receptor antagonists (e.g. granisetron). Laxative use is permitted. Peripheral neuropathy This is a specific taxane side effect and patients should be asked about symptoms after each taxane treatment. It tends to be accumulative. If a patient has persistent sensory symptoms in the hands or feet and/or is developing difficulty with tasks such as doing up buttons then the case needs to be discussed with the consultant concerned before any further taxane is given. Myalgia/Arthralgia These symptoms often occur with taxane-based chemotherapy, typically 3 days after treatment. It is self-limiting, but the patient can take analgesia as necessary and this should also be recommended for subsequent cycles. Docetaxel is reported to be more likely to cause these symptoms than paclitaxel and in patients with severe myalgia/arthralgia a change to paclitaxel can be considered.

73 73 Fertility, pregnancy and treatment Women of child-bearing age who are advised to have chemotherapy may be particularly concerned about the potential side effects of ovarian suppression and subsequent infertility. This risk is very much age-related. The risk is low (<10%) in women under 30 years and rises steadily through their thirties to >90% in patients aged 40 or over. The risk also relates to the duration of chemotherapy. Patients for whom fertility is an issue, should have access to a rapid consultation with a fertility specialist, although they should be aware that any treatment may delay the start of chemotherapy and that there is a question mark over the use of ovulatory stimulating agents in patients with breast cancer. Conversely, all patients of child-bearing age that start chemotherapy should be strongly advised to use contraception (not pill) during chemotherapy and for at least 6 months afterwards. There is a small amount of evidence that the use of zoladex prior to and during chemotherapy may protect the ovaries from chemotherapy-induced follicle damage. This is the subject of a current trial. The date of the last menstrual period should be recorded at each visit. Assisted Conception Unit referrals for ER positive pre-menopausal women due to have chemotherapy Patients need to have a realist expectation and understand risk of relapse and importance of timing for neo-adjuvant and adjuvant chemotherapy. Fertility reserve needs to be considered in women of all ages when considering IVF as regular menses not necessary imply good fertility reserve. Women over 40 years old need to be aware of the low likelihood of successful IVF but embryo cryopreservation can be considered. However oocyte preservation (women without a partner) is not advisable as pregnancy outcome is extremely poor in this group. There is no NHS funding available for women over 40 years old or who herself or her partner has already a child. When referring a patient to the ACU it is good practice to try and estimate risk of recurrence and urgency of need to start chemotherapy as this will help the ACU team guide the patient s management.

74 74 Vaccinations in the immunocompromised The Department of Health guideline (1996) Immunization against infectious disease outlines the risks associated with use of live vaccines in immunocompromised individuals. Patients may not be able to mount a normal immune response and can suffer severe manifestations with live vaccines such as BCG, Measles, Oral Typhoid and Yellow Fever. Live vaccines should be avoided until 6 months after all chemotherapy or generalized radiotherapy. Live vaccines should be avoided until 3 months after high dose steroids (prednisolone 40mg od for at least 1 week or equivalent). Inactivated vaccines are not dangerous to patients receiving chemotherapy, but as an appropriate immune response may not be mounted they may be ineffective. Seasonal flu vaccines and pneumococcal vaccine should be offered to patients and administered before chemotherapy starts. If this is not possible administer the vaccine dose on the day before or day 1 of the chemotherapy cycle. As the immune response mounted to vaccines is likely to be compromised during treatment with chemotherapy the following is recommended for swine flu (H1N1 virus) protection: Pre-chemotherapy - 1 dose of swine flu vaccine During chemotherapy - 2 doses of swine flu vaccine After chemotherapy - 1 dose of swine flu vaccine. 1.3 Trastuzumab (Herceptin) All women with breast cancer should have tumour tissue tested for HER2 expression. Patients with HER2 overexpression at the 3+ level by immunohistochemistry or with gene amplification by fluorescent in-situ hybridization (FISH) should be considered for therapy with trastuzumab as per NICE guidance. Trastuzumab is a recombinant humanised IgG1monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2). Five randomized clinical trials have now reported benefits with the use of adjuvant trastuzumab. In the HERA study women had surgery and completed standard chemotherapy before they were entered into the study and randomly allocated to receive either no treatment or trastuzumab once every 3 weeks for either 1 or 2 years (N=5090). The results of the HERA study showed 87.1% of patients in the control arm and 92.5% of patients in the trastuzumab arm free from disease at 1 year follow up. In terms of overall survival 97.6% of patients in the control arm and 98.2% of patients in the trastuzumab arm were alive at 1 year follow

75 75 up. The incidence of serious cardiac adverse events was 0.6% in the trastuzumab arm versus 0.1% in the control arm. Three additional studies (NCCTG N9831, NSABP B-31, BCIRG 006) investigated adjuvant trastuzumab as well as taxane-containing adjuvant chemotherapy and showed benefits in survival. Another trial (FinHer) used a weekly regimen for 3 months. Patient numbers (N=231) were smaller than the other studies but the trastuzumab arm still demonstrated superior outcomes.the update of the NCCTG N9831 trial presented at the SABCS 2009 showed better results for adjuvant trastuzumab given concurrently with taxane than the sequential arm. NICE guidance states that trastuzumab, given at 3-week intervals for 1 year or until disease recurrence (whichever is the shorter period), is recommended as a treatment option for women with early-stage HER2 positive breast cancer following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable).trastuzumab should not be offered to women who have any of the following: 1 a history of documented congestive heart failure 2 high-risk uncontrolled arrhythmias 3 angina pectoris requiring medication 4 clinically significant valvular disease 5 evidence of transmural infarction on electrocardiograph (ECG) 6 poorly controlled hypertension. From April 2010 cardiac assessment, monitoring and management for patients receiving trastuzumab will be performed according to the guidelines produced by the United Kingdom National Research Institute (UKNCRI) published in 2009 (AL Jones et al. British Journal of Cancer (2009) 100, ), as follows: Revised treatment and monitoring algorithm for trastuzumab The current algorithm for monitoring LVEF and interrupting trastuzumab treatment was derived from the HERA clinical trial protocol (Figure 2). The high incidence of cardiac dysfunction seen in the preceding metastatic breast cancer trials led to stringent inclusion criteria, and many women with normal left ventricular function

