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Complications of Breast-cancer Radiotherapy
Clinical Oncology (2006) 18: 229e235 doi:10.1016/j.clon.2005.11.004
Overview
Complications of Breast-cancer Radiotherapy E. Senkus-Konefka, J. Jassem Department of Oncology and Radiotherapy, Medical University of Gdan´sk, Gdan´sk, Poland
ABSTRACT: Although the beneficial effect of postoperative radiotherapy for breast cancer is well documented, this treatment may be related to a number of complications, which may affect patient quality of life and possibly survival. Among significant long-term irradiation sequelae are cardiac and lung damage, lymphoedema, brachial plexopathy, impaired shoulder mobility and second malignancies. The risk of these complications, particularly high with old, suboptimal irradiation techniques, has decreased with the introduction of modern technologies. In this paper, we review the contemporary knowledge on the toxicity of breast-cancer radiotherapy and discuss possible preventive measures. Senkus-Konefka, E., Jassem, J. (2006). Clinical Oncology 18, 229e235 ª 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Breast cancer, complications, mortality, radiotherapy
Introduction Cumulating data confirm the beneficial effect of radiotherapy in women with breast cancer. After mastectomy and breast-conserving surgery, this effect is expressed by a significant decrease in the local relapse rate and, in the former, by increased survival [1e4]. Postoperative radiotherapy, however, is associated with some complications that may affect patient quality of life and possibly survival. This review summarises the contemporary knowledge on morbidity and mortality related to breast-cancer radiotherapy, and provides possible means to decrease the incidence and severity of complications. As cardiovascular toxicity is covered by a separate paper in this issue, it will not be addressed here.
Pulmonary Complications Pulmonary complications of radiotherapy are usually divided into early (radiation pneumonitis) and late (lung fibrosis) [5,6]. Both are confined to radiation portals: anterolateral peripheral lung after breast or chest wall irradiation, or lung apex after irradiation of the supraclavicular area [6]. Like all forms of diffuse alveolar damage, radiation lung injury is divided into three sequential pathologic phases: exudative, organising or proliferative and chronic fibrotic [7]. Radiation lung damage results from the combined effect of two interrelated mechanisms. The first includes microcapillary vascular damage leading to ischaemic tissue injury and fibrotic healing, and the second includes damage to type I and II pneumocytes in the presence of increased vascular permeability, leading to altered surfactant production, atelectasis, reduced ventilation and secondary vascular atrophy [8,9]. It is 0936-6555/06/180229C07 $35.00/0
suggested that, pathophysiologically, radiation pneumonitis resembles acute respiratory distress syndrome, resulting from tumour necrosis factor production [8]. Radiation pneumonitis usually develops 4e12 weeks after completing radiotherapy, and presents as dry cough, dyspnoea and low-grade fever [5,6,10e12]. In most cases, these symptoms are mild and resolve spontaneously, although some women may require corticosteroid treatment [10,13]. In women diagnosed with moderate-grade pneumonitis, the mean reduction in vital capacity is equivalent to loss of three-quarters of the lung lobe [14]. Some repair of early injury (as assessed by perfusion and ventilation assays and computed tomography) may be found 18 months after radiotherapy, but no further improvement is observed at 48 months [15]. Lung fibrosis appears after 6e24 months, usually remains stable after 2 years [6,12] and is accompanied by limited, but irreversible, changes in pulmonary function tests [15,16]. From the functional point of view, the lung represents a parallel structure, but some data suggest differences between radiation sensitivity of superior and inferior parts of the lung, the latter being more sensitive [5,17]. Interestingly, the incidence of radiation pneumonitis seems to correlate with increased radiological lung density in central, but not apical, parts of the lung [11]. The apical damage seems to be less consequential, as these parts are less perfused and ventilated at rest [11]. Chest radiography initially shows a diffuse haze with obscuring of vascular outlines, gradually progressing to patchy consolidation and then coalescing to form relatively sharp edges conforming to treatment portals [6]. Occasionally, small pleural effusions may accompany acute radiation pneumonitis [6]. These lesions may gradually clear and disappear completely or progress to permanent fibrous
