Breast. Ian Kunkler ANATOMY. Lymphatic drainage. PATHOLOGY Epidemiology

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1 CHAPTER CONTENTS Anatomy 432 Lymphatic drainage 432 Pathology 432 Epidemiology 432 Aetiology 433 Ductal and lobular carcinoma-in-situ 434 Malignant transformation from carcinomain-situ 434 Histology 434 Lymphatic spread 435 Natural history Breast Ian Kunkler Diagnosis 435 Staging 437 Treatment of ductal carcinoma-in-situ 438 Treatment of early breast cancer 438 Importance of locoregional control of breast cancer 440 Management of the axilla 441 Trials of adjuvant postoperative radiotherapy 442 Target volume and techniques for locoregional irradiation 445 Morbidity of radical radiotherapy 450 Results of radical radiotherapy 451 Adjuvant hormonal and cytotoxic therapy 451 Rationale 451 Who benefits? 452 Adjuvant tamoxifen 452 Adjuvant ovarian suppression 453 Adjuvant combination chemotherapy (polychemotherapy) 453 Management of locally advanced breast cancer 455 Clinical features 455 Principles of management 455 Neoadjuvant therapy 455 Role of surgery 455 Systemic therapy 455 Concurrent chemoradiation 456 Intra-arterial chemotherapy 456 Radical radiotherapy 456 Palliative radiotherapy 456 Palliative surgery 457 Results of treatment 457 Medical management of metastatic disease 457 Principles of management 457 Cytotoxic therapy 459 Overall survival in breast cancer 461 Follow-up 461 Breast cancer in pregnancy 463 Breast cancer in males 464 ANATOMY Most of the breast tissue extends from the edge of the sternum to the anterior axillary line and from the second or third to the sixth or seventh costal edge. It overlies the second to the sixth ribs. Breast tissue can be found beyond these areas as high as the clavicle and laterally to the edge of the latissimus dorsi muscle. It is composed of lobules of glandular tissue lying in fat. The lobules are divided by fibrous ligaments (Cooper s ligaments) which run between the superficial fascia of the breast and the deep fascia overlying pectoralis major. Lymphatic drainage A knowledge of the lymphatic drainage of the breast (Fig. 26.1) is important. The principal lymphatic drainage of the breast is to the axillary nodes lying between the second and third intercostal spaces. Additional drainage occurs to the supraclavicular nodes through the pectoralis major and to the internal mammary chain adjacent to the sternum. PATHOLOGY Epidemiology Breast cancer is the commonest form of malignancy in western countries and accounts for 12% of all cancers, 18% of all female cancers, 10% of all cancer deaths and 20 25% of all female cancer deaths. Worldwide there are approximately one million new cases annually. In the UK over women die of the disease per year, and at least half a million worldwide. The risk of a woman developing the disease at some stage of her life is 1 in 12. The UK has the highest age standardised incidence and mortality for breast cancer in the world. The prevalence of breast cancer is 2%. Of every 1000 women aged 50, 15 will have had a diagnosis of breast cancer. 432

2 BREAST 433 Axillary nodes Apical group Central group Anterior group Posterior group Lateral group A Axillary vein Pectoralis minor Internal mammary nodes affected. Women who have a first-degree relative with premenopausal or bilateral breast cancer are at particularly high risk. Two breast cancer predisposing genes, BRCA1 and BRCA2, have been identified. The mode of inheritance is usually autosomal dominant with incomplete penetrance. It is important to note that the genetic susceptibility can be passed on by both males and females. Most cases of breast cancer with a genetic basis will have occurred by the age of 65. From a validated family history the risks of women at higher than normal risk of developing breast cancer can be identified. Those at very high risk will have four or more relatives affected with breast or ovarian cancer over three generations and one living affected relative. Those at substantial risk include women with: Three first- or second-degree relatives with breast or ovarian cancer One first-degree relative with bilateral breast cancer Two first- or second-degree relatives with breast cancer diagnosed under the age of 60 or ovarian cancer at any age on the same side of the family. First-degree relatives are mother, sister or daughter. Second-degree relatives are grandmother, granddaughter, aunt or niece. B Fig A The lymph nodes of the axilla. B Diagram of the principal pathways of lymphatic drainage of the breast. These follow the venous drainage of the breast to the axilla and to the internal mammary chain. (Reproduced with permission from Ellis, Clinical Anatomy, 5th edn, Blackwells, 1975.) Breast cancer is rare below the age of 30. Male breast cancer is rare (1% of all breast cancer). Aetiology The aetiology of breast cancer is unknown in most cases but a number of predisposing factors have been identified. Both genetic and acquired factors are thought to play a part. Genetic factors It is estimated that up to 10% of breast cancers have a genetic basis. The sisters and daughters of a woman with breast cancer have a threefold increased risk of developing the disease. The risk of breast cancer for a woman whose sister is affected is doubled. This rises to 10-fold for women who have a mother and a sister Acquired Benign breast disease. A number of benign conditions (e.g. fibroadenomas, palpable cysts) in the breast increase the risk of breast cancer, although the effect is small. Overall the risk of breast cancer is raised by a factor of for women with previous benign breast disease but rises to ninefold in women with severe atypical breast hyperplasia and a family history of an affected first-degree relative. Menstruation. Breast tissue is subject to repeated monthly cyclical changes under hormonal stimulation. The epithelium of the breast proliferates during ovulatory cycles. This may be due to the stimulus of either progesterone or oestrogen. This causes temporary growth of the milk-secreting glandular tissue in preparation for possible pregnancy. The greater the number of years of menstruation, the higher the risk of breast cancer. If the menarche starts before the age of 12, the risk of breast cancer is nearly double that of women who begin to menstruate after the age of 13. If menstruation continues above the age of 55, the risk of breast cancer is doubled compared with a normal menopause at 45 years. Furthermore, if a woman undergoes an artificial menopause (e.g. due to a hysterectomy and oophorectomy under the age of 40), there is a fourfold fall in the incidence of breast cancer.

3 434 RADIOTHERAPY AND ONCOLOGY Oral contraceptive pill and hormonal replacement therapy. The role of the ovarian oestrogens in the genesis of breast cancer is strongly suspected. Reductions in oestrogen levels may protect against breast cancer. Oral oestrogens, either as the contraceptive pill or as hormone replacement therapy, may accelerate the development of breast cancer. There is a small increased risk in women who are taking the oral contraceptive pill and for 10 years after cessation. However, type of oral contraceptive and duration of use do not influence risk of breast cancer. There is a small increase in risk among current users of hormone replacement therapy or those using it 1 4 years previously. Combined preparations of oestrogen and progestogen confer a higher risk. Age at time of first pregnancy. The risk of breast cancer in a woman rises with her age at first pregnancy. It is three times higher in women who have their first baby over the age of 30, compared with those under the age of 18. Lactation. Women who have breast-fed their children are slightly less prone to breast cancer. Age at first full-term pregnancy. Pregnancy itself seems to have a protective role. Women who first become pregnant before the age of 30 have a lower risk of breast cancer than women who first give birth after the age of 30. This effect only applies to completed pregnancies. Diet. Adiet high in animal fats may promote the development of breast cancer. It is possible that the link between fat and breast cancer may be that many of the carcinogens acting on the breast are absorbed in the diet and are soluble in fat. There is some evidence that a high intake of alcohol is linked to breast cancer. Weight. In obese postmenopausal women, the risk of breast cancer is increased. This might be due to increased quantities of oestrogens stimulating malignant transformation of the breast. Radiation. Exposure to ionising radiation increases the risk of breast cancer. This is true of women who underwent low-dose breast irradiation for benign mastitis. There is a linear relationship between dose and incidence of breast cancer up to 4 Gy. Beyond this the incidence plateaus. It has been calculated that one extra cancer per year after 10 years may be caused by radiation from a single mammogram among 2 million women over the age of 50. The risk is small compared to the incidence of breast cancer of 2000 per million women aged 60. Children irradiated by the atomic bombs dropped on Nagasaki and Hiroshima showed an increased risk of breast cancer with dose. Ductal and lobular carcinoma-in-situ Premalignant in situ carcinoma may occur in the lobules (lobular carcinoma-in-situ (LCIS) ) or ducts (ductal carcinoma-in-situ (DCIS) ). With the advent of breast screening the diagnosis of DCIS has increased three to four times and now accounts for 15% of cases detected by mammography. Before screening, DCIS was mostly associated with symptomatic breast disease. Its natural history among asymptomatic women selected for screening is unknown and may differ. At post-mortem, the incidence of DCIS is much higher in women with breast cancer (40%) compared with those with normal breasts (5%). DCIS is associated with a substantial risk of progression to invasive carcinoma, with a mean delay of about 7 years. LCIS is associated with an increased risk of tumour in both breasts, particularly infiltrating ductal carcinoma. Malignant transformation from carcinoma-in-situ When malignant cells are confined to the ductal lobular system, they are termed carcinoma-in-situ. In situ carcinoma has the potential to become invasive cancer but it is not clear how often this transformation occurs. Histology A lump in the breast may be benign or malignant. Benign lesions include cysts, fibroadenomas and papillomas. Malignant tumours mainly arise from the glandular epithelium (adenocarcinomas). Breast cancers are classified as of no special type or of special type. The majority (80%) are of no special type. The histological types of breast cancer are shown in Table Invasive cancers have traditionally been classified by their microscopic appearance and by histological grade. Grading is based on nuclear pleomorphism, Table No special type 2. Special type a. Tubular b. Mucoid c. Cribriform d. Papillary e. Medullary f. Classic lobular Classification of invasive breast cancer