76 76 were excluded from the trial. There was no attempt to ameliorate cardiac risk factors or actively manage asymptomatic LVEF decline during the study, and the only permissible response was interruption or discontinuation of drug. There is greater understanding of the pathophysiology of trastuzumab-related LVSD, and in particular its potential reversibility. The clinical trial population does not map onto the whole population of women with HER2 positive breast cancer, some of whom, on the basis of arbitrarily set cardiac criteria, are excluded from receiving trastuzumab, even though they might benefit from treatment without long-term adverse cardiac sequelae. The algorithm has been re-evaluated to allow proactive intervention that facilitates the initiation and continuation of trastuzumab therapy, where it may previously have been omitted or discontinued. KEY RECOMMENDATIONS Baseline cardiac assessments before cytotoxic chemotherapy Patients receiving chemotherapy may be considered to be at increased risk of developing cardiac dysfunction Stage A heart failure in ACC/AHA guidelines (Bonow et al, 2005). The following assessments are recommended before initiating chemotherapy, for all patients with HER2 positive breast cancer. Although these recommendations relate only to HER2 positive tumours, similar pre-treatment assessments would be desirable in any patient for whom cytotoxic chemotherapy is being considered. Medical history o To determine previous cardiac events and risk factors. Physical examination o Blood pressure (hypertension is a potent and modifiable risk factor for the development of cardiac dysfunction, and should be assessed before each cycle of treatment a blood pressure of >140/85 mmhg should be treated with an ACE inhibitor). o Auscultation of the heart to identify murmurs (significant valvular heart disease is a risk factor for cardiac dysfunction). o Signs of heart failure (raised venous pressure, crepitations over the lung fields or pedal oedema). 12-lead electrocardiogram (ECG) looking for possible markers of structural heart disease including left ventricular damage/dysfunction o For arrhythmias (atrial fibrillation, atrial flutter, heart block). o For evidence of previous myocardial infarction (Q-waves, left bundle branch block). o For evidence of left ventricular hypertrophy. Left ventricular ejection fraction measurement using Echo or radionucleotide multiple-gated acquisition (MUGA) scan. o This baseline test is not recommended in present NCRI guidelines. The associated resource use is offset by a reduction in the requirement for testing during trastuzumab administration.

77 77 In routine clinical practice, LVEF can be measured with echocardiogram or radionucleotide MUGA scan. Where the ECG is significantly abnormal at baseline, Echo is recommended whenever satisfactory images can be obtained, because it provides additional information on heart valve function. Serial LVEF assessments are required to guide treatment, and a high degree of reproducibility is essential; MUGA has some advantages in this respect, but requires the use of significant ionising radiation (Healthcare Commission, 2000). The same monitoring modality should be used throughout the course of treatment and, where possible, this should also include the same operator, machine, and calculation algorithm. Each institution should establish a normal range for the methods used. Left ventricular ejection fraction is a dynamic physiological function varying from day to day depending on heart rate and loading conditions, but every effort must be made to provide an accurate and precise assessment of LVEF to guide clinical decisions about trastuzumab therapy, in the same way as this information is essential for implantable cardioverter defibrillator (NICE, 2006b) and cardiac resynchronisation therapies (NICE, 2006c). Clinicians interpreting LVEF values should consider confounding factors if they receive unexpected results. Interventions at baseline Referral to a cardiologist This is recommended for patients who have evidence of LVSD, cardiac dysrhythmias, or structural heart disease, including evidence of previous infarction or significant modifiable cardiovascular risk factors, such as poorly controlled hypertension. Modification of planned chemotherapy regimen Assessment of baseline LVEF before chemotherapy in all patients informs the choice of cytotoxic regimen. Patients with low or borderline LVEF may benefit from a nonanthracycline-containing regimen. The combination of Docetaxel and cyclophosphamide has been compared with doxorubicin and cyclophosphamide, and has shown at least equivalent efficacy (Jones et al, 2006). Prophylactic ACE inhibitor therapy may also be considered for such patients. The use of ACE inhibitors to control hypertension Hypertension is a potent modifiable risk factor for the development of heart failure during breast cancer treatment, with a statistically significant hazard ratio of 1.45 (95% CI, ) (Pinder et al, 2007). Blood pressure should be measured in all breast cancer patients at routine oncology clinic visits, and where readings are above the second Joint British Societies guidelines (British Cardiac Society et al, 2005), target of <140/85 mmhg, they should be treated with an ACE inhibitor licensed for the treatment of heart failure (Table 2). Angiotensin-converting enzyme inhibitors are recommended as first-line antihypertensive