ª 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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changes, presenting as well-defined areas of atelectasis with parenchymal distortion, pleural thickening and, in the case of massive involvement, traction bronchiectasis and mediastinal shifting [6]. In the supraclavicular area, these lesions may mimic pulmonary tuberculosis [6]. On computed tomography imaging, the acute exudative phase is represented by ground glass attenuation, homogeneous consolidation or patchy consolidation not conforming to the shape of portals. The following organising (proliferative) phase presents as discrete consolidation conforming to the shape of portals, but not outlining it uniformly. The final chronic fibrotic phase is represented by solid consolidation, which conforms and involves the irradiated portion of the lung [18]. Differential diagnosis of these radiological abnormalities must, among other things, include local recurrence, lymphangitic spread of the tumour and infectious pneumonitis [6]. Only a part of radiological lung changes are accompanied by clinical symptoms [10,12,19]. The incidence of clinically evident radiation pneumonitis in different series ranges from 0% to 31% [5,10,13,20,21]. However, retrospective studies might underestimate low-grade changes [11]. More pronounced injury, requiring steroid treatment, is present in 0e11% of women with breast cancer [10,13]. On radiological examination, lung fibrosis is seen in up to 87% of women [12,22e24]. Although the exact tolerance of normal lung tissue is not known, radiation lung damage is rarely seen below 20 Gy, whereas it is common in areas receiving 30e40 Gy, and almost inevitable over 40 Gy [6,10]. The probability of lung damage is related to total dose, fractionation and irradiated lung volume [5,6,10,12]. The effect of other factors is less clear [10,11,13]. Suggested variables include age, performance status, the use of chemotherapy, tamoxifen (or both), smoking, preexisting reduced lung function, co-existing heart disease and short overall treatment time [5,10e13,23,25e27]. The data on the effect of high-dose chemotherapy are contradictory, whereas concomitant paclitaxel was reported to increase the risk of pneumonitis [10]. The difference in the risk of radiation injury among particular studies is predominantly related to various radiotherapy techniques and irradiated volumes. Locoregional radiotherapy, in particular, including the internal mammary chain, is generally associated with significantly higher risk [10,12,13,28]. A good predictor of lung complications of breast or chest wall only irradiation is central lung distance, with values less than 2e3 cm considered safe [13,14,29e31]. More fibrosis is usually seen in patients receiving radiotherapy with single en face electron field [11]. Improved lung protection may be achieved by use of individual bolus to even out localised differences in chest wall thickness [10,23]. Other approaches include treatment at deep inspiration [32] and the use of conformal threedimensional planning [29], although the value of the latter for breast or chest wall only irradiation is disputable [10]. A rare syndrome related to lung irradiation, and for unknown reasons obviously limited almost exclusively to women with breast cancer, is bronchiolitis obliteransorganising pneumonia [33,34]. It can be described as bilateral lymphocytic alveolitis, and is believed to occur
as a result of immunological reactions mediated by lymphocytes [33,34]. Radiological abnormalities include diffuse haze progressing into patchy alveolar infiltrates with air bronchograms [34]. A migratory pattern of dense alveolar infiltrates is characteristic, with lesions originating usually from the irradiated area and spreading to both lungs [34]. Symptoms include cough, dyspnoea, fever, asthenia and weight loss, and respond well to corticosteroid treatment, although high recurrence rate is observed at treatment discontinuation, often requiring long-term lowdose steroid treatment [34]. The prognosis of bronchiolitis obliterans-organising pneumonia is excellent, with virtually no progressive or chronic fibrosis [34].