4 BREAST 435 degree of glandular formation and frequency of mitoses. Grading yields useful prognostic information; both disease-free survival and overall survival are shorter for high-grade cancers. If in excess of 25% of the main tumour mass contains non-invasive (in situ) disease and in situ disease is present in the adjacent breast tissue, the tumour is described as having an extensive in situ component. Such patients are at risk of developing invasive cancer elsewhere in the breast and are not suitable for breast conservation. Lymphatic or vascular invasion within the tumour confers an increased risk of local and distant recurrence. Inflammatory carcinomas are typified by an enlarged warm breast, associated with an ill-defined underlying mass. Histologically, there is infiltration of the subdermal lymphatics. Prognosis is poor. In contrast, medullary carcinoma is slow growing and has a much better prognosis. Lobular invasive carcinomas are often bilateral (40%) and multicentric. Paget s disease of the nipple is commonly associated with an underlying ductal adenocarcinoma. Lymphatic spread Most tumours develop within the ducts and spread along the ducts and fascia into the mammary fat, the lymphatic channels of the breast and into the peripheral lymphatics. Invasive tumour may infiltrate the dermal lymphatics of the breast, causing oedema of the skin (peau d orange). Tumours of the upper outer quadrant are more likely to have involved axillary nodes. The larger the tumour, the higher is the incidence of involvement of the axillary nodes. The higher the level of axillary involvement, the worse is the prognosis. Palpable supraclavicular nodes reflect advanced disease (M1). In the presence of palpable axillary nodes there is a higher probability of involvement of the internal mammary nodes in tumours of the lower inner quadrant (72%), upper inner quadrant (45%) and central part of the breast (45%) compared with the lower outer quadrant (19%) and upper outer quadrant (22%). Natural history Tumours are commoner on the left side. Bilateral tumours are detected at the time of diagnosis (synchronous) in 1 2% of patients. A subsequent (metachronous) tumour in the opposite breast occurs in 7 8%. Breast cancer shows a very wide range of behaviour, with great differences in rate of growth and tendency to metastasise. The majority of tumours (40%) originate in the upper outer quadrant of the breast. 30% occur in the central part of the breast, 15% in the upper inner quadrant, 10% in the lower outer quadrant and 5% in the lower inner quadrant. Although many tumours do progress locally and then regionally, blood-borne metastases do occur even when the primary is small or impalpable. A few, often young patients may die from rampant metastatic disease within a few weeks of the diagnosis. By contrast, particularly in the elderly, the disease may grow slowly and remain confined to the breast. DIAGNOSIS The patient may notice a lump herself on routine or casual self-examination. Sometimes it is detected by her general examination as part of clinical examination for other reason or as a result of routine examination in hospital. With the introduction of the breast-screening programme in the UK, asymptomatic breast cancer is being more frequently diagnosed among women routinely screened for breast cancer between the ages of 50 and 64. In % of women (1.2 million) aged were screened, detecting 7000 cancers, a yield of 0.6% (6 per 1000). With the extension of the breastscreening programme to older women up to the age of 69, the number of breast cancers detected through breast screening is likely to rise. Estimates of the cost per life saved range from million pounds. Patients should be referred to a specialist breast unit with multidisciplinary management from surgeon, oncologist, radiologist, pathologist and breast care nurse. There is evidence that patients managed in specialist breast centres have better outcomes than those in non-specialist centres. Clinical assessment A full history is required, including details of breastrelated symptoms, particularly breast pain, nipple discharge, changes noted in the skin (erythema, dimpling) or shape of the breast, indrawing or distortion of the nipple, axillary lumps and systemic symptoms of weight loss, anorexia, nausea, vomiting, bone pain, breathlessness, headache or motor or sensory disturbance. A full menstrual history should be taken including onset of menarche, menopause, parity, age of first pregnancy, breast/bottle feeding and use of the contraceptive pill and hormone replacement therapy.

5 436 RADIOTHERAPY AND ONCOLOGY Mammography Breast screening by mammography in the UK is recommended to women between the ages of every 3 years. Not all women have access to routine breast screening. The age when screening should begin and the frequency with which it should be done is controversial. Interval cancers (cancers presenting between screens) are an index of the effectiveness of screening. Interval cancers are commoner in the year preceding the next due screen, suggesting that biennial rather than triennial breast screening would be preferable. In younger women the breast tissue is more radiodense and tumours may be difficult or impossible to identify. In older women the breast tissue tends to be more radiolucent and tumours easier to see. This suggests that breast screening may be particularly beneficial in older patients. In the UK two views of the breast are obtained (oblique and craniocaudal). Mammography requires compression of the breast and women often find the investigation painful. None the less, in the countries where it has been widely applied (e.g. in Sweden) its use has been shown to reduce the mortality of breast cancer by 30%. For such results to be achieved, high levels of compliance to invitations to attend (> 70%) has to be achieved and maintained. A strict quality assurance programme is essential to maintain the quality of a breast-screening service. Features suggestive of malignancy are small microcalcifications, stellate opacities with legs extending into the surrounding tissues (Figs 16.8 and 16.9) or distortion of architecture. Mammography may also show enlarged nodes in the axilla. About 15% of cancers are not detected by mammography and nearly 4% are neither palpable nor visible on mammography. MRI scanning (Fig. 26.2) may have an important role in the assessment of (a) the local extent of the primary tumour and of multifocality in younger women where the density of the breast is often a limiting factor to the resolution of mammography and (b) recurrent disease in the irradiated breast 18 months or more after radiotherapy has been completed. Breast ultrasound Ultrasound of the breast has an important role in helping to distinguish benign from malignant lesions, particularly when mammography is normal or equivocal. Malignant tumours tend to show an abnormal echo pattern (Fig. 26.3). Colour Doppler ultrasound may show changes caused by increased tumour vasculature both in primary tumours and in lymph nodes. Obtaining a histological diagnosis It is important to obtain a histological diagnosis of breast cancer to confirm suspicious clinical or radiological features. If the tumour is palpable (usually 1 cm or larger), fine needle aspiration cytology (FNAC) is recommended as the initial method of confirming the diagnosis. Ideally this should be examined by a specialist pathologist to determine whether malignant cells are present. It should noted that FNAC does not remove sufficient tissue to determine whether invasion is present or the architecture of the tumour. Occasionally false-positive cytology may occur from what prove to be benign lesions such as a fibroadenoma. In view of this possibility, a decision to proceed to a mastectomy requires additional evidence of malignancy (such as a malignant mammogram). Core biopsy under local anaesthetic for palpable lesions or stereotactic image-guided core biopsy for impalpable lesions is becoming increasingly popular as an adjunct to FNAC. If FNAC is negative or equivocal, core biopsy can be helpful since it provides more tissue available for histological analysis. Oestrogen receptor status can be established on FNAC or core biopsy. Fig MRI scan showing recurrent cancer in the breast. (Courtesy of Mr M. Dixon, Edinburgh Breast Unit.) Fig Ultrasound of the breast showing indistinct outline of carcinoma (right) compared to well-defined margins of benign fibroadenoma (left). (Courtesy of Mr M. Dixon, Edinburgh Breast Unit.)

6 BREAST 437 Unfortunately, lumps that appear to be clinically and radiologically benign (e.g. fibroadenomas) occasionally turn out to be malignant. For this reason there is an increasing trend for such lumps to be excised for histological analysis. If excision or core biopsy shows the lump to be benign, the patient can be reassured. Preoperative diagnosis is important since it enables the plan of management to be discussed with the patient by the surgeon and oncologist. STAGING Staging is important to assess the local, regional and metastatic spread of breast cancer since management may differ significantly depending on the extent of the disease. Staging involves clinical, radiological and laboratory assessment. The simplest staging system which is still in use in shown in Table However, the TNM classification of the International Union Against Cancer (Table 26.3) has gained widespread acceptance. For the T and N classification, the size and mobility of the tumour and any tethering to the skin or underlying muscle or chest wall should be noted. The regional lymph nodes are palpated (axillary and supraclavicular nodes) on both sides. Respiratory examination may show a pleural effusion. Whether palpable nodes are histologically involved is often difficult to assess. Hard nodes, especially if they are tethered or fixed in the axilla, are usually malignant. Soft mobile nodes may be benign or malignant. Staging investigations For patients with T1 2N0M0 disease a full blood count, liver biochemistry and chest radiograph are recommended. For patients with (a) T3 or T4 tumours (b) N1 3 or MI, or (c) T0 2N0 disease with symptoms which could be due to metastatic disease (e.g. unexplained bone pain or weight loss), a liver ultrasound and a bone scan are recommended. Bone marrow aspiration and trephine biopsy should be performed if Table 26.2 Stage I II III IV Clinical staging of breast cancer Clinical findings Freely movable (on underlying muscle). No suspicious nodes As stage I but mobile axillary node(s) on the same side Primary more extensive than stage I, e.g. skin invaded wide of the primary mass or fixation to muscle. Axillary nodes, if present, are fixed; or supraclavicular nodes involved Extension beyond the ipsilateral chest wall area, e.g. opposite breast or axilla; or distant metastases Table 26.3 Stage TNM classification of breast cancer Clinical findings Primary tumour Tis T0 T1 T1a T1b T1c T2 T3 T4 T4a T4b T4c Regional lymph nodes N0 N1 N2 N3 Distant metastases M0 M1 Carcinoma-in-situ No demonstrable tumour in the breast Tumour less than 2 cm in greatest dimension confined to the breast Tumour 0.5 cm or less in maximum dimension Tumour more than 0.5 cm but not more than 1 cm in greatest dimension Tumour more than 1 cm but not more than 2 cm in greatest dimension Tumour more than 2 cm but less than 5 cm in greatest dimension Tumour more than 5 cm in its greatest dimension Tumour of any size with direct extension to chest wall or skin Fixation to chest wall Oedema, infiltration or ulceration of the skin of the breast Both of above No palpable nodes Mobile ipsilateral nodes Fixed ipsilateral nodes, fixed to each other or to other structures Ipsilateral internal mammary nodes No distant metastases Distant metastases including skin involvement beyond the breast area and supraclavicular nodes

7 438 RADIOTHERAPY AND ONCOLOGY Fig Nodular local recurrence on the skin flaps of a mastectomy scar. with high-grade DCIS, postoperative whole-breast irradiation should be given, since it reduces the risk of local recurrence and of invasive cancer. For low- or intermediate-grade DCIS, the role of radiotherapy is less clear and still the subject of investigation. Randomised trials have shown that tamoxifen given in addition to radiotherapy following conservative surgery for localised DCIS reduces the cumulative incidence of invasive cancer from 7.2% to 4.1% at 5 years and of non-invasive cancer from 6.2% to 4.2%. The overall prognosis of DCIS is excellent with in excess of 97% of patients alive and disease free 10 or more years following diagnosis. TREATMENT OF EARLY BREAST CANCER The treatment of early breast cancer (usually defined as T0 3aN0 1M0) has always been controversial. Over the last decade there has been an increasing trend to offer women breast-conserving surgery rather than the more extensive operation of simple mastectomy. Fig Widespread nodular recurrence over left chest wall following mastectomy, extending to the other breast. anaemia (typically leucoerythroblastic) from marrow infiltration is suspected. All patients with locally recurrent disease following mastectomy (Figs 26.4 and 26.5) or breast-conserving therapy, regional or metastatic recurrence require bone scan and liver ultrasound in addition to full blood count, liver function tests and chest radiograph. TREATMENT OF DUCTAL CARCINOMA-IN-SITU Until the 1980s total mastectomy was the standard treatment for DCIS and still remains the most reliable curative treatment. Mastectomy remains the treatment of choice for multicentric DCIS and for large unicentric lesions. Regular mammography of the contralateral breast should be carried out, since there is an increased rate of contralateral breast cancer of approximately 7 per If the extent of the lesion is not more than 3 4 cm, then an attempt at conservative surgery may be made, aiming to achieve complete excision. The margins of clearance should be at least 1 cm. For patients Historical perspective For the first half of the last century it was believed that regional lymphatic spread of breast cancer was the important route to systemic spread. The logical treatment was a radical mastectomy, an operation pioneered by an American surgeon, William Halsted. This involved removal of the breast in continuity with the local musculature (pectoralis major and minor) and a full axillary dissection. This was a very mutilating procedure with a high risk of lymphoedema and substantial psychological morbidity from the change in body image. That said, it was an operation that provided good local control. Patients who underwent a Halsted mastectomy are still seen disease free in breast follow-up clinics years after surgery. Radical radiotherapy was first employed as an alternative to radical mastectomy in the 1920s. A limited excision of the tumour was carried out and radium needles implanted throughout the breast. Although a crude form of interstitial implantation by modern standards, it was shown to provide comparable results (albeit not from a randomised trial) to radical mastectomy. In patients where the tumour was confined to the breast, the 5-year survival was about 70%. This conservative approach, introduced by Sir Geoffrey Keynes as early as 1924, did not fit in with the prevailing dogma of the locoregional spread of the disease and did not gain popularity until the 1960s when