78 78 agents. Trial data support their efficacy in reducing blood pressure, and for the prevention and treatment of left ventricular dysfunction and heart failure (SOLVD Investigators, 1992; AIRE Investigators, 1993; Moyé et al, 1994; Arnold et al, 2003). There is also direct trial evidence for the efficacy of ACE inhibitors in preventing the decrease in LVEF observed in patients after high-dose chemotherapy (Cardinale et al, 2006) It is recommended that dose titration and renal function monitoring be performed in primary care in accordance with current cardiac guidance (NICE, 2003). Patients with breast cancer whose hypertension cannot be controlled with standard pharmacological treatment should be referred to a specialist. Lifestyle recommendations Patients should be advised by their GP and oncologist about lifestyle changes that reduce their cardiovascular risk: Table 2 Currently available ACE inhibitors licensed for heart failure, and their recommended dosing schedules (BNF, 2007) NB Refer to Trust formulary for locally available ACE inhibitors ACE inhibitor Starting dose Dose titration Captopril mg twice Maintenance: 25 50mg twice daily daily Maximum: 150 mg daily in divided doses Cilazapril 0.5 mg once daily Maintenance: mg once daily Maximum: 5mg once daily Enalapril maleate 2.5 mg once daily Maintenance: 20 mg once daily Maximum: 10 20mg twice daily Fosinopril sodium 10 mg once daily Maintenance: mg once daily Maximum: 40mg once daily Lisinopril 2.5 mg once daily Maintenance: 20 mg once daily Maximum: 35mg once daily Perindopril 2mg once daily Maintenance: 4mg once daily erbumine Maximum: 4mg once daily

79 79 Quinapril 2.5 mg once daily Maintenance: 10 20mg once daily Maximum: 40mg once daily Ramipril 1.25 mg once daily Maintenance: mg once daily Smoking cessation. Improving diet. o o o Moderate alcohol consumption (up to 14 units a week for women heavy alcohol consumption can both increase blood pressure and reduce cardiac function). Reducing dietary salt. Reducing fat. o Increasing fruit and vegetable consumption (five a day). Increasing physical activity. Weight loss where appropriate. Management of cardiac function during trastuzumab Use of the present algorithm for monitoring cardiac function in trastuzumab-treated patients (Figure 1) has resulted in a low incidence of clinical heart failure in routine practice. However, the algorithm has a number of limitations. Specifically, it: Is susceptible to misinterpretation. Requires the determination of LVEF with a precision and reproducibility that cannot often be achieved in routine clinical practice. Does not take account of the normal ranges for LVEF of different imaging modalities, in different institutions. Requires a high frequency of monitoring compared with the risk of clinical heart failure. Does not specify a pre-chemotherapy LVEF assessment as a baseline for the evaluation of cytotoxic drug-related cardiac damage and dysfunction. Does not provide guidance for the optimisation of cardiac health before trastuzumab therapy. Does not make recommendations on the treatment of patients with LVSD other than the interruption of trastuzumab therapy. Does not facilitate successful rechallenge with trastuzumab.

80 80 Figure 1 Current recommendations for cardiac monitoring in trastuzumab-treated patients (reproduced from Suter et al, 2007; online Appendix only). Reproduced with permission of the American Society of Clinical Oncology, from Suter et al, Assessment of LVEF before trastuzumab treatment Left ventricular ejection fraction should be further assessed in all patients after completion of chemotherapy and before initiating trastuzumab therapy (Figure 2). Some patients (7% in NASBP-B31) will experience a decrease in LVEF that precludes trastuzumab treatment (Romond et al, 2005). These patients are not eligible to commence trastuzumab and should be started on an ACE inhibitor and referred to a cardiologist. Repeat assessment of cardiac function should take place after 3 months (but before the time window for starting trastuzumab specified by NICE expires).a significant decrease in LVEF (e.g., 0.10 points) during the course of anthracycline chemotherapy is most likely to indicate a left ventricle that has been left in a damaged, haemodynamically compromised state, and is thus at increased susceptibility to trastuzumab. Prophylactic ACE inhibitor therapy may therefore be considered for such patients. Initiation of trastuzumab therapy Trastuzumab may be initiated in patients with LVEF above the LLN for the institution (Figure 2A and D). Monitoring frequency

81 81 Routine LVEF monitoring is recommended at 4 and 8 months. A further assessment at the end of treatment is recommended for patients requiring cardiovascular intervention during treatment. The minimum number of LVEF assessments when following this recommendation is four, compared with five using the NCRI guidelines. Additional testing is required in patients who have LVSD, but the frequency of these additional tests is no more than in the present guidance. This slightly reduced frequency of monitoring reflects the more proactive approach to preventing cardiac events, and increased understanding of the time course and reversibility of trastuzumab-induced LVSD. Symptomatic heart failure Patients developing signs and symptoms of heart failure should have their trastuzumab treatment interrupted, have ACE inhibitor therapy initiated by the oncologist, and be referred to a cardiologist. Investigation and treatment is recommended in accordance with present guidelines (NICE, 2003; Bonow et al, 2005; Swedberg et al, 2005). Asymptomatic decrease in LVEF For the purposes of these recommendations, an LVEF of 0.40 or less has been taken to represent biologically important LVSD. This is in keeping with the many studies showing that at this level of LVEF, intervention with pharmacotherapy influences an otherwise adverse outcome. If the LVEF decreases to 0.40, trastuzumab should be interrupted, as significant LVSD has occurred. An ACE inhibitor should be started by the oncologist, and the patient should be referred to a cardiologist. Investigation and treatment is recommended in accordance with national and international guidelines on the management of CHF in adult (NICE, 2003; Bonow et al, 2005; Swedberg et al, 2005). The LVEF measurement should be repeated after 6 8 weeks. Trastuzumab may be re-initiated if the LVEF is restored to a level above the LLN. If the LVEF decreases to below the LLN but >0.40, trastuzumab may be continued, but an ACE inhibitor should be initiated. If this decrease occurs despite pre-existing ACE inhibitor therapy, the patient should be referred to a cardiologist. Monitoring should be repeated after 6 8 weeks. This may require a cultural shift among senior oncologists, but the members of the group have embraced this change in practice, which is working well in their centres. In the past decade, ACE inhibitor therapy has become the standard of care in the treatment of hypertension, primary and secondary prevention of cardiovascular disease, heart failure, and renal impairment. There are robust trial data to support these treatments, which are now often initiated, and almost universally monitored and titrated, in primary care. Angiotensinconverting enzyme inhibitors are some of the most widely used drugs in modern cardiology. They are very effective in a wide range of cardiovascular conditions, including asymptomatic LVSD (Moyé et al, 1994), heart failure due to LVSD (CONSENSUS Trial Study Group, 1987; SOLVD Investigators, 1991), LVSD following a myocardial infarction (Pfeffer et al, 1992; AIRE Investigators, 1993; Torp- Pedersen and Køber, 1999), hypertension (Dahlöf et al, 2005), and stable coronary artery disease (Yusuf et al, 2000; Fox et al, 2003). Their use is now included in all