Second Malignancies The data on the incidence of second malignancies in breastcancer survivors are contradictory. Most studies do not report a large increase in the risk of second primary malignancies among women receiving radiotherapy for breast cancer compared with women who do not receive radiotherapy or with the general population [24,35e37]. This general statement applies to contralateral breast cancer and to non-breast tumours [35,38]. It is noteworthy, however, that most studies had limited power to detect a relatively small increase in incidence [39]. Ten- and 15-year cumulative incidences of all second tumours in women receiving radiotherapy for breast cancer are in the range of 16e19%, with a similar proportion of contralateral breast cancer and other tumours [35,37,40,41]. Among the latter, as in the general population, the most common are skin, endometrial, colorectal and pancreatic cancers [40]. However, some tumours seem to occur with relatively higher frequency [38]. These include ovarian (standardised incidence ratio [SIR] 2.0), renal (SIR 2.5), uterine (SIR 1.9) and lung cancers, leukaemias (SIR 3.1), malignant melanomas (SIR 2.7) and sarcomas (SIR 13) [37,42]. A proportion of these cases may be a result of misclassification of metastatic disease. Some of these malignancies may be related to interaction between radiation and genetic factors [42,43]. Indeed, in some series, the use of radiotherapy was related to an overall increase in the risk of second tumours [42,44], whereas others demonstrated no effect [24,45]. For example, breastcancer radiotherapy increases the risk of leukaemias and lymphomas, but not of thyroid cancer [42,46]. The increased risk is observed predominantly in women diagnosed with breast cancer at a young age [37,42]. Several studies have reported an increased risk of contralateral breast cancer, with [47] or without radiotherapy [40,48] in young women, although, in the SEER (Surveillance Epidemiology and End Results) data, increased risk was observed over the age of 55 years, and was not related to radiotherapy [41]. The data from other studies are conflicting [38]. Of the six randomised studies comparing radiotherapy with no radiotherapy, one showed increased risk in the irradiated group, two a trend towards increase, and three a decreased incidence of contralateral breast cancer [38]. Among retrospective cohort
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and caseecontrol studies, increased risk was shown in two, a trend for increased risk in five and decreased risk in another five studies [38]. No study, however, showed an increase in the relative incidence of tumours appearing in the medial part of the breast (i.e. in the area of higher scatter dose, where the carcinogenic effect of radiation is expected to be more pronounced) [38]. As the carcinogenic effect of radiation on breast tissue was shown in many studies [38,49], it is reasonable to make every effort to limit the doses of incidental irradiation. Conventional tangential fields result in a substantial dose absorbed by contralateral breast (average 2e5 Gy) [38,47,50]. The amount of scatter radiation is dependent on distance from field edge in the medial beam, use of SSD (source skin distance) (as opposite to isocentric) technique, use of multiple fields and non-alignment of deep field edges, use of wedges, half beam blocks (or both) [38,50]. Significant lowering of scatter may be achieved by replacing some of these accessories by dynamic wedges and asymmetric jaws [38]. Dose to the opposite breast is also increased by irradiation of internal mammary chain [38]. In relation to the opposite breast dose, it is thus recommended to apply the ALARA (as low as reasonably achievable) strategy. This may partly be accomplished by the use of wedges in lateral field and by shielding the opposite breast [38]. Introduction of conformal three-dimensional radiotherapy allows for a decrease in radiation exposure of normal tissues, whereas the use of intensity-modulated radiotherapy may significantly increase the doses to normal tissues (including opposite breast) [38,39]. The total body dose is expected to be two to three times higher, predominantly owing to the increased number of beams used, as well increased leakage radiation (resulting from increased ‘beam on’ times) [39]. Intensity-modulated