8 BREAST 439 Pierquin in France popularised the use of conservative surgery and breast irradiation. In 1955 it was first demonstrated in a non-randomised study by McWhirter in Edinburgh that simple mastectomy with postoperative locoregional radiotherapy provided a less morbid form of treatment than radical mastectomy with postoperative radiotherapy but with comparable local control and survival. In the early 1970s there was an increasing appreciation that breast cancer was often a systemic disease. This era saw the focus of breast cancer management shift to the development of adjuvant systemic therapy to treat subclinical systemic micrometastatic disease. More recently there is growing awareness that breast cancer is a heterogeneous disease with some patients with truly localised disease and others with systemic disease from the time of diagnosis. Part of the difficulty in determining whether or not breast cancer is systemic is the limitation of the resolution of our current staging investigations. Bone marrow taken at the time of primary surgery and subjected to immunocytochemical analysis for tumour infiltration may show malignant cells. There is some evidence that the detection of bone marrow metastases by monoclonal antibodies may provide better discrimination as a prognostic factor than axillary node status. However, the biological significance of these marrow metastases is uncertain. Prognostic factors While there are a large number of biological prognostic factors for breast cancer, none has surpassed the value of assessing the number of histologically involved nodes and tumour size. There is a direct correlation between number of involved nodes and survival (Fig. 26.6). 10-year survival is about 40 65% with 1 3 positive nodes, and 20 42% for those with 10 or more positive nodes. 10-year survival is about 65 70% in women with negative nodes. By contrast, in excess of 50% of all women who are axillary node positive die within 10 years despite treatment. Within any category of nodal status, tumour size is an independent prognostic factor. The decline in survival with increasing size of the primary tumour is shown in Figure Less than 30% of patients with stage IIIb disease (T4) are alive at 10 years. Similarly survival declines with increasing tumour grade. 5-year survival falls from 80% for grade 1 to 25% for grade 3. Oestrogen receptor (ER) status is predictive for disease-free and overall survival. Irrespective of stage, ER positivity predicts for longer disease-free (Fig. 26.8) and overall survival. Higher recurrence and lower survival Survival Probability Time (year) Positive Nodes Fig Survival by axillary node status. (Reproduced with permission from Veronesi U (ed) Baillière s Clinical Oncology, 1988.) Percentage survival > 20 1cm 2 cm 3 cm over 3 cm Year Fig Age-corrected survival rates by tumour size for patients treated for breast cancer apparently confined to the breast. (Reproduced from Halnan, Treatment of Cancer, 1st edn, Chapman & Hall, 1982.) rates are found in ER-negative patients. About 60% of ER-positive patients will respond to hormonal manipulation. Progesterone receptor (PgR) status may also help. Oestrogen stimulates PgR production in normal reproductive tissue and in human breast cancer cell lines. The highest response and disease-free survival rate is seen in ER+/PgR+ tumours. Very few tumours are ER /PgR+, consistent with the production of progesterone receptors being dependent on oestrogen synthesis. Lowest

9 440 RADIOTHERAPY AND ONCOLOGY Survival Probability Time (years) Fig Survival by axillary node status and oestrogen receptor status in 854 patients: 1 = negative nodes ER+; 2 = negative nodes, ER ; 3 = positive nodes, ER+; 4 = positive nodes ER. (Reproduced with permission from Baillière s Clinical Oncology, International Practice and Research, 1988.) response and disease-free survival rates are seen in ER /PgR tumours (Fig. 26.9). Of the biological markers of prognosis including p53, cathepsin D, epidermal growth factor receptor and HER2/neu, HER2/neu is the most reproducible. Patients overexpressing HER2/neu have a higher risk of recurrence and shorter survival. There is evidence that tumours that overexpress HER2/neu are relatively resistant to chemotherapy with cyclophosphamide, methotrexate and 5-FU (CMF) and have greater responsiveness to anthracyclines. Importance of locoregional control of breast cancer Locoregional control of breast cancer is important for a number of reasons. First, there is evidence, at least from DF Survival Probability Time (years) ER+/PgR+ ER+/PgR ER /PgR Fig Disease-free survival by oestrogen and progesterone receptor status in pathological stage II patients. (Reproduced with permission from Baillière s Clinical Oncology, International Practice and Research, 1988.) patients at high risk of local recurrence after mastectomy, that local residual disease compromises survival. If the sole site of residual disease is locoregional, radiotherapy given to these areas in addition to systemic therapy may improve survival. If there is no residual local disease, survival is dictated by micrometastatic disease. Secondly, uncontrolled local disease with its complications of persistent discharge, odorous infection and bleeding, and usually partial and transient responses to local or systemic treatment, causes immense distress to patients and a poor quality of life. A high quality of surgery (with or without radiotherapy as appropriate) is needed at the primary site and in the axilla to minimise the probability of residual locoregional disease. Mastectomy or breast conservation The decision as to whether to perform a mastectomy or breast-conserving surgery should be discussed preoperatively in a multidisciplinary clinic by surgeon and oncologist, once the results of staging investigations are available. A joint decision should be taken. In making this decision, due weight should be given to the patient s own preference. Breast care nurses acting as the patient s advocate may help provide additional information on the patient s views. The technical feasibility of local surgery, suitability for radiotherapy, cosmesis and locoregional morbidity all need to be taken into consideration. In considering the possibility of breast-conserving surgery, the tumour size, the size of the breast and the mammographic appearance or histology from excision or core biopsy are important. As a general rule, most tumours in excess of 3 cm are unsuitable for breastconserving therapy unless the breast size is sufficiently large not to result in a marked tissue defect marring cosmesis. Greater flexibility in offering breast conservation is possible with the availability of newer surgical techniques to fill the tissue defect from local excision by a graft. Tumours of 3 cm or greater, judged clinically or radiologically, are generally best treated by mastectomy and axillary node clearance. Patients who have clinical or radiological evidence of multifocal disease or have an extensive intraduct component (EIC) are not suitable for breast conservation. Studies of patients who have undergone mastectomy show that invasive cancer and ductal carcinomain-situ are often present more than 2 cm from the primary tumour. It is therefore important to try to confirm radiologically that the tumour is localised if breast conserving surgery is to be recommended.

10 BREAST 441 There is evidence that local recurrence rates following breast-conserving surgery are higher in younger women (under the age of 40). This may in part be due to the difficulty with mammography of identifying multifocal disease in the radiologically denser breast in young women. Women under the age of 35 have a two- to fourfold higher risk of local recurrence after breast-conserving surgery and radiotherapy. Lobular cancer Some histological forms of breast cancer, typically lobular cancer, are commonly multifocal but poorly imaged by mammography. If a core or excision biopsy of an apparently localised tumours shows lobular carcinoma, an initial wide local excision may be carried out. If the margins are involved or there is evidence of multifocal disease histologically, then breast conservation is not safe and mastectomy is advised. Where the margins are clear (by at least 1 mm superiorly, inferiorly, medially and laterally) then a breast-conserving approach for lobular cancer is feasible. Long-term follow-up of patients treated for lobular carcinomas with clear margins shows similar local control to other histological subtypes. Reconstruction after mastectomy Patients should be offered the possibility of immediate breast construction, often with the assistance of a plastic surgeon. Common reconstructive procedures include a latissimus dorsi flap to build up the breast mound and breast implants which are progressively inflated to the desired size postoperatively. Reconstruction of the nipple areola complex is also possible. The main challenge is to match the ptosis and projection of the contralateral breast. Reconstruction using the rectus abdominis muscle (TRAM flap) is available in some specialist centres. Patients not suitable for or declining a reconstruction should be offered a breast prosthesis. Conservation therapy (limited surgery and postoperative radiotherapy) In patients with T1 and small T2 tumours (up to 3 cm) some form of local surgery should be considered. The most popular choice is a wide local excision to obtain clear histological margins. This involves excision of the tumour with a margin of 1 2 cm. If the margins are found to be involved, a re-excision to clear the margins is recommended. If re-excision of the margins still shows tumour at the margin, breast conservation is not appropriate and a mastectomy is advised. Alternatively, a more extensive local excision of the whole quadrant affected in the breast (quadrantectomy) may be carried out. The advantage of quadrantectomy is that local recurrence rates (about 1% at 5 years when combined with postoperative radiotherapy) are lower than after wide local excision and radiotherapy (about 5% at 5 years). The disadvantage is that the cosmetic result is generally poorer because of the asymmetry caused by the greater volume of tissue removed. Quadrantectomy or a very wide local excision may be considered in patients refusing or not fit for mastectomy or breast radiotherapy. This may be advisable in some older patients where comorbidity may compromise suitability for mastectomy. Criteria for breast conservation are summarised in Table Local recurrence after breast-conserving therapy. The treatment of choice of local recurrence after radical radiotherapy is a mastectomy. Neoadjuvant therapy In patients who are keen to avoid mastectomy with clinically and mammographically localised disease, preoperative neoadjuvant therapy with hormonal or cytotoxic therapy selected on the basis of oestrogenreceptor status may be considered. Experience to date suggests that rates of mastectomy can be reduced by neoadjuvant therapy. However, long-term data on local control and survival are not yet available. Until they are, neoadjuvant therapy should only be carried out in the context of a clinical study. Management of the axilla The management of the axilla is controversial. Some form of surgical procedure to obtain nodal histology is advised in all women with operable breast cancer. This needs to be decided jointly by the oncologist and the surgeon. For tumours 2 cm or less in diameter where the risk of axillary nodal involvement is lower than in larger tumours, a lower axillary node sample is advised. In this procedure, a minimum of four nodes Table 26.4 Criteria for breast-conserving therapy 1. Tumours up to 3 cm 2. Satisfactory cosmetic result anticipated 3. Postoperative whole breast radiotherapy technically feasible 4. Medically fit for surgery 5. Clear histological margins at primary excision or re-excision 6. Able to attend for regular clinical and mammographic follow-up