82 82 the major national and international guidelines for the treatment of these conditions, both in primary and secondary care. If the LVEF decreases by 0.10 points or more and remains above the LLN, trastuzumab may be continued, but an ACE inhibitor should be initiated. Monitoring should be repeated after 6 8 weeks. A decrease of 0.10 or more may suggest an increased risk of heart failure, and intervention with an ACE inhibitor is recommended to reduce this risk. Figure 2 Traffic light system to prevent, monitor, and manage cardiac events in patients undergoing cytotoxic chemotherapy. (A) Patient assessment during trastuzumab therapy; (B D) indications for ACEi therapy and referral to a cardiologist before (B) and after (C) chemotherapy, and (D) during trastuzumab therapy, when additional cardiac assessments may also be required. ACEi=angiotensin-converting enzyme inhibitor A green light indicates LVEF above the LLN, no signs or symptoms of CHF and any trastuzumab-related LVEF decrease being <0.10.

83 83 An amber light indicates LVEF between the LLN and 0.40, with no signs or symptoms of CHF, or a trastuzumab-related LVEF reduction of 0.1 or more. A red light indicates LVEF 0.40 or symptoms and signs of cardiac failure. Before chemotherapy (Figure 2B), green indicates go. Red or amber indicates careful consideration of decision to start chemotherapy, with consideration of nonanthracycline-containing regimens. Both amber and red are indications for the initiation of ACE inhibitors and referral to cardiology for the optimisation of cardiac function. Post-chemotherapy (Figure 2C), green indicates go. Amber indicates defer until green. Red indicates that it is unlikely to be safe to start trastuzumab. Both amber and red are indications for the initiation of ACE inhibitors and referral to cardiology for the optimisation of cardiac function. It is recommended that LVEF is reassessed after 3 months, and that trastuzumab is not commenced unless LVEF is within normal limits at that point. During trastuzumab (Figure 2D), green is an indication to continue treatment. Amber is also an indication to continue treatment, but patients should also be taking an ACE inhibitor. Patients who drop into the amber range while on an ACE inhibitor should be referred for a cardiology opinion. Red is an indication to interrupt trastuzumab, start on an ACE inhibitor if applicable, and refer for a cardiology opinion. Patients whose trastuzumab is interrupted (i.e., red light) should not restart until LVEF is within the normal range (i.e., green light). Monitoring procedures in early and metastatic breast cancer These recommendations were primarily developed for use in patients with early breast cancer who are expected to complete a full 12-month course of trastuzumab therapy. In patients with metastatic breast cancer, trastuzumab is continued until disease progression, but the recommendations are still suitable for monitoring cardiac effects during the first few months of therapy. During trastuzumab therapy, patients with metastatic breast cancer should be monitored for 8 months according to our recommendations. Assuming no complications have occurred, cardiac monitoring should be performed at the discretion of the treating physician, after discussion with the patient, and in accordance with local guidelines. Patients with metastatic disease have a very different oncology risk profile to those receiving adjuvant treatment; the monitoring strategy and thresholds for treatment discontinuation should thus be individualised in consultation with the oncologist and cardiologist when appropriate. Administration

84 84 The recommended initial loading dose is 8 mg/kg body weight and subsequent doses are trastuzumab 6 mg/kg body weight 3-weekly. For the individual protocol details see the website Side effects Infusion related symptoms: during the first infusion chills and/or fever are commonly observed. These are usually mild and occur infrequently with subsequent infusions. These symptoms are treated with an analgesic such as paracetamol or an antihistamine such as piriton. Severe adverse reactions include hypotension, bronchospasm and respiratory distress can be serious and potentially fatal. Serious pulmonary events: rare complications of pulmonary infiltrates, acute respiratory distress syndrome, pneumonitis, acute pulmonary oedema and respiratory insufficiency have been reported. They may occur as an infusion related event or with a delayed onset. Patients with severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy should not be treated with trastuzumab. 1.4 Bone health The following advice is based on the UK Expert Group lead by David M Reid, Professor of Rheumatology, University of Aberdeen, reviewed and supported by the NCRI Breast Cancer Study Group and the National Osteoporosis Society (November 2007) The known major risk factors for osteoporotic fracture are: Previous fragility fracture above the age of 50 years; Parental history of fracture; A body mass index (BMI) of <22; Alcohol consumption of 4 or more units per day;