radiotherapy may therefore increase the incidence of second tumours in 10-year survivors; this will predominantly include tumours resulting from low exposure, such as leukaemias and carcinomas [39]. Better discrimination of high-dose volume may, however, decrease the incidence of tumours related to high radiation exposure, such as sarcomas [39]. Another factor strongly associated with increased risk of contralateral breast cancer is family history [38,40] and, in particular, a presence of BRCA1 or BRCA2 mutations [38]. As protein products of BRCA1 and BRCA2 interact with repair of double strand breaks, it has been suggested that these patients may be particularly vulnerable even to small radiation doses [38]. Another tumour of confirmed relationship to radiation exposure is lung cancer. Three large studies confirmed a significantly increased incidence of ipsilateral (compared with contralateral) lung cancer after irradiation for breast cancer [49,51e53]. In most studies, this increase was related to post-mastectomy and not to post-lumpectomy radiotherapy [52,53]. Increased risk was observed in smokers and non-smokers, but the exposure to both agents (radiation and smoking) seemed to have a multiplicative effect (relative risk 32.7) [49,51]. Tumours with the largest relative increase of incidence in breast-cancer survivors are soft-tissue sarcomas (SIR 13)
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[42]. Women exposed to radiotherapy harbour over a fourfold relative risk of sarcomas compared with women not exposed to radiotherapy [42]. Radiation-related soft-tissue tumours appear after a mean latency of 10e12 years [43,54]. In the Swedish Cancer Registry study, 63% of these tumours occurring in breast-cancer survivors were located within the breast and ipsilateral arm, and over one-third were angiosarcomas [43]. This accounted for 20% of all angiosarcomas registered, whereas other soft-tissue sarcomas in breast-cancer survivors constituted only 2% of all tumours of this type [43]. Most angiosarcomas developed in the vicinity of the breast, particularly within the lymphoedematous arm (StewarteTreves syndrome) [43]. Angiosarcoma may also develop within the skin of the conserved breast [43,55]. The risk of developing soft-tissue sarcomas other than angiosarcomas is related to integral radiation dose, although the risk decreased above a certain dose threshold, which is compatible with cell sterilisation at high doses. Risk of angiosarcomas is not directly related to history of irradiation, but correlates strongly with presence of lymphoedema, which in turn is often induced or aggravated by radiotherapy [43]. Overall, however, the risk of developing radiation-induced sarcomas is small, comparable to mortality due to anaesthesia [56].
Shoulder and Arm Complications Shoulder and arm complications are among the most troublesome sequelae of breast-cancer treatment [25,57,58]. Some arm problems are estimated to occur in up to 90% of women with breast cancer [58,59]. Most important complications include arm lymphoedema, brachial plexus neuropathy and impaired shoulder mobility [25,57]. These morbidities often appear together and, to some extent, share common pathogenic elements (e.g. neural damage leads to restricted mobility, which in turn may aggravate lymphoedema) [25,58,60]. These complications may be related to muscular and subcutaneous fibrosis or to vascular injury [25]. All of these symptoms influence the ability to carry out common daily activities [57]. They may lead to change in clothing habits or may require job change [22]. The gross effect in particular women is, however, the product of severity of symptoms and individual’s ability to cope [25].
Lymphoedema Lymphoedema is considered a most significant complication of locoregional treatment of breast cancer [61]. It may result in significant psychological and functional morbidity, and markedly worsens quality of life [20,62]. Once established, in most cases it cannot be cured. It is thus essential to prevent or minimise this condition [63]. Chronic lymphoedema is often associated with skin changes, the socalled ‘brawny oedema’ [63]. In most women, it is also accompanied by pain, numbness and shoulder stiffness [58]. It may also predispose to development of cellulitis and limits the arm mobility [20,25,57].