11 442 RADIOTHERAPY AND ONCOLOGY are identified from the lower axilla. A randomised trial in Edinburgh showed that if the node sample is negative, then this is representative of the rest of the axilla (i.e. skip metastases are very uncommon). For patient with tumours > 2 cm or with ipsilateral palpable nodes (N1) a level III axillary clearance up to the level of the medial end of the first rib is recommended. Normally there should be at least 10 axillary nodes in a level III clearance and commonly The local control in the axilla from a level III clearance is similar to a policy of axillary radiotherapy for patients with a positive lower axillary four-node sample. With either policy the axillary recurrence rate is 5% at 5 years. It is important that if the axilla is dissected rather than sampled it should not be irradiated unless there is macroscopic residual disease that the surgeon cannot clear (e.g. stuck around the axillary vein). In the uncommon circumstance that postoperative radiotherapy is required to residual disease in the axilla after axillary clearance, the patient should be informed of the greater risks of morbidity (see below). Morbidity of axillary treatment Side-effects of an axillary clearance include postoperative seroma and numbness in the upper limb. Lymphoedema occurs in 7 8% of cases. If axillary radiotherapy is added to the dissection, the risk of lymphoedema is substantially higher (between 30 40%). With the risk of axillary clearance of causing lymphoedema, less-invasive methods of staging the axilla (sentinel node biopsy) are being explored. After conventionally fractionated radiotherapy (e.g Gy in fractions) to the axilla, the risk of lymphoedema is about 3 5%, i.e. lower than after axillary dissection. However, there is an increased risk of long-term restriction of shoulder movement and a small risk of brachial plexopathy (1% or less). This is a rare but serious complication and is usually irreversible. Very careful attention to radiotherapy technique with avoidance of overlap between axillary and breast/chest wall fields or moving the patient between the treatment of these fields is essential. Sentinel node biopsy Sentinel node biopsy is currently under investigation to see if it might avoid the need to carry out a full axillary dissection with its attendant morbidity. The sentinel node is the node most likely to drain the primary tumour. It is identified first by the injection of a vital blue dye (Plate 2.6) or a radioactive tracer, or a combination of both. In most patients the sentinel node is in the axilla but in a few medially placed tumours it may be in the internal mammary chain. The axilla is normally explored to identify the sentinel node either by the blue colour of the dye within it or by the high radioactivity scintillation count over it. If histology of the sentinel node shows no tumour, no further axillary surgery is needed. If the sentinel node biopsy is positive, the surgeon may proceed to a complete axillary dissection or refer the patient for axillary irradiation. Sentinel node biopsy poses new dilemmas since it may detect micrometastases ( 2 mm). It is not clear how these should be managed. If the pathologist is asked to give the sentinel node special attention, the yield of positive sentinel nodes rises by 5 10%, and by a further 5 10% if the sentinel node is analysed by immunohistochemistry. If even more sensitive tests such polymerase chain reaction to a range of tumour antigens are carried out, the yield of positive sentinel nodes is likely to rise even further. The prognostic significance of these micrometastases is not certain. The timing of the injection of the radionuclide and imaging by gamma camera needs to be carefully coordinated and requires the services of a nuclear medicine department. It is still not clear whether sentinel node biopsy will be generalisable to all cancer units undertaking breast surgery or should be confined to specialist centres. In specialist centres sentinel node biopsy has 97% accuracy. An additional factor that has to be addressed is the pathology time needed to examine slices of the sentinel node by stains for cytokeratin to detect tumour involvement. Such examination is likely to put significant pressures on pathology laboratories. If widely adopted and with adequate standards of quality assurance, sentinel node biopsy could significantly reduce the number of axillary dissections and attendant morbidity. Trials of adjuvant postoperative radiotherapy Historical aspects Paterson in Manchester in 1948 conducted the first randomised trial of postmastectomy radiotherapy. He demonstrated that adjuvant irradiation given immediately postoperatively rather than delayed until the time of recurrence reduced the risk of local recurrence from 32% to 19% at 5 years. There was, however, no difference in overall survival. A Cancer Research Campaign trial in the 1970s in stage I and II disease with simple mastectomy with or without postoperative radiotherapy showed a reduction in local recurrence

12 BREAST 443 from 30% to 10% but similarly no difference in survival. In 1987 an overview of randomised trials showed a 20% reduction in risk of death among patients who had not received adjuvant postoperative radiotherapy following radical mastectomy. The excess mortality of non-breast-cancer deaths was largely due to vascular causes related to irradiation of the heart. This was a particular risk of older radiotherapy techniques using orthovoltage where the divergence of the beam made unwanted cardiac irradiation difficult to avoid. Areanalysis in 1994 confined to the more modern radiotherapy trials using megavoltage radiotherapy showed no adverse effect of radiotherapy. Indeed, there was a trend, albeit not statistically significant, to improved survival in irradiated patients. However, no particular subgroup could be identified in which survival was improved by radiotherapy. Randomised trials in Denmark and Canada have shown a 9 10% survival advantage from the addition of locoregional radiotherapy to systemic therapy in high-risk premenopausal and postmenopausal women. However, the 2000 Oxford overview of randomized trials of adjuvant irradiation showed no difference in survival between irradiated and non-irradiated patients. If vascular damage from radiotherapy could be avoided, the Oxford overview predicts a small (2 4%) gain in 20-year survival from adjuvant irradiation. The possible reasons for the lower survival benefit in the overview compared to the Danish and Canadian trials is discussed later in this chapter. 1. After breast-conserving surgery In general, postoperative whole-breast irradiation should be delivered following wide local excision or quadrantectomy as part of breast-conserving therapy. A number of randomised trials comparing wide excision alone with appropriate systemic therapy have shown a reduction in local recurrence from the addition of whole breast irradiation. A Scottish trial of patients with tumours up to 4 cm with or without involved nodes showed a 6% recurrence rate from the addition of breast radiotherapy to systemic therapy compared to 25% in the non-irradiated group. It is important that the whole breast is irradiated, since the recurrence rate is substantial if radical radiotherapy is confined to the primary site. A trial in Manchester confining radical electron beam irradiation to the tumourbearing area alone showed a 16% recurrence rate at 5 years compared to 8% for whole breast irradiation. These findings are consistent with radiotherapy sterilising subclinical disease remote from the tumourbearing area. Is there a group of patients treated by breast conservation and adjuvant systemic therapy in whom radiotherapy can be omitted? Most of the evidence from randomised trials shows a reduction in risk of local recurrence in patients treated by breast irradiation (Table 26.5). The extent of tumour margins is the most important factor influencing local recurrence rates. Where wide margins of normal tissue are taken (e.g. quadrantectomy) the risks of local recurrence without radiotherapy are smaller. Whether breast radiotherapy is required in patients at low risk of local recurrence (e.g. node-negative patients with tumours of special type) after conservative surgery and systemic therapy is unclear. A number of randomised trials are currently addressing this issue. The need for breast irradiation in older patients is unresolved, largely because patients over the age of 70 were excluded from randomised trials. Older frailer patients may prefer to avoid prolonged attendance over 5 6 weeks for radiotherapy, particularly if this involves hospitalisation remote from their family. There is some evidence that recurrence rates fall in this older group of patients. However, until mature results of these trials assessing the role of breast radiotherapy in these subgroups of patients are known, most patients should be considered for breast irradiation. It needs to be borne in mind that breast conservation carries a constant risk of local recurrence (1%) per year up to at Table 26.5 Results of randomised trials of breast-conserving surgery (BCS) with or without radiotherapy (RT) (modified from Wong J S and Harris J R 2001 Lancet Oncology 2: 11 17) Local recurrence (%) Median follow-up Analysis BCS alone BCS + RT (months) NSABP B years actuarial Canadian years crude Scottish years actuarial Swedish years actuarial Milan III years actuarial

13 444 RADIOTHERAPY AND ONCOLOGY least 15 years. However, in the older patient this needs to be balanced against the morbidity of radiotherapy and diminishing life-expectancy due to comorbidity. With the rising incidence of breast cancer among older patients, the determination of whether a more selective policy of breast radiotherapy can be adopted will assume even greater importance. 2. Following mastectomy More than half of the locoregional recurrences following mastectomy occur on the chest wall. Where there are multiple sites of locoregional recurrence, the chest wall may be involved in 60 80% of patients. The mastectomy scar is the commonest site of recurrence on the chest wall. It is probable that secondary tumour emboli, particularly in the lymphatics, result in residual disease after mastectomy. This explanation is supported by the higher likelihood of locoregional recurrence where there is lympho-vascular invasion in the primary tumour or extensive axillary lymph node involvement. The role of adjuvant radiotherapy following mastectomy remains controversial but is assuming greater importance with the evidence that it may confer a substantial survival advantage when given in addition to adjuvant systemic therapy in pre- and postmenopausal women at high risk of local recurrence. In 1997, randomised trials in Denmark and Canada showed a 9 10% survival benefit from the addition of locoregional radiotherapy following mastectomy to adjuvant CMF chemotherapy. The much larger Danish trial (Fig ) of over 3000 patients led by Marie Overgaard showed that a significant advantage accrued to patients receiving adjuvant irradiation (10-year survival 54% vs 45%). A trial from the same group (Fig ) shows a similar 9% survival (45% vs 36%) benefit in high-risk postmenopausal women receiving locoregional regional irradiation in addition to adjuvant tamoxifen. However, the survival advantage only emerged late (i.e. at 10 years). In both the Danish and Canadian trials all of the peripheral lymphatics (axilla, supraclavicular and internal mammary chain) were irradiated. It is not clear whether irradiation of all of these areas, particularly the internal mammary chain is essential. A European trial is currently assessing the role of internal mammary irradiation. Internal mammary recurrences are uncommon in clinical practice despite the fact that if the axillary nodes are involved, the internal mammary nodes will be involved in 25% of cases. The radiotherapy technique in the Danish trial (Fig ) differed from the use of a pair of tangential fields in most UK centres to treat the chest wall. A combination Overall Survival (%) Radiotherapy + CMF CMF P < Radiotherapy + CMF (54%) CMF (45%) Years after Mastectomy Fig Survival in Danish Cooperative Group trials of locoregional radiotherapy after adjuvant CMF in high-risk premenopausal women. (Reproduced with permission of the Editor, from Overgaard et al, 1997, New England Journal of Medicine 337: ) Overall survival (%) Overall survival 45% 36% 0 P = Time since Mastectomy (years) Patients at risk Radiotherapy tamoxifen Tamoxifen only Fig Survival in Danish Cooperative Group trials of locoregional radiotherapy after adjuvant tamoxifen in highrisk postmenopausal women. (Reproduced with permission from Elsevier Science from The Lancet, 1999; 353: 1642.) of electron beam with limited penetration beyond the chest wall was used to treat the medial part of the chest wall and matched with a photon field to treat the lateral half of the chest wall. 10-year follow-up data showed no excess of cardiac morbidity or mortality in the radiotherapy + systemic therapy group compared to those