85 85 Diseases known to increase fracture risk such as premature menopause, rheumatoid arthritis, ankylosing spondylitis, immobility and Crohn s disease; and Prior oral corticosteroid use for more than 6 months. Osteoporosis and adjuvant therapy Bone health is an important issue in women undergoing adjuvant treatment for breast cancer. Two groups of women will be at risk of developing osteoporosis as a consequence of such therapy. Women with a premature menopause as a consequence of chemotherapy or ovarian suppression, ablation or removal; Post-menopausal women receiving treatment with aromatase inhibitor. Both groups of women should be given general advice on maintenance of bone health Adequate calcium intake in diet (1200mg/day) Adequate vitamin D intake in diet ( u/day) Weight bearing exercise such as walking Avoidance of smoking Moderation of caffeine intake Sensible exposure to sunlight Referral to a dietician is advised in at risk women. All women aged 65 and older who are receiving treatment with aromatase inhibitors should receive bisphosphonates for the duration of their exposure to the aromatase inhibitor and bone mineral density monitoring (DXA scan) or calcium supplementation is not required. This should be prescribed by their GP. No specific monitoring or treatment is required for women who continue to menstruate after treatment for early breast cancer or postmenopausal women above 45 years of age who do not require endocrine treatment or who are receiving tamoxifen.

86 86 Measurement of bone density Both groups of at risk women (please note above recommendation for women 65 and older) should be referred for a baseline measurement of bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA). BMD should be done at the lumbar spine and at one or both total hip sites. For premature menopausal women a baseline BMD assessment should be obtained within 3 months of commencing ovarian suppression therapy or oophorectomy and within 12 months of developing postchemotherapy amenorrhoea. For postmenopausal women receiving aromatase inhibitors a baseline BMD assessment should be obtained within 3 months of commencing aromatase inhibitor. Osteoporosis is defined as a BMD 2.5 standard deviations (expressed as a T-score) below peak bone mass or the mean bone density for young adult women. Osteopaenia is defined as a T-score -1 to -2.5 below the normal score for young adult women. Management For post menopausal women receiving adjuvant treatment with aromatase inhibitors three risk groups are defined: High-Risk group baseline T-score of <-2 or known vertebral fracture should receive biphosphonate therapy at osteoporosis doses in addition to lifestyle advice, calcium and vitamin D supplementation. DXA should be repeated after 24 months to assess compliance and response. Poor compliance and secondary osteoporosis explain most cases of poor response. Medium-Risk group baseline T-score between -1 and -2 should receive lifestyle advice plus calcium and vitamin D supplementation. DXA should be repeated after 24 months to exclude a clinical significant reduction in BMD (T-score of <-2 or >4% per annum decline in BMD). Patients who exceed these limits should be treated as per high-risk group.

87 87 Low-Risk group baseline T-score of >-1 (normal BMD) should receive lifestyle advice only and no follow up DXA is required. For premature menopause women receiving a concomitant aromatase inhibitor, only 2 groups are defined: High-Risk group T-score of <-1 or known vertebral fracture should receive bone protection with bisphosphonates as described above; Medium-Risk group T-score of >-1 should follow recommendations for all medium risk groups. The choice of biphosphonate should be based on local protocols. Weekly oral alendronate 70 mg or risedronate 35 mg, monthly oral ibandronate 150 mg, 3-monthly intravenous ibrandronate 3 mg, or 6-monthly intravenous zoledronic acid 4 mg are all considered appropriate. The patient should be referred to the osteoporosis clinic if intravenous biphosphonate is to be considered. Bisphosphonates are contraindicated in patients with low glomerular filtration rate (<30 ml/min/1.73 m 2 ) or hypocalcaemia. Oral bisphosphonates should be used with caution in patients with oesophageal disease although intravenous bisphosphonates will be appropriate in such patients. Calcium supplementation should be given at a dose of 1g/d and vitamin D at a dose of IU/d. Please note women with ER negative breast cancer who develop premature menopause are at risk of osteoporosis and recommendations for this specific group are due on the next update of the guidelines. Consider referral to the menopause clinic for women with premature menopause and/or poorly tolerated symptoms despite above measures. RECOMMENDATIONS

88 88 For the purpose of these recommendations, menopause is defined as amenorrhoea for at least 12 months and/or age over 60 years. Pre-menopausal women (Including women who were pre-menopausal at the time of initiation of chemotherapy but whose periods have stopped following chemotherapy). The standard of care is for tamoxifen for 5 years. Any changes should be discussed at the MDT meeting. If there is contraindication to tamoxifen an aromatase inhibitor with goserelin or oophorectomy should be considered. Peri-menopausal women (defined as women not clearly post-menopausal) should also receive 5 years of tamoxifen and be considered for extended adjuvant endocrine therapy with aromatase inhibitor at the completion of the 5 year period if appropriate. Plus see above for ovarian suppression Women with high risk breast cancer who were pre-menopausal and become amenorrhoeic secondary to chemotherapy and are on tamoxifen should only be switched to an aromatase inhibitor with extreme caution, preferably in the presence of goserelin or after a laparoscopic oophorectomy. This decision should only be made by a consultant oncologist. All pre- or perimenopausal women with ER positive breast cancer that became amenorrheic secondary to chemotherapy and completed 5 years of tamoxifen should be considered for extended adjuvant treatment with an aromatase inhibitor. This group of patients should have serum levels of FSH/LH/Oestradiol measured 3 months after discontinuing tamoxifen and, if biochemically postmenopausal, 5 years of letrozole should be offered. All pre-menopausal and peri-menopausal women with node positive breast cancer who completed 5 years of adjuvant tamoxifen should be considered for extended adjuvant endocrine therapy with an aromatase inhibitor for 5 years when become post menopausal.