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The pathogenesis of lymphoedema includes radiationinduced fibrosis, causing venous and lymphatic vessel obstruction and lymphocyte depletion with fatty replacement and local fibrosis [25]. These factors strongly interact with surgery, possibly due to reduced lymphatic regeneration after surgical interruption [25]. The contribution of haemodynamic factors is also relevant [25]. The incidence of lymphoedema in particular studies varied greatly between 4% and 39% [20,57,61,64]. This is partially due to different definitions of increased arm dimensions: volume increase greater than 200 ml, circumference increase greater than 2 cm or increase of diameter greater than 5% [20,63,64]. The median latency is usually in the range of 1.5e4 years [20,25,61,65]. As lymphoedema may develop as many as 10 years after radiotherapy, its observed incidence depends also on the length and completeness of follow-up [61,63]. The risk of lymphoedema is mainly related to the treatment applied [64]. The risk after surgery only varies between 1% and 30% [20,25,63], and depends primarily on the extent of lymph-node dissection [20,22,25,58,61,64]. Radiotherapy to the axilla considerably increases incidence and severity of this complication, with relative risk ratio reaching 4.6 [20,57,61,64]. It is estimated that these two treatment modalities contribute to the development of lymphoedema to a similar degree [57]. The effect of radiotherapy is highly dependent on the size of dose per fraction (low a/b value). The doseeresponse relationship is strongly affected by surgery and, similarly to other late end points, is very steep (which translates to large effects of small changes of fractionation and dose distribution) [25]. Concomitant use of tamoxifen or chemotherapy may increase the risk of lymphoedema [25,63], although a bias associated with the selection of patients with more advanced disease cannot be excluded [61]. Other risk factors can be divided into patient-related and disease-related factors. The first group includes obesity, older age, lower education, history of hypertension and infection or inflammatory process within the arm [20,22,25,58,61,63,64]. Disease-related factors include stage and, in particular, pathological nodal (N) status [61,63]. The mechanism involved here may be lymphostasis secondary to malignant involvement of lymphatic channels and scarring caused by successful eradication of disease [61]. It is hoped that widespread use of the sentinel node technique will significantly decrease the risk of lymphoedema [25]. Ongoing studies are testing whether full lymph-node dissection in node-positive patients can be replaced by axillary radiotherapy (European Organisation for Research and Treatment of Cancer ‘‘After Mapping of the Axilla: Radiotherapy Or Surgery’’ EORTC AMAROS study). On the other hand, the need for nodal irradiation after adequate lymph-node dissection is questionable [64,66].
Brachial Plexopathy Brachial plexus neuropathy is a relatively rare complication of modern radiotherapy, although, in the past, its incidence was much higher [60,65e69]. It has been predominantly
observed in women treated with high dose per fraction or with overlapping fields [60,68]. The most remarkable data on this complication come from the Umea series, in which, over 30 years after hypofractionated radiotherapy with possible field overlapping, more than 90% of women developed complete paralysis of the arm [67]. The estimated biologically equivalent dose in 2 Gy fractions in these women was 85e92 Gy [65]. Interestingly, the damage continued to progress up to 30 years after radiotherapy [67,68,70]. The latency period for this complication ranges from 1.5 to 10 years (7e14 years for complete paralysis), and is similar for motor and sensory impairment [25,60,65,67,68,70]. The late presentation of damage results from slow turnover of tissues, which attempt cell division many years after injury. Lost tissue is then replaced by fibrosis, leading to formation of dense, inelastic and constricting tissue [67]. Brachial plexus neuropathy is defined as motor or sensory symptoms or physical signs, with or without accompanying pain in a nerve-root distribution in the arm. Neurological manifestations may include paresthesia in the fingers or hands, hypoesthesia, hypoalgesia, disesthesia, paresis, hyporeflexia and muscular atrophy [25,60,67,68,70]. The limb weakness may be selectively distal, global with more marked distal deficits or a complete flaccid paralysis [60]. Most women have abnormal neurophysiology findings: absent sensory nerve action potential, axonal changes, myokymia and prolonged F-waves [60]. Magnetic resonance imaging studies show only soft-tissue fibrosis [60]. Brachial plexopathy is strongly correlated with late fibrosis and muscle atrophy within the shoulder region [60,65]. The damage may encompass the whole plexus or only its lower part [60]. Plexopathy is irreversible [70]. Its incidence depends on total dose, dose per fraction (low a/b value), patient age and concomitant use of chemotherapy [25,64,65,68,70]. Frequently, the toxicity results from unplanned overdosage originating from field overlap caused by changing the woman’s position between treatment fields or from ‘matchline’ problems [25,60,65,67,68]. One of the suggested pathomechanisms of radiationinduced neuropathy is nerve entrapment by radiationinduced fibrosis, chronic oedema, or both [25,67,68]. Another postulated cause was direct damage to neurones or glial cells and ischaemic damage resulting from microvascular injury [25,65,68]. There are probably two phases of radiation-induced neuropathy: the first includes more direct changes in electrophysiology and histochemistry, whereas the second involves fibrotic changes around the nerves and injury of the adjacent vessels [25,71].