14 BREAST 445 receiving systemic therapy alone. The results of the Danish trial emphasise the importance of good radiotherapy technique in minimising the dose to the heart. In the 2000 update of the Oxford overview, postoperative radiotherapy reduced the risk of locoregional recurrence by two-thirds. Breast cancer mortality was reduced but non-breast-cancer mortality increased, particularly due to vascular causes. Overall 20-year survival was 37.1% with radiotherapy, compared to 35.9% for controls. The difference was not statistically significant. Patients irradiated over the age of 60 were particularly at risk of radiation-induced vascular mortality. The much lower estimates of a survival benefit from adjuvant radiotherapy in the Oxford overview are at variance with the much higher levels of benefit shown in the Danish and Canadian trials. In part this may be due to the inclusion within the Oxford overview of trials of radiotherapy using older treatment techniques where a survival benefit would have been reduced or negated by higher levels of radiation-induced cardiac mortality. homogeneous irradiation of the target areas, avoidance of overlap of chest wall/breast with fields to the peripheral lymphatics, and minimising dosage to critical structures (lung, heart and the brachial plexus). This is not an easy task because of the variation in shape and thickness of the chest wall and breast in the craniocaudal and transverse planes. In addition, the sternum slopes when the patient is lying flat. The proximity of the lung to the target volume means that some lung is commonly irradiated. As a result it is difficult to reduce the variation in dose distribution across the volume to the ± 5% that is achievable by radical radiotherapy at other tumour sites. Dose inhomogeneity is exacerbated by lung effects due to scatter and lung transmission. The aim should be to achieve a variation between the maximum and minimum dose of better than 15%. Whatever technique is adopted, a careful audit needs to be kept of locoregional control, survival and morbidity in each centre. Indications for postmastectomy radiotherapy International consensus supports the routine use of postmastectomy radiotherapy for patients who have a 20% or more risk of locoregional recurrence: 1. Tumours greater than 5 cm in diameter 2. Four or more histologically involved axillary nodes. In addition radiotherapy is indicated for: 3. Close or involved surgical margins 4. Chest wall recurrence following mastectomy. Cumulatively greater probability of local recurrence is conferred with the following risk factors: 1. Axillary nodal involvement 2. Grade 3 histology 3. Lymphatic/vascular invasion. How these factors should be weighted in the selection of patients for postmastectomy radiotherapy is not clear. In the absence of definitive data, a reasonable policy is to offer radiotherapy to patients with two or more of these factors. Trials are ongoing to assess the role of postmastectomy radiotherapy in the group with 1 3 nodes positive and the value of other risk factors such as grade and lymphovascular invasion. Target volume and techniques for locoregional irradiation Awide variety of radiotherapy techniques are in use. In choosing a technique, guiding principles should be CT simulation Conventionally in UK centres most adjuvant irradiation has been planned without the benefit of CT planning or with only a single or limited number of CT slices. While modern simulators may give a better appreciation of the inclusion of part of the myocardium within the field, they are unable to give the volumetric assessment of the inclusion of these critical structures compared to multislice CT scanning. Full CT scanning of the breast allows better selection of beam arrangements to minimise cardiac and pulmonary irradiation (Plate 2.7). CT scanning with a wider than the normal (70 cm) bore is usually needed to enable the patient in the treatment to be encompassed with the arm abducted to 90 degrees. Radiotherapy technique There are two main radiotherapy techniques adopted: multifield and en bloc. Multifield treatment is preferable since it provides a more homogeneous dose distribution within the target volume with less unwanted irradiation of the lung and the heart than en bloc techniques. Immobilisation. Some form of immobilisation is essential to provide a reproducible treatment set-up. A variety of devices are in use. These may include a breast board (see Fig ) that fits onto the simulator and treatment couch, a custom-made foam mould from the head to the knees or a jig (Fig ). The patient is treated supine with the arm abducted to

15 446 RADIOTHERAPY AND ONCOLOGY Fig Breast jig for radical treatment of patients with large or mobile breasts or for locally advanced disease. The jig is filled with bolus bags. 90 degrees. The breast board can be inclined to a range of angles to flatten the chest wall/breast. This technique simplifies matching and avoids the need for rotating the collimator. The disadvantage is that it increases the volume of lung irradiated in the shoulder field. Alternatively the patient can lie supine with the arm abducted to 90 degrees. Rotation of the collimator is needed to keep the posterior beam edge parallel to the slope of the contour. The disadvantage is difficulty in matching the chest wall to the shoulder field. For the large or very mobile breast some additional form of immobilisation (shell or sling or jig [Fig ]) is needed. The very mobile breast tends to fall laterally, moving the posterior beam edge further back than the midaxillary point and increasing the volume of lung irradiated. The immobilising device will bring the breast medially and reduce the volume of lung irradiated. Multi-field. Separate fields (Fig ) are planned to cover (1) supraclavicular fossa, axilla and, if desired, the upper internal mammary chain and (2) chest wall/breast and, if desired, the internal mammary match plane 1 3 Fig Diagram showing fields to the chest wall/breast, axilla, supraclavicular fossa and internal mammary chain. (Reproduced with permission of the Editor of the British Journal of Radiology, 1984; 57: 736.) 2 chain. Whether it is necessary to irradiate the internal mammary chain is still controversial and most UK oncologists do not attempt to include it in the target volume. If the internal mammary nodes are to be irradiated, it is best to use a direct electron field of appropriate energy to cover them. Individualised CT planning is needed to ensure adequate coverage while limiting transmitted dosage to the underlying heart and lungs. Trying to include the internal mammary nodes within tangential fields is not recommended because of the greater risks of pneumonitis from the larger volume of lung irradiated and the uncertainty of adequate coverage. A computer plan of the dose distribution over the breast or chest wall should be derived from a manually or CT derived outline through the central plane. With three-dimensional CT planning, beam entry and exit points can be adjusted to minimise dosage to these structures. The use of conformal radiotherapy techniques using intensity-modulated radiation therapy may improve the homogeneity of dose distribution within the breast while reducing the dose to heart, lung and contralateral breast. Shoulder field. Adirect anterior megavoltage field (Fig ) covers the supraclavicular fossa and axilla. The upper margin should be at the level of the thyrohyoid groove. The lateral margin should encompass the lateral border of the axilla. The length of the shoulder field should rarely exceed 10 cm, since the volume of lung irradiated rises as the lower edge of the treatment volume is extended inferiorly. This increases the risk of pneumonitis. The shoulder joint and the part of the larynx within the field should be shielded by lead blocks. Some centres angle the shoulder field 15 degrees to exclude the spinal cord, although this is not essential as long as the dosage and fractionation are within cord tolerance. The lower border of the shoulder field should be nondivergent to avoid overlap with the tangential fields. The axillary and supraclavicular nodes are commonly at the same depth and therefore a single anterior field may suffice. Some centres use a small direct posterior field (posterior axillary boost) to supplement the dose to the axillary nodes. The given dose to the posterior axilla is calculated to bring the mid axilla to the prescribed dose. With 6 MV photons, roughly 20% of the prescribed midaxillary dose is delivered from the posterior field. The posterior field is often treated on alternate days. Supraclavicular field. Where the axillary clearance shows the nodes to be involved, irradiation of the ipsilateral supraclavicular nodes should be considered. There is no consensus on the threshold for medial

16 BREAST 447 supraclavicular fossa irradiation. This varies from any axillary involvement to a minimum of four involved nodes. If the axilla is to be cleared, the surgeon should be asked to place metal clips up to the medial extent of the axillary dissection to ensure that the lateral margin of the supraclavicular field abuts on, but does not overlap, the field of the axillary clearance. Chest wall and breast. The chest wall or breast is treated isocentrically and can normally be encompassed in a pair of wedged tangential fields (Fig ) keeping the posterior beam edges parallel to minimise divergence into the lung. This should cover the scar of local excision or of the mastectomy. It normally extends from the level of the second costal cartilage down to 1 2 cm below the inframammary fold. The medial margin is the midline. The lateral margin is normally the midaxillary line. Occasionally the lateral margin may be slightly more posterior in the conserved breast for a laterally placed tumour or if the mastectomy scar extends beyond this point. Some Fig Two tangential breast fields. By keeping the posterior beam edges parallel, irradiation of the lung is reduced. compromise is necessary in defining these field margins, balancing adequate coverage of the target volume with the need to avoid excessive lung irradiation. A typical dose distribution in the breast is shown in Figure Internal mammary node irradiation. If the internal mammary nodes are to be irradiated, a separate direct electron internal mammary field should be used, which will need to cross the midline. This has the advantage of sparing excessive dosage to the heart. The internal mammary chain (IMC) lies deep to the midline and about 2 3 cm to each side of the midline. Part of the IMC field may be overlapped by the curved shape of the tangential field. This area of overlap should be blocked when the IMC field is treated. Limitation of lung volume irradiated. At the time of simulation, the thickness of lung encompassed in the tangential fields should be measured (the central lung distance perpendicularly from the inner aspect of the chest wall to the posterior beam edge). The central lung distance should not exceed 3 cm. If it exceeds 3 cm, consideration should be given to using an internal mammary photon field to cover the medial part of the chest wall/breast and tangential fields to the lateral chest wall/breast or bringing the medial and/or lateral margins of the fields inwards, as long as this does not involve skimping on the coverage of the wide excision or mastectomy scars. To avoid divergence into the lung, the posterior beam edges should be kept parallel. Skin bolus. To overcome the skin-sparing effect of megavoltage skin bolus (0.5 1 cm depending on the energy of photons) should be applied to the chest wall to ensure full skin dosage in patients where the skin is involved by tumour. Practice varies in the use of bolus for postmastectomy radiotherapy when the skin is not involved. Some centres apply bolus to a limited area above and below the scar (where recurrences are commonest) or to the whole of the chest wall, either for the POST GA cm SSD 100 cm 60 W WT 55% RIGHT GA cm SSD 100 cm 60 W WT 55% LEFT = MAX 110% Fig Isodoses of a pair of wedged tangential breast fields shown in Figure ANT