89 89 Women with very poor risk ER positive breast cancer who continue to menstruate after 5 years of tamoxifen should be considered for an aromatase inhibitor together with an LHRH agonist or bilateral oophorectomy. Patients on tamoxifen who wish to become pregnant should be advised to discontinue tamoxifen for a minimum of two months before trying to become pregnant. Post-menopausal women At Outset All postmenopausal women with ER positive tumours should receive adjuvant endocrine therapy with letrozole for 2 years followed by tamoxifen for 3 years. After 2-3 years of tamoxifen Women who are already on tamoxifen and are not on the low risk group should be considered for a switch to an aromatase inhibitor (anastrozole or exemestane) for the remainder of the 5 year period. After 5 years of tamoxifen Women who have completed 5 years of tamoxifen and originally had node positive or high risk node negative breast cancer should be offered 5 years of letrozole. Letrozole is only licensed for this indication if commenced within 3 months of finishing tamoxifen. Patients who were originally advised to receive 5 years of letrozole should complete 5 years of letrozole and stop. Co-morbidity and potential side effects should be considered when discussing the above options with patients. For example, a post-menopausal woman with a history of thromboembolism should not be treated with tamoxifen.

90 90 2. Treatment and Management of Metastatic disease: 2.1 General Principles The aim of treatment is symptom relief. Prophylactic palliation may be justified in some patients with minimal or no symptoms. Age, performance status, sites of disease and previous therapy affect the first line modality used. Local therapy with radiation or limited palliative surgery should be considered where local symptoms predominate. Before introducing a change in systemic therapy document the nature and severity of the symptoms for subsequent subjective assessment of patient response. Avoid any treatment with side effects worse than those caused by the patient s cancer. Nominate marker lesions for objective assessment of patient response. Ensure bi-dimensional measurements are documented making use of diagrams and photographs as appropriate. Endocrine therapy often works slowly and patients with stable disease do almost as well as those whose tumours achieve a partial response. Treatment with endocrine therapy should, therefore, be continued for as long as the patient is well, with relief of symptoms, and without evidence of progression, whether or not there is objective evidence of tumour regression. In contrast, chemotherapy is generally reassessed after 2-3 courses and treatment should only be continued beyond this if there is clear cut evidence of symptom relief and/or tumour regression. This should be seen as a guideline rather than a hard and fast rule, based on a balance between clinical benefit and side effects of treatment. In general, patients with metastatic disease should be considered for any appropriate clinical trials. Standard treatment should only be given if there is no appropriate trial or the patient declines entry. Chemotherapy should only be used for patients with ECOG performance status 0-2. Exceptions can be made for younger patients by the consultant in charge. Occasionally, remarkable responses, which are clinically valuable are seen in patients with PS3 secondary to liver metastases. The great majority of such patients, however, does badly and is better treated in conjunction with the palliative care team.

91 91 It is policy to liaise with the Palliative Care team as early as possible in the course of metastatic disease. Patients who develop unpleasant symptoms, particularly pain, should be referred early and their disease managed jointly by the two units. There are many potential options for the treatment of metastatic breast cancer and the individual management of a patient will need to take into account many factors. Therefore the following represent a general framework rather than specific guidelines. As a principle, if possible, it is worth obtaining a biopsy of the metastatic disease in order to reevaluate the ER and the HER2 status of the metastatic tumour which may be influenced by prior therapies and clonal outgrowth. 2.2 Endocrine therapy Women who have ER positive breast cancer (defined as in the adjuvant setting as an Allred score of 3 or more) should be considered for systemic endocrine therapy. 1 Post menopausal women who have not had an aromatase inhibitor: First line therapy should be with letrozole 2.5mg per day or anastrazole 1mg per day Second-line tamoxifen 20 mg per day exemestane 25 mg per day Third line megestrol acetate 160mg per day Consider this in patients with a long natural history and/or with slow indolent disease In accordance with the London Cancer New Drugs Group (LCNDG) guidance, fulvestrant is recommended for the treatment of postmenopausal women with metastatic breast carcinoma who are intolerant of aromatase inhibitors.

92 92 Intolerance is defined as Allergic reaction Severe arthralgia/myalgia despite the use of anti-inflammatories Other severe drug related adverse events should be discussed with a Consultant Oncologist before Fulvestrant is considered In addition, postmenopausal women with oestrogen receptor positive locally advanced or metastatic breast cancer which relapsed on or after adjuvant anti-oestrogen therapy or progressed on therapy with an anti-oestrogen and has had two lines of hormonal treatment with at least one aromatase inhibitor are eligible for treatment with Fulvestrant. This is currently funded by the Cancer Drugs Fund. Application forms are available on the SELCN website. 2 Women who have had an aromatase inhibitor in the adjuvant setting can be rechallenged with the same treatment if there is a long disease-free interval (usually taken to be greater than 1 year). Otherwise: tamoxifen 20 mg per day or exemestane 25 mg per day 2.3 Trastuzumab (Herceptin) All women with advanced breast cancer should have tumour tissue (either original primary or fresh biopsy) tested for HER2 expression. Patients with HER2 overexpression at the 3+ level by immunohistochemistry or with gene amplification by fluorescent in-situ hybridization should be considered for therapy with trastuzumab as per NICE guidance (see below). As monotherapy in patients who have received at least 2 chemotherapy regimens for their metastatic disease. Prior chemotherapy will generally have included at least an anthracycline and a taxane unless patients are unsuitable for these treatments.