Impaired Shoulder Mobility A proportion of women with breast cancer experience some degree of post-surgery shoulder stiffness, which may further be aggravated by the use of axillary radiotherapy [22]. Symptoms usually include reduced flexion, external rotation and abduction, and pain at movement or at rest [25,57]. In some women, this leads to reduced working ability [25].
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Shoulder stiffness is usually caused by fibrosis of the major pectoralis muscle and damage to vasculature or to the joints [25]. Movement range may also be decreased as a result of lymphoedema or neural damage [25]. Symptoms usually appear after a median latency of 4 years [25]. Increased risk of radiation-related impaired shoulder mobility is related to the use of large doses per fraction (low a/b value), older age, use of concomitant systemic treatment, co-existence of subcutaneous fibrosis and degree of movement impairment at the start of radiotherapy [25,72]. To diminish the consequences of shoulder and arm problems, women should be recommended physical exercise programmes [25,64]. However, some women with oedema or neurological deficits may not be able to follow these programmes [25].
Other Complications Less frequently encountered problems after breast-cancer radiotherapy include rib fractures, chronic pain, axillary vein thrombosis and bone necrosis [20,22,65,66,73]. Rib fractures usually involve anterior aspects of third, fourth and fifth rib, are frequently multiple, spontaneous and asymptomatic and may be slow to unite. Bone complications seemed to be particularly common in the orthovoltage era, most probably due to more energy attenuation in bone [74].
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Conclusion Women undergoing radiotherapy for breast cancer should be followed-up lifelong for complications, as these problems tend to appear after long latency periods and damage may be progressive [25,60,70]. Long observation is particularly important before confirming the safety of new (in particular hypofractionated) irradiation schedules and techniques. The injury developing after many years means, however, that these women have survived all these years symptom free, possibly thanks to radiotherapy [25]. Much of the experience on the radiation-induced damage with long latency periods comes from old series, applied obsolete radiotherapy techniques, whereas contemporary treatments seem to be less harmful [25]. The application of modern radiotherapy techniques, including conformal three-dimensional radiotherapy, intensity-modulated radiotherapy, gated, image-guided irradiation, or both, as well as tailored use of radiotherapy, will hopefully further decrease the incidence of complications [75].
_ Author for correspondence: Elzbieta Senkus-Konefka, Department of Oncology and Radiotherapy, Medical University of Gdan ´sk, Dxbinki 7, 80-211 Gdan ´sk, Poland. Tel: C48-58-3492271; Fax: C4858-3492270; E-mail: [email protected]
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38 Unnithan J, Macklis RM. Contralateral breast cancer risk. Radiother Oncol 2001;60:239e246. 39 Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 2003;56:83e88. 40 Fowble B, Hanlon A, Freedman G, Nicolaou N, Anderson P. Second cancers after conservative surgery and radiation for stages IeII breast cancer: identifying a subset of women at increased risk. Int J Radiat Oncol Biol Phys 2001;51:679e690. 41 Gao X, Fisher SG, Emami B. Risk of second primary cancer in the contralateral breast in women treated for early-stage breast cancer: a population-based study. Int J Radiat Oncol Biol Phys 2003;56:1038e1045. 42 Rubino C, de Vathaire F, Diallo I, Shamsaldin A, Le MG. Increased risk of second cancers following breast cancer: role of the initial treatment. Breast Cancer Res Treat 2000;61:183e195. 43 Karlsson P, Holmberg E, Samuelsson A, Johansson KA, Wallgren A. Soft tissue sarcoma after treatment for breast cancer d a Swedish population-based study. Eur J Cancer 1998;34:2068e 2075. 