17 448 RADIOTHERAPY AND ONCOLOGY whole or part of the course of radiotherapy. It is not clear which approach is optimal. Field matching One of the main challenges in breast/chest wall planning is to match the tangential fields to the shoulder field. Immobilisation should minimise movement between the treatment of fields to avoid the risk of over/underlap at the junction. Fields may be matched using the light beam and lasers by eye using couch rotation (usually 5 6 degrees) and some collimator rotation. Alternatively one can use: 1. A half beam block (Fig A) to counteract beam divergence, allowing the field edges to be abutted. Asymmetric jaws facilitate this. The match plane can be vertical (Fig B) or angled (Fig C). 2. A vertical hanging block. 3. A single isocentre with blocks, avoiding the need for couch movement between fields. Dosimetry Planning is normally on a single CT slice. However, multislice CT scanning of the breast gives a better appreciation of the volume of lung and heart irradiated. 6 MV photons are adequate for most patients. Wedges are needed to compensate for missing tissue. Lung transmission increases the dose to the posterior breast. A correction factor of 10% may be needed. Variations in depth dose across the breast may be ± 20%, particularly in larger breasts. Build-up to 100% is 5 10 mm from the skin surface for 6 MV photons. The skin surface dose for tangential fields is 50 70% of the prescribed dose. En bloc. An en bloc technique is recommended for the very large or mobile breast or for a large primary tumour contiguous with the axillary node. The chest wall/breast and, if necessary, axilla and supraclavicular nodes are encompassed en bloc in a rectangular Perspex jig. The jig is filled with bolus (Fig ). No computer plan is used. The ipsilateral arm is placed behind the head, holding a horizontal bar, and the body rotated slightly to the opposite side and supported on a foam wedge. The drawback of this technique is that when the peripheral lymphatics are irradiated some of the arm and shoulder are irradiated and cannot be satisfactorily blocked from the beam. Supraclavicular Match plane Tangential fields A B B C A D Fig Matching fields in a breast treatment. A Using a rotated half beam block to counteract beam divergence between cervico-axillary and breast fields. B Lead block to trim superior edge of the tangential fields to form a vertical match plane. C Match plane vertical on an inclined breast board. D Match plane angled in supine position. (Reproduced with permission of the Editor of the British Journal of Radiology, 1984, 57: 737.)

18 BREAST 449 Amixture of photons to the supraclavicular and axillary region and anterior electron field to treat the internal mammary nodes and the medial chest wall (Fig ) was used in the Danish postmastectomy radiotherapy trials. Importantly, there was no excess of cardiac morbidity or mortality from postmastectomy added to systemic therapy compared to systemic therapy alone. Conservation therapy Boost to the tumour. Some form of boost of irradiation to the primary tumour is desirable to bring the tumour dose to 60 Gy in women under the age of 50. This is either given by electrons or by an iridium-192 implant (Fig. 22.9). Either form of boost will give comparable local control. However, the higher surface dose of electrons will cause telangiectasia on the treated skin. For implants, telangiectasia at the skin entry and exit points of the iridium wire can be avoided if the sources lie just beneath the skin surface. In general, the breast tissue tends to be thinner in the more medial and lateral parts of the breast. In these sites there may be inadequate tissue for an implant and electrons are preferable. An iridium implant does enable a higher dose to be delivered than electrons for a similar level of morbidity. However, there is no compelling evidence that electrons are inferior to an implant in terms of local control in conservation therapy. Fig Radiotherapy technique using mixed photon and electron beams for locoregional radiotherapy after mastectomy in the Danish Breast Cooperative Group trials. Adirect photon field (I) treats the lateral chest wall and axilla and an electron field treats the medial chest wall (III) and internal mammary nodes (II). (Reproduced with permission from Elsevier Science: The Lancet, 1999, 354: 1426.) Dose, energy and fractionation Megavoltage irradiation (6 MV photons) is used for the tangential field to the chest wall or breast. Radical radiotherapy schedules vary across the UK. The commonest regimes are 40 Gy in 15 fractions, 45 Gy in 20 fractions and 50 Gy in 25 fractions. The latter is the standard in the USA and most of continental Europe. 1. Multifield a. Shoulder field (supraclavicular + axilla) 45 Gy maximum dose in 20 daily fractions over 4 weeks (6 MV photons) (with posterior axillary boost brings midaxillary dose to 45 Gy treating alternate days) b. Medial supraclavicular fossa 45 Gy maximum dose in 20 fractions over 4 weeks (6 MV photons) c. Breast or chest wall 45 Gy target absorbed dose (TAD) in 20 fractions (6 MV photons) 2. En bloc (jig technique) 45 Gy maximum in 20 daily fractions over 4 weeks (6 MV photons) Boost to the primary. It has been conventional to boost the site of tumour excision either with electrons of appropriate energy or temporary interstitial implantation using iridium-192. However, most of the data for both methods of boosting on which this policy was based were retrospective and subject to selection bias. A randomised trial in France using electrons (10 Gy) to the site of excision after whole breast irradiation (50 Gy) showed a slight but statistically significant reduction in local recurrence from 3.6% at 5 years compared to 4.5% with whole breast irradiation alone. A much larger EORTC trial of over 5500 patients showed an overall 40% reduction in the risk of local recurrence with the use of the boost. Patients with clear margins after wide local excision were treated with whole breast irradiation (50 Gy in 25 fractions over 5 weeks) and randomised to either a boost (electrons 10 Gy) or implant. Age was an independent risk factor for recurrence. In women under the age of 40 the local recurrence with the boost was 10% compared to 20% without the boost. The absolute reduction in recurrence was smaller in women over the age of 40, but still statistically significant up to the age of 50. Similar benefits in local control were conferred whatever type of boost was used (external beam or implant). On this basis, for patients with clear excision margins, a boost is not recommended in women who

19 450 RADIOTHERAPY AND ONCOLOGY are 50 or older. In patients for whom re-excision of positive margins is not possible, an electron or iridium-192 implant boost would still be indicated. Implantation can be carried out intraoperatively or postoperatively. Electrons. The appropriate electron energy, usually 9 12 MeV, is chosen according to the depth of the breast tissue at the site of the tumour-bearing area. This is usually judged clinically but is more accurately measured by ultrasound or CT postoperatively. In order to avoid transmission of unwanted irradiation to the underlying lung, a Perspex degrader of appropriate thickness can be interposed between the electron applicator and the skin to attenuate the beam. The boosted volume should cover the tumour-bearing area with a margin of 1 2 cm (to take account of the inbowing of electron isodoses at depth) judged from clinical, mammographic and peroperative findings. Surgeons should be encouraged to place metal clips at the site of the excision, which assist the clinical oncologist in the identification of the tumour bed. Electron boost dose 15 Gy maximum dose in 5 daily fractions over 1 week Special situations 1. Women with larger breasts In patients with larger breasts or following breast reconstruction, the same total dose may be given over a longer overall treatment time (e.g. 5 weeks rather than 4) to reduce the acute skin morbidity. 2. Local recurrence after mastectomy If local recurrence occurs on the chest wall, spot recurrence should be locally excised if feasible. For multiple spot recurrences this is unlikely to be practical. Following radical chest wall irradiation, a boost with electrons should be considered to limited volumes of macroscopic recurrent disease. The same boost doses are used as for breast-conservation therapy. Practical points in setting up the patient 1. Ensure that the patient lies in a comfortable and relaxed position at the time of simulation to ensure that the same position is maintained during treatment. Therapy radiographers have an important role in helping the patient to relax by explaining the planning process. 2. Take care to avoid overdosage and underdosage at field junctions. 3. Where irradiation of the breast or chest wall may include an excessive volume of the heart or lung to be irradiated, it may be necessary to limit the medial or lateral margins of the tangential fields. Where the tumour lies laterally in the breast, the medial margin can be reduced, and vice versa when the tumour is in the medial half of the breast. General care During treatment If the margins of the treatment fields are marked by a small number of tattoos, the patient can wash the treatment area during a course of radiotherapy. The only restriction is avoiding washing the electron boost area after whole breast irradiation in breastconserving therapy since the margins of the treatment area are usually outlined by temporary skin marks. Apply proprietary baby powder to the treated area to keep it dry. If the skin becomes sore during radiotherapy, the application of cold air from a hairdryer may help. Shoulder exercises to keep the joint supple should be taught by a physiotherapist and practised by the patient during and after treatment After treatment Apply an emollient cream, such as oilatum or aqueous cream to areas of dry desquamation. A small amount should be applied to the treated area twice daily. Apply antibiotic ointment (e.g. Graneodin) or Flamazine to areas of moist desquamation. Continue shoulder exercises indefinitely (particularly patients treated by axillary irradiation where restriction of shoulder movements may occur). Morbidity of radical radiotherapy Intact breast 1. Breast oedema is common, particularly in the first year after radiotherapy. It is commoner in patients who have had an axillary clearance. It tends to diminish after a year. 2. Subcutaneous fibrosis is common and may give rise to shrinkage of the irradiated breast over a period of years. The extent of fibrosis is clinically unpredictable. It tends to be more marked at the site of the breast boost.

20 BREAST 451 Intact breast and postmastectomy 1. Skin telangiectasia. 2. Lymphoedema of the ipsilateral arm. 3. Rib fractures. These occur in 1% of patients and are uncommon with conventionally fractionated radiotherapy. They tend to occur in the lateral 4th 7th ribs where the maximum dose points tend to occur from tangential breast or chest wall irradiation. 4. Pneumonitis and lung fibrosis. Virtually all patients will develop some degree of impaired lung function as an effect of radical breast or chest wall irradiation, especially if the peripheral lymphatics are irradiated. However, it is unusual for these changes to give rise to breathlessness unless there is pre-existing impairment of lung function or excessive volumes of lung have been irradiated. Occasionally transient cough occurs during radiotherapy but usually settles within a few weeks. Some degree of fibrosis is observed on chest radiograph. 5. Fibrosis of the shoulder joint can occur if the axilla is irradiated, restricting shoulder movement. Appropriate shoulder exercises should be taught to such patients during radiotherapy and continued indefinitely after treatment to minimise limitation of shoulder movements. 6. Cardiac morbidity. Patients, particularly if irradiated over the age of 60, are at increased risk of coronary artery disease and potentially of disease of other cardiac structures. Every effort should be made to minimise the volume of the heart within the irradiated volume by appropriate planning techniques. 7. Radiation-induced sarcoma. This is an extremely rare complication with a mean latency of 13 years from the time of radiotherapy. Prognosis is very poor. Mean survival is 15 months. 8. Hypothyroidism may occur because of inclusion of the thyroid gland in the shoulder or medial supraclavicular field. Results of radical radiotherapy Postmastectomy. Data from randomised trials and overviews of postmastectomy radiotherapy suggest that adjuvant irradiation reduces the local recurrence threefold. Typical recurrence rates at 5 years are 4% for stage I, 10% for stage II and 20% for stage III. Local recurrence after mastectomy is a poor prognostic factor with more than 90% of patients developing clinically overt metastases within 5 years. Conservation therapy. The 5-year local recurrence rate for T1 2N0 N1M0 should be not more than 5% overall. The risks of local recurrence are higher in younger Fig Excellent cosmetic result of postoperative radiotherapy and iridium implant following lumpectomy for early carcinoma of the left breast. (Courtesy of Dr D Ash, Leeds.) women and may approach 10 15% in women under the age of 40. The recurrence rates may be substantially lower in node-negative patients with small (< 2 cm) node tumours. Long-term follow-up of the British Association of Surgical Oncology trial (BASO 2) investigating the role of postoperative breast irradiation and adjuvant tamoxifen alone or in combination are still awaited. The survival of patients treated by breast-conserving therapy and salvage mastectomy for local recurrence is no different from that of patients treated by mastectomy ab initio. Cosmetic results are good in 87% of T1 and 54% of T2 tumours. An example of excellent cosmesis is shown in Figure Cosmetic results tend to be poorer in patients with larger breasts. This may relate to the poorer homogeneity of dose distribution in larger breasts. ADJUVANT HORMONAL AND CYTOTOXIC THERAPY Rationale It is generally accepted that a substantial number of patients with apparently localised breast cancer harbour systemic micrometastases. These are currently beyond the detection of the conventional staging. Axillary involvement has for more than three decades been the strongest prognostic factor for systemic relapse. All patients should be considered for some form of adjuvant systemic therapy to try to eradicate micrometastases. The benefits have been determined from meta-analyses of the long-term follow-up of all randomised trials comparing women treated with or without adjuvant hormonal or cytotoxic therapy.