93 93 In combination with Docetaxel or paclitaxel in patients who have not received chemotherapy for their metastatic disease and for whom an anthracycline is not suitable. Patients should be of performance status 0 2 and have a life expectancy of >3 months. The standard treatment recommended by SELCN for HER2 positive patients in the metastatic setting is (if appropriate for the particular case) combined taxane/trastuzumab regimen followed by trastuzumab monotherapy (once taxane treatment is completed) until disease progression when trastuzumab should be discontinued and the patient treated with cytotoxic chemotherapy only. However, if CNS is the only site of metastatic progression trastuzumab should be continued. There is evidence that continued anti-her2 therapy beyond progression can improve response rates and progression-free survival. However this is not currently funded in the NHS. Patients can be made aware of co-payment or private arrangements. Exclusions: Patients are to be excluded if Pregnant or lactating. Brain metastases not suitable for active treatment (radiotherapy or surgery). Significant cardiac disease (eg ventricular arrhythmia s, congestive heart failure or myocardial infarction within 6 months). Care should be exercised if an anthracycline has been given at a dose of >300 mg/m 2 of doxorubicin or 750 mg/m 2 of epirubicin. Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy. Care should also be exercised if there is a history of allergies to mouse proteins or drugs containing polysorpat 20. Investigations A per UKNCRI recommendations (see section on adjuvant trastuzumab)

94 94 Administration Although the licensed indication of trastuzumab is with once-weekly dosing the SELCN, in common with most major cancer centres, usually employ three-weekly scheduling. The recommended initial loading dose is 8 mg/kg body weight and subsequent doses are trastuzumab 6 mg/kg body weight IV 3-weekly. Dose reduction no reduction in the dose of Trastuzumab is normally necessary. In patients who cannot tolerate Trastuzumab the treatment will be stopped. Concomitant anti-emetics before Trastuzumab are not necessary. In the event of cardiac toxicity see UKNCRI recommendations. The use of trastuzumab for first line metastatic progression outside of NICE guidance, for example in combination with vinorelbine is occasionally considered on an individual patient basis. 2.4 Chemotherapy The exact choice of regimen will depend on a number of factors including: Prior chemotherapy and previous response Cumulative anthracycline exposure Patient choice and fitness

95 95 It is not possible therefore to recommend which regimen should be used in which circumstance (except to note the NICE guidance). The following regimens are all acceptable: Anthracyline naïve or retreatment (NB maximum allowable dose for doxorubicin is mg/m 2, and for epirubicin 950mg/m 2 although less if other cardiac risk factors present or prior mediastinal radiotherapy Single agent epirubicin three weekly Dose usually mg/m 2 iv day 1 Single agent epirubicin weekly Dose usually mg/m 2 iv day 1 EC - Epirubicin and cyclophosphamide Dose usually mg/m 2 and 600 mg/m 2 respectively iv day 1 FEC (as per adjuvant) Taxanes Given according to NICE guidance: 1. The use of Docetaxel in combination with an anthracycline in first line treatment of advanced breast cancer is not currently recommended. As paclitaxel is not licensed for first-line use with an anthracycline, its use has not been considered in this indication. 2. Docetaxel and paclitaxel are recommended as an option for the treatment of advanced breast cancer where initial chemotherapy (including an anthracycline) has failed or is inappropriate.

96 96 Doses Docetaxel Starting dose 100 mg/m 2 or 75 mg/m 2 iv day 1 depending on patient factors Primary prophylaxis with GCSF should be given with Docetaxel 100mg/m 2 Paclitaxel Starting dose usually 175 mg/m 2 iv day 1 three-weekly or mg/m 2 iv day 1 weekly Gemcitabine and Paclitaxel May be considered for selected young patients Other chemotherapy agents for advanced breast cancer Vinorelbine Intravenous therapy Doses mg/m 2 given on day 1 and 8 every 21 days. Vinorelbine Oral therapy Doses Cycle 1: 60 mg/m 2 D1 and D8 Cycle 2: 60 mg/m 2 D1 and escalate to 80 mg/m 2 on D8 if no grade 4 neutropenia (<0.5 x 10 9 /l) or febrile neutropenia.

97 97 The subsequent cycles should be given with the same dose as D8 cycle 2. Capecitabine Dose 1250 mg/m 2 orally twice daily on days 1-14 every 21 days Consider commencing at 1000 mg/m 2 for frail patients. Consider discontinuing Capecitabine after 6 cycles if SD (benefits and risks should be balanced) Combination therapy: Combination treatment is sometimes considered for the treatment of advanced disease: Docetaxel and Capecitabine MVP Mitomycin C 8mg/m 2 on cycles 1,2,4 and 6 only Vinblastine 6 mg/m 2 (max 10 mg) Cisplatin 50 mg/m 2 MVCarbo Mitomycin C 8mg/m 2 on cycles 1,2,4 and 6 only Vinblastine 6 mg/m 2 (max 10 mg) Carboplatin typically at AUC 5

98 98 Please see below for agreed protocols Paclitaxel +/- Herceptin 1 st line if previous anthracycline 6 cycles Paclitaxel weekly +/- Herceptin Herceptin monotherapy 1 st line if previous anthracycline Maintenance after a course of chemotherapy or patients to do not wish/cannot tolerate cytotoxics Up to 18 cycles Until disease progression Epirubicin 3-weekly 1 st line if no previous anthracycline and frail Epirubicin weekly 1 st line if no previous anthracycline and frail 6 cycles Up to 18 cycles For the individual protocol details for each of these chemotherapy regimens, see the website Click on the Chemotherapy button on the left hand side of the page (no password required) then click oncology then breast, the protocols will then be listed. Each protocol describes the drug doses, the schedule of treatment, administration guidelines, extravasation and ematogenic potential, regular investigations required, common toxicities, drug interactions and guidance for the management of common toxicities. 2.5 Metastatic bone disease Patients with metastatic bone disease (lytic and/or sclerotic lesions) should be treated with intravenous bisphosphonates such as zoledronic acid for 6 months then changed to an oral bisphosphonate (e.g. ibandronic acid or clodronate) providing the disease remains clinically stable. Patients should be informed at the start of biphosphonate treatment the intent to switch to an oral biphosphonate such as ibandronate 50mg once daily following 6 infusions of zoledronic acid.