44 Houghton J, Baum M, Haybittle JL. Role of radiotherapy following total mastectomy in patients with early breast cancer. The Closed Trials Working Party of the CRC Breast Cancer Trials Group. World J Surg 1994;18:117e122. 45 Lavey RS, Eby NL, Prosnitz LR. Impact of radiation therapy and/or chemotherapy on the risk for a second malignancy after breast cancer. Cancer 1990;66:874e881. 46 Huang J, Walker R, Groome PG, Shelley W, Mackillop WJ. Risk of thyroid carcinoma in a female population after radiotherapy for breast carcinoma. Cancer 2001;92:1411e1418. 47 Boice JD, Jr, Harvey EB, Blettner M, Stovall M, Flannery JT. Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med 1992;326:781e785. 48 Bernstein JL, Thompson WD, Risch N, Holford TR. Risk factors predicting the incidence of second primary breast cancer among women diagnosed with a first primary breast cancer. Am J Epidemiol 1992;136:925e936. 49 Neugut AI, Murray T, Santos J, et al. Increased risk of lung cancer after breast cancer radiation therapy in cigarette smokers. Cancer 1994;73:1615e1620. 50 Fraass BA, Roberson PL, Lichter AS. Dose to the contralateral breast due to primary breast irradiation. Int J Radiat Oncol Biol Phys 1985;11:485e497. 51 Prochazka M, Granath F, Ekbom A, Shields PG, Hall P. Lung cancer risks in women with previous breast cancer. Eur J Cancer 2002;38:1520e1525. 52 Zablotska LB, Neugut AI. Lung carcinoma after radiation therapy in women treated with lumpectomy or mastectomy for primary breast carcinoma. Cancer 2003;97:1404e1411. 53 Deutsch M, Land SR, Begovic M, Wieand HS, Wolmark N, Fisher B. The incidence of lung carcinoma after surgery for breast carcinoma with and without postoperative radiotherapy. Results of National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials B-04 and B-06. Cancer 2003;98:1362e1368. 54 Lagrange JL, Ramaioli A, Chateau MC, et al. Sarcoma after radiation therapy: retrospective multiinstitutional study of 80 histologically confirmed cases. Radiation Therapist and Pathologist Groups of the Federation Nationale des Centres de Lutte Contre le Cancer Radiology 2000;216:197e205. 55 Autio P, Kariniemi AL. Angiosarcoma. A rare secondary malignancy after breast cancer treatment. Eur J Dermatol 1999;9: 118e121. 56 Parker RG. Radiation-induced cancer as a factor in clinical decision making (the 1989 ASTRO Gold Medal address). Int J Radiat Oncol Biol Phys 1990;18:993e1000.
RADIOTHERAPY COMPLICATIONS 57 Kwan W, Jackson J, Weir LM, Dingee C, McGregor G, Olivotto IA. Chronic arm morbidity after curative breast cancer treatment: prevalence and impact on quality of life. J Clin Oncol 2002;20: 4242e4248. 58 McCredie MR, Dite GS, Porter L, et al. Prevalence of selfreported arm morbidity following treatment for breast cancer in the Australian Breast Cancer Family Study. Breast 2001;10: 515e522. 59 Hack TF, Cohen L, Katz J, Robson LS, Goss P. Physical and psychological morbidity after axillary lymph node dissection for breast cancer. J Clin Oncol 1999;17:143e149. 60 Fathers E, Thrush D, Huson SM, Norman A. Radiation-induced brachial plexopathy in women treated for carcinoma of the breast. Clin Rehabil 2002;16:160e165. 61 Powell SN, Taghian AG, Kachnic LA, Coen CW, Assaad SI. Risk of lymphedema after regional nodal irradiation with breast conservation therapy. Int J Radiat Oncol Biol Phys 2003;55: 1209e1215. 62 Tobin MB, Lacey HJ, Meyer L, Mortimer PS. The psychological morbidity of breast cancer-related arm swelling. Psychological morbidity of lymphoedema. Cancer 1993;72:3248e3252. 63 Kocak Z, Overgaard J. Risk factors of arm lymphedema in breast cancer patients. Acta Oncol 2000;39:389e392. 64 Johansen J, Overgaard J, Blichert-Toft M, Overgaard M. Treatment morbidity associated with the management of the axilla in breast-conserving therapy. Acta Oncol 2000;39:349e 354. 65 Johansson S, Svensson H, Larsson LG, Denekamp J. Brachial plexopathy after postoperative radiotherapy of breast cancer patients: a long-term follow-up. Acta Oncol 2000;39:373e382. 66 Pierce LJ. Treatment guidelines and techniques in delivery of postmastectomy radiotherapy in management of operable breast cancer. J Natl Cancer Inst Monogr 2001;117e124.