21 452 RADIOTHERAPY AND ONCOLOGY Who benefits? The Early Breast Cancer Trialists Group has provided a series of 5-yearly meta-analyses of over women with early breast cancer. The advantage of this approach of meta-analysis is that it brings together large numbers of randomised trials. By virtue of the very large numbers of patients analysed it provides much greater power to detect significant effects of different treatments. The overview shows clearly that both hormonal (tamoxifen or oophorectomy) and cytotoxic therapy (CMF or anthracycline-containing combination chemotherapy) reduce the relative risk of relapse or death by up to 30% at 10 years. The overall survival benefits are more modest, with a 4 12% gain in overall survival. The benefits in overall survival are greater in premenopausal than postmenopausal women. Following polychemotherapy, women aged gain a 14% reduction in risk of death compared to 8% in women aged The survival gains in the under 50 and age groups are shown in Figure Life expectancy is likely to be prolonged on average by 4 years for women under the age of 50 and by 1 3 years in women over the age of 50. Adjuvant chemotherapy reduces 10-year breast cancer mortality by 27%. For a woman who has a 50% chance of dying from breast cancer under the age of 50, the approximate reduction in risk of death is 13.5% (50% 0.27). For a woman with a 10% risk of death at 10 years, the risk of death is about 8% (10% 0.27 = 2.7%; 10% 2.7% = 7.3%). 100 ~ 5 year's treatment Adjuvant tamoxifen Adjuvant tamoxifen in a dose of 20 mg orally daily used to be given for life or until time of recurrence. The degree of benefit appears to depend on both the duration of treatment and whether the disease is node positive or negative. Adjuvant tamoxifen reduces the annual risk of death by about 15%. The reduction in risk is 22% among women who have received 5 years of tamoxifen. The survival benefits of adjuvant tamoxifen are shown in Figure Women with oestrogen receptor (ER)-rich tumours have 3 10 times the benefits of ER-poor patients. Life expectancy is increased by 2 3 years in women on tamoxifen for 2 3 years. If tamoxifen is Mortality from any cause (%) (i) Age < 50 years Polychemotherapy Control Follow-up (years) Age years Node-negative Node-positive Mortality from any cause (%) Tamoxifen Control 5 10 Follow-up (years) Node-negative Node-positive Fig Survival with and without adjuvant polychemotherapy in early breast cancer in women under the age of 50 years and years. (Reproduced from Parmar M K B, Adjuvant Therapy, Medicine 1999; 27:12: by kind permission of The Medicine Publishing Company) Mortality from any cause (%) (ii) Polychemotherapy Control Follow-up (years) Node-negative Node-positive Fig Survival with and without 5 years of adjuvant tamoxifen in early breast cancer. (Reproduced from Parmar M K B, Adjuvant Therapy, Medicine 1999; 27:12: by kind permission of The Medicine Publishing Company)

22 BREAST 453 added to chemotherapy in ER-rich tumours, additional benefit accrues, as also happens when chemotherapy is added to tamoxifen. In addition, tamoxifen reduces the risk of contralateral breast cancer. The optimal duration of administration of tamoxifen is not clear but most of the current evidence suggests that 5 years is probably optimal. There is good evidence that 5 years duration is more effective than 2 years and that 2 years is superior to 1 year of therapy. Tamoxifen given for at least 2 years reduces the risk of recurrence by 28% and breast cancer mortality by 21%. 5 years of tamoxifen achieves a 22% reduction in odds of death. Tamoxifen confers a similar reduction in risk of death in node-positive and node-negative women. However, the absolute reduction in risk is greater in node-positive women. The absolute gain in 10-year survival between 5 years of tamoxifen and no tamoxifen is 6% for nodenegative and 11% in node-positive women. It confers benefit in both premenopausal and postmenopausal ERpositive women. Beyond 5 years the reduction in risk by tamoxifen is thought to decline and has to be balanced against the small risk of tamoxifen-induced endometrial cancer. In women less than 50 the benefits are less than in those over the age of 50. Adding tamoxifen to chemotherapy in ER-positive patients confers additional benefit. All patients who are ER positive regardless of their menopausal or nodal status should be considered for tamoxifen for 5 years. Toxicity of tamoxifen Postmenopausal symptoms of hot flushes, vaginal dryness and sexual dysfunction are experienced by 20 40% of patients. Cognitive deficits also occur (as they do after cytotoxic chemotherapy). These symptoms can significantly interfere with a patient s quality of life and should be regularly monitored at follow-up visits. Transient thrombocytopenia occurs in 5 10% and vaginal bleeding in 5%. Tamoxifen increases the development of benign endometrial changes such as hyperplasia. The risk of endometrial cancer, particularly in women who have been on tamoxifen for 5 years or more, is increased three- to fourfold, although the risk remains very small. There appears to be some interaction between radiotherapy and tamoxifen with an increase in subclinical lung fibrosis when tamoxifen is given synchronously with radiotherapy. It should be noted that tamoxifen also increases the risk of thromboembolism. Care should be taken to avoid giving tamoxifen concurrently with chemotherapy. Adjuvant ovarian suppression Suppression of ovarian function is one of the longest established of adjuvant therapies. It was Beatson, a surgeon in Glasgow, who in 1895 first showed that oophorectomy could reduce the activity of breast cancer. A small randomised trial conducted in Edinburgh comparing patients with operable breast cancer treated by adjuvant oophorectomy or CMF chemotherapy showed that oophorectomy had a significant advantage over CMF in ER-positive patients and CMF over oophorectomy in ER-negative patients. Until the Oxford overview in 1995 the value of adjuvant oophorectomy was not well supported because of the small numbers in individual studies. The Oxford overview showed a highly significant increase in recurrence-free survival (25%) in premenopausal women under the age of 50. For node-positive premenopausal women the gains in recurrence-free and overall survival at 15 years were 10.5% and 13% respectively. Much smaller but still statistically significant benefits in both these parameters were seen in premenopausal node-negative women. Medical ovarian suppression by goserelin (3.6 mg given subcutaneously monthly) provides a reversible means of stopping ovarian function. Goserelin is commonly given for 2 years. It has the advantage that if the patient finds the premenopausal symptoms intolerable (e.g. flushing and sweating) it can be stopped. If after 6 months of goserelin, menopausal symptoms are found still to be tolerable, the alternatives are to stay on goserelin or to proceed to an oophorectomy. If the patient prefers to stay on goserelin, it can be stopped after 2 years to check whether the patient is menopausal (raised LH and FSH with reduced oestradiol levels). Adjuvant combination chemotherapy (polychemotherapy) The 2000 Oxford overview shows no significant reduction in recurrence or risk of death comparing prolonged single-agent chemotherapy vs no chemotherapy. Prolonged combination chemotherapy (typically CMF) shows highly significant reductions in recurrence and death in women under the age of 50 and those aged The reduction in risk of recurrence emerged in the first 4 years following treatment and the advantage in survival persists up to 15 years. There do not appear to be any large differences in effects between different types of combination chemotherapy. The age-specific benefits do not appear to be influenced by the ER status of the primary tumour, menopausal status or the administration of adjuvant

23 454 RADIOTHERAPY AND ONCOLOGY tamoxifen. There did not appear to be any increase in non-breast cancer deaths from adjuvant chemotherapy. The proportional reductions in risk were similar in node-positive and node-negative patients. The absolute differences in 10-year survival are 11 12% for nodepositive patients and 4 5% for node-negative disease. For the and age groups, combination chemotherapy improved 10-year survival by 4% and 2% respectively. More recently the use of anthracycline-based chemotherapy (e.g. containing doxorubicin or epirubicin) has increased. The Oxford overview shows highly significant additional reductions in recurrence or death from anthracycline-containing regimes compared to CMF. The proportional reduction in risk did not appear to be affected by the age at diagnosis or by axillary nodal status. There were absolute gains of approximately 4% in survival, which persisted to 10 years. Table 26.7 (a) Doxorubicin + CMF (Bonnadonna) adjuvant regime; (b) epirubicin + CMF a. Doxorubicin + CMF Doxorubicin 75 mg/m 2 i.v. Repeated every 21 days for 4 courses Followed by 8 cycles of CMF Repeated every 21 days b. Epirubicin + CMF Epirubicin 100 mg/m 2 on day 1 Repeated every 21 days for 4 cycles Followed by 4 cycles of CMF Table 26.8 Palliative doxorubicin/epirubicin and cyclophosphamide Doxorubicin 60 mg/m 2 or epirubicin 75 mg/m 2 Cyclophosphamide 600 mg/m 2 Repeated every 21 days Duration of treatment The optimal duration of adjuvant cytotoxic therapy is not known. 6 cycles of adjuvant CMF chemotherapy (Table 26.6) are generally recommended or 4 cycles of epirubicin/doxorubicin followed by 4 8 cycles of CMF (Table 26.7). There is no evidence that more prolonged chemotherapy confers additional benefit at any age. Choice of drugs For patients at intermediate risk of recurrence (1 3 nodes positive) 6 cycles of CMF are recommended. With 4 or more positive axillary nodes, the anthracycline-containing regime is more intensive (Table 26.8) with 4 cycles of doxorubicin followed by 8 cycles of CMF chemotherapy. More recently, epirubicin has been used as an alternative to doxorubicin since it causes less nausea and vomiting. Morbidity Morbidity of adjuvant cytotoxic therapy may be both physical and psychological. For CMF chemotherapy acute toxicity includes nausea and vomiting, temporary alopecia, lassitude, and soreness of the eyes (the latter due to secretion of methotrexate into the tears). Neutropenia-related infection is less common with CMF than with more intensive anthracycline-based chemotherapy. The anthracyclines (doxorubicin and epirubicin) cause complete, although reversible, alopecia. They are also potentially cardiotoxic, and cardiac function, judged clinically by electrocardiogram and cardiac ejection fraction, should be adequate before use. Otherwise congestive cardiac failure may result. Anxiety and depression are common sequelae of treatment as a result of toxicity, change in body image and the cumulative emotional toll of the diagnostic Table 26.6 Adjuvant CMF regimes Classical Cyclophosphamide 100 mg/m 2 orally Days 1 14 Methotrexate 40 mg/m 2 i.v. bolus Days 1 and 8 5-fluorouracil 600 mg/m 2 i.v. bolus Days 1 and 8 Repeated every 28 days Alternative Cyclophosphamide 750 mg/m 2 i.v. 3-weekly Methotrexate 50 mg/m 2 i.v. 3-weekly 5-Fluorouracil 600 mg/m 2 i.v. 3-weekly