99 99 Zoledronic acid is known to be associated with osteonecrosis of the jaw and all patients commencing intravenous bisphosphonates should have a dental check up and sign informed consent prior to commencing treatment. 2.6 Managing common chemotherapy-related toxicity Follow guidelines for the adjuvant setting. Please note that in the metastatic setting chemotherapy should only be given if the neutrophil count is 1.5 x 10 9 /l, unless PS 0 when neutrophil count of greater than 1.0 x 10 9 /l is acceptable.

100 100 Survivorship guidelines SELCN Breast Tumour Working Group Draft august 2011 Context It is estimated that around 2 million people in the UK are currently living with and beyond cancer and the number is rising by approximately 3% a year (1). Macmillan Cancer Support define a cancer survivor as anyone who has completed initial cancer management and has no apparent active disease or is living with progressive disease and may be receiving cancer treatment but not in the last six months of life. Research shows that many patients have unmet needs following completion of treatment (2, 3). The need to review and redesign current practice to find innovative ways to address unmet needs is recognised throughout National Policy and Guidance (4, 5,6). The Commissioning Cancer Services document (2011) highlights areas of best practice in care delivery for people living with and beyond cancer (7). co-ordinated care within and across organisations with the patient being clear about whom to contact for support, especially out of hours high quality patient information to aid decision-making about treatment options and where treatment might take place effective face-to-face communications between professionals and patients individual, holistic patient needs assessment access to supportive and holistic services culturally sensitive service provision and availability routine data collection on patient experience across the patient pathway assessment on completion of treatment, supported by an individual plan for ongoing support and follow-up. Assessment and care planning The need to undertake post treatment assessments of and developing an on-going care plan for patients who have finished treatment is recognised as an important component of care (1, 8, 9). A SELCN holistic needs assessment has been developed and this should be implemented locally in line with Network guidance. The National Cancer Survivorship Initiative (6) recommends that the patient should receive a personalised care plan and a written summary of the treatment they have received, a copy of this should be sent to the GP. The care plan should highlight any specific needs that the patients may have and the plans for addressing those needs. The plan should also include designated named professionals, dates for review of adjuvant therapies, details of surveillance mammography, contact details for immediate referral to specialist care and contact details for support services in line with NICE Guidance (10). This will become national policy in Teams should put in place plans to meet this policy change locally. Addressing health and wellbeing promoting self management Patients should be offered access to services offering education and support during and beyond treatment empowering to self manage aspects of their care and signposting patients to further services available. Patients across the SELCN have access to post-surgery courses for example Recovery in Motion for Kings Health Partner patients and the Post operative and Wellbeing Clinic held at the Princess Royal Hospital. Patients completing treatment for early breast cancer

101 101 should be offered access to other survivorship services promoting self management such as Surviving Cancer Living Life and the Breast Cancer Care Moving Forward Programme if appropriate. Information about lifestyle changes/choices such as exercise and weight management should be made available in local services and the structured services mentioned above. Patients should be offered access to the local professionally led support groups available across the Network and made aware of the services of Breast Cancer Care. Active and advanced disease Patients with active and advanced disease should have access to a CNS and services should be working towards meeting the standards set by the Breast Cancer Care Secondary taskforce (11). Consequences of cancer treatment A third of patients report that they have moderate or severe unmet needs for support with a range of issues (physical, psychological, social, sexual and with negotiate the health care system) (2). Early and late effects of treatments received must also be considered. For breast cancer patients these may include: Menopausal symptoms Concerns re; bone health Fatigue Fertility issues Lymphoedema Body image worries Emotional or psychological concerns Sexual problems Financial worries Difficulty maintaining or returning to employment Patients should be offered information about local services in (community, hospital based and voluntary sector) to address identified on-going care needs. References: 1. Macmillan Cancer Support (2008) Two Million Reasons. The Cancer Survivorship Agenda. Macmillan Cancer Support: London s.pdf

102 Armes, J. Crowe, M. Colbourne, L. Morgan, H. Murrells, T. Oakley, C. Palmer, N. Ream, E. Young, A. Richardson, A. (2009) Patients' supportive care needs beyond the end of cancer treatment: A prosepctive longitudinal study. Journal of Clinical Oncology Vol 27, No Macmillan Cancer Support (2008) Health and Wellbeing Survey. Macmillan Cancer Support: London 4. Department of Health (2007) Cancer Reform Strategy. Department of Health: London 5. National Institute of Health and Clincial Excellence (2009) Early and Locally Advanced Breast Cancer: Quick Reference Guide. NICE: London 6. Department of Health (2010) National Cancer Survivorship Initiative: Vision. Department of Health: London 7. Department of Health (2011) Commissioning Cancer Services. Department of Health : London 8. National Cancer Action Team (2007) Holistic Common Assessment of Supportive and Palliative Care Needs for Adults with Cancer - Assessement Guidance. National Cancer Action Team: London 9. Macmillan Survivorship Research Group (2009) Care After Cancer. University of Southampton and Macmillan Cancer Support rshipreport2009.pdf 10. NICE (2009) Early and locally advanced breast cancer. NICE: London 11. Breast Cancer Care (2008) Improving the care of women with metastatic breast cancer: Final Report. Breast Cancer Care Secondary Task Force: London