24 BREAST 455 pathway and prolonged treatment. It is important to recognise and treat them, if necessary referring for specialist advice to a psychiatrist or clinical psychologist. MANAGEMENT OF LOCALLY ADVANCED BREAST CANCER (LABC) Locally advanced breast cancer (T3 or T4 or N2 or N3M0) still presents a major challenge in management. It accounts for between 5% and 30% of patients presenting to the breast clinic. A typical example in shown in Figure These are a very heterogeneous group of tumours with widely differing natural histories. While there have been substantial improvements in local response to a combination of systemic therapy and radiotherapy, the development of metastatic disease remains a major problem. Patients should be assessed by the multidisciplinary team. Clinical features The main features of LABC are skin nodules, peau d - orange (T4b), inflammatory changes (T4d), ulceration and fixity to the chest wall (T4a), fixed axillary nodes (N2) or lymphoedema (N3). Local pain, bleeding, ulceration and infection are common symptomatic problems. Principles of management The main aim of management of LABC is to provide durable local control. The natural history of locally advanced disease varies widely. In some patients distant metastatic disease will rapidly supervene, in others the disease remains locoregional and relatively indolent. Some of the most difficult patients to manage are young with aggressive locoregional disease but who remain free of metastatic disease. Fig Locally advanced and inoperable carcinoma of the right breast (T4). Neoadjuvant therapy The use of initial (neoadjuvant) systemic therapy is based on the observation that patients with LABC frequently develop metastatic disease. The aim of neoadjuvant therapy is to treat both local and micrometastatic disease and to downstage the disease prior to local therapy. Initial treatment should be systemic with either hormonal or cytotoxic therapy depending on ER status. This should aim at maximum cytoreduction before proceeding to mastectomy (if skin oedema or inflammatory changes have settled) followed by radiotherapy, or by radiotherapy alone if skin oedema or inflammatory changes persist after systemic therapy. Role of surgery Surgery has a more limited role in the management of locally advanced disease. It encompasses: (i) initial core biopsy for diagnosis and ER status; (ii) mastectomy and axillary clearance in operable patients; (iii) mastectomy (ideally with myocutaneous flap reconstruction) for residual masses after chemotherapy and radical radiotherapy; and (iv) palliative debriding of infected and/or necrotic areas to reduce odour. There are occasionally patients with small T4 tumours in the inferior part of the breast or inframammary fold who can be managed by standard breast-conserving surgery, postoperative radical radiotherapy and appropriate systemic therapy. Systemic therapy In general LABC in younger patients tends to be high grade and ER negative. For patients with inflammatory (T4d) disease irrespective of ER status initial treatment should, subject to general medical fitness, be with chemotherapy because of the aggressive nature of this form of the disease. Combination therapy is more effective than singleagent therapy. A number of different combinations are possible. The optimal regime and scheduling has yet to be established. Doxorubicin and cyclophosphamide are an effective combination (Table 26.8). Between 4 and 6 cycles are given before local therapy depending on the response and 4 6 cycles after local treatment, again dependent on the initial response to neoadjuvant chemotherapy. If there is no response to chemotherapy after the first 2 cycles, chemotherapy should be abandoned and the patient should proceed directly to radical radiotherapy. Neoadjuvant therapy may debulk the tumour sufficiently for mastectomy or

25 456 RADIOTHERAPY AND ONCOLOGY occasionally breast-conserving surgery to be made possible. Trials are assessing the benefits of using a different non-cross-resistant adjuvant therapy regime after local therapy in an attempt to eradicate residual tumour cells resistant to initial chemotherapy. While the taxanes have an established role in the treatment of metastatic disease, their efficacy in locally advanced disease has yet to be established. Studies of dose intensification are in progress. Concurrent chemoradiation There are good theoretical reasons for giving chemotherapy and radiotherapy concomitantly since chemotherapeutic agents such as 5-FU are radiosensitisers and may increase the cytotoxicity of radiotherapy. An additional advantage is the shortened overall treatment time. Concurrent chemoradiation, however, carries risks of enhancing complications of radiotherapy such as soft tissue necrosis, brachial plexopathy, radiation pneumonitis and cardiac failure. Until long-term data confirm the safety and efficacy of concomitant chemoradiation, sequential therapy is recommended. Intra-arterial chemotherapy Where local recurrence has occurred despite conventional chemotherapy and radiotherapy, intra-arterial chemotherapy has been successfully administered via the internal mammary artery. Although response rates in some centres are impressive, only small series of patients have been reported. Radical radiotherapy Technique The principles of radical radiotherapy for early breast cancer apply also to locally advanced disease both for the intact breast or following mastectomy. The only difference is that cm of skin bolus should be applied to the breast or chest wall to ensure that the skin receives a full dose (to overcome the skin-sparing effect of megavoltage radiotherapy). Axillary surgery is not normally carried out at staging and therefore the peripheral lymphatics will normally be irradiated. If mastectomy and clearance have been carried out, the axilla is not irradiated. Where there is macroscopic disease which would cross the conventional breast/shoulder field junction, it is best to use an en bloc technique, treating both the breast and the peripheral lymphatics in a Perspex jig (see Fig ). Dosage and fractionation While there is evidence of a dose response effect in locally advanced disease, escalating dosage beyond Gy is associated with an increased risk of major complications. Hyperfractionated radiotherapy may have advantages in reducing repopulation during radiotherapy. The long-term results of studies of hyperfractionated radiotherapy are awaited. Until there is convincing evidence of improved local control, conventional dosage and fractionation are recommended. 1. Post-mastectomy 45 Gy TAD in 20 fractions over 4 weeks (6 MV photons) (applying skin bolus) 2. Intact breast 45 Gy TAD in 20 fractions over 4 weeks (6 MV photons) (applying skin bolus) Boost 15 Gy maximum dose in 5 daily fractions over 1 week with electrons of appropriate energy To judge the appropriate choice of energy of electrons, an ultrasound scan should be carried out towards the end of the radical course of breast irradiation and the distance from the skin surface over the tumour to the maximum depth of the tumour measured. The other dimensions of the tumour should also be measured to help the selection of the appropriate electron field size. Palliative radiotherapy In some patients radical radiotherapy is not advised either because of poor medical condition, advanced age or evidence of metastatic disease elsewhere. Palliative radiotherapy can be very effective for symptomatic relief of local bleeding, ulceration, pain from axillary involvement and secondary upper limb lymphoedema. Responses are usually only partial but may be prolonged or short-lived. However, even some shrinkage can be worthwhile, improving the morale of the patient where chemotherapy or hormonal therapy has been unsuccessful. Technique This should be simple, either with parallel-opposed or tangential fields at megavoltage confined to the macroscopic area of tumour using a small Perspex jig, or, for flat limited areas of tumour, by a single electron field using a Perspex degrader to bring up the skin to full dose. Dose 20 Gy in 5 daily fractions over 1 week (electrons or 4 6 MV photons)

26 BREAST 457 Bone metastases Patients with symptomatic bony metastases should be considered for up to 2 years of bisphosphonate therapy (e.g. pamidronate 90 mg monthly by intravenous infusion or oral clodronate 1600 mg daily) in addition to palliative radiotherapy. Patients at risk of pathological fracture should be referred to an orthopaedic surgeon for consideration of mechanical stabilisation (Fig ) followed by postoperative palliative radiotherapy. Technique Single or parallel-opposed fields are used. Single fields suffice for the thoracic, lumbar spine and sacroiliac joints. The cervical spine can be treated by a single posterior field but this will cause a sore throat due to the exit dose through the mouth. Lateral opposed fields reduce the dose to the mouth. Dose Single fractions of 8 Gy are recommended at megavoltage. Following surgical stabilisation, fractionated radiotherapy is given: 20 Gy in 5 fractions over 1 week at megavoltage Palliative surgery Where there is extensive ulceration and secondary infection causing distressing and offensive odour, surgical debridement of the affected area is often helpful in improving these symptoms. This can be repeated if necessary. Cerebral or choroidal metastases. See Chapter 30 (p. 551, 563) for treatment. Fig Radiograph of pelvis showing pinning of pathological fracture of right hip due to extensive mixed and sclerotic disease from breast cancer. Results of treatment Overall the outcome of patients with locally advanced disease remains poor, largely because of the high incidence of development of metastatic disease. The only systemic therapy that improves long-term survival for LABC is tamoxifen. The main effects of systemic therapy and radiotherapy are on local control. In general, response to neoadjuvant systemic therapy predicts survival. Preoperative neoadjuvant therapy can be very successful with response rates in excess of 50%. Response rates to systemic therapy combined with radiotherapy are of the order of 89%. About 75% of patients with ER-rich tumours will respond to hormonal therapy. The size of the primary tumour (especially over 8 cm), high grade and axillary involvement are major prognostic factors for outcome. 5-year survival rates vary widely from 5% to 45% with the best results being achieved in patients achieving a complete response to neoadjuvant chemotherapy and the worst in patients with progressive disease despite neoadjuvant therapy. 5-year survival from radiotherapy alone is 20 25% with barely any survivors among patients with inflammatory disease. The addition of surgery to radiotherapy improves the 5-year survival to 40 50%. MEDICAL MANAGEMENT OF METASTATIC DISEASE Although about 90% of patients present with localised disease, about 50% of patients with involved nodes and 10% of those who are node negative will relapse within 5 years. This comes as a blow to most patients and psychological support from the breast care team is an important element in the care of such patients in addition to individualised medical management. Treatment is still essentially palliative since the average life expectancy from the time of diagnosis of metastatic disease is of the order of 18 months. None the less, durable and clinically useful disease control can be obtained by hormonal, and/or cytotoxic therapy. In addition, therapy with bisphosphonates can be useful in reducing the risk of complications of bony metastases. Principles of management The choice of treatment must take into account the age and general medical condition of the patient, menopausal status, oestrogen receptor (ER) status, sites of metastatic involvement and the tempo of the disease. It is important that all centres should have access to ER status, since responses to hormonal treatment in