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67 Johansson S, Svensson H, Denekamp J. Timescale of evolution of late radiation injury after postoperative radiotherapy of breast cancer patients. Int J Radiat Oncol Biol Phys 2000;48: 745e750. 68 Johansson S, Svensson H, Denekamp J. Dose response and latency for radiation-induced fibrosis, edema, and neuropathy in breast cancer patients. Int J Radiat Oncol Biol Phys 2002;52: 1207e1219. 69 Dobbs HJ. Radiation therapy for breast cancer at the millennium. Radiother Oncol 2000;54:191e200. 70 Bajrovic A, Rades D, Fehlauer F, et al. Is there a life-long risk of brachial plexopathy after radiotherapy of supraclavicular lymph nodes in breast cancer patients? Radiother Oncol 2004;71: 297e301. 71 Gillette EL, Mahler PA, Powers BE, Gillette SM, Vujaskovic Z. Late radiation injury to muscle and peripheral nerves. Int J Radiat Oncol Biol Phys 1995;31:1309e1318. 72 Olsen NK, Pfeiffer P, Johannsen L, Schroder H, Rose C. Radiation-induced brachial plexopathy: neurological follow-up in 161 recurrence-free breast cancer patients. Int J Radiat Oncol Biol Phys 1993;26:43e49. 73 Fehlauer F, Tribius S, Holler U, et al. Long-term radiation sequelae after breast-conserving therapy in women with earlystage breast cancer: an observational study using the LENTSOMA scoring system. Int J Radiat Oncol Biol Phys 2003;55:651e 658. 74 Mesurolle B, Qanadli SD, Merad M, et al. Unusual radiologic findings in the thorax after radiation therapy. Radiographics 2000;20:67e81. 75 Johansson J, Isacsson U, Lindman H, Montelius A, Glimelius B. Node-positive left-sided breast cancer patients after breastconserving surgery: potential outcomes of radiotherapy modalities and techniques. Radiother Oncol 2002;65:89e98.
Overview
Complications of Breast-cancer Radiotherapy E. Senkus-Konefka, J. Jassem Department of Oncology and Radiotherapy, Medical University of Gdan´sk, Gdan´sk, Poland
ABSTRACT: Although the beneficial effect of postoperative radiotherapy for breast cancer is well documented, this treatment may be related to a number of complications, which may affect patient quality of life and possibly survival. Among significant long-term irradiation sequelae are cardiac and lung damage, lymphoedema, brachial plexopathy, impaired shoulder mobility and second malignancies. The risk of these complications, particularly high with old, suboptimal irradiation techniques, has decreased with the introduction of modern technologies. In this paper, we review the contemporary knowledge on the toxicity of breast-cancer radiotherapy and discuss possible preventive measures. Senkus-Konefka, E., Jassem, J. (2006). Clinical Oncology 18, 229e235 ª 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Breast cancer, complications, mortality, radiotherapy
Introduction Cumulating data confirm the beneficial effect of radiotherapy in women with breast cancer. After mastectomy and breast-conserving surgery, this effect is expressed by a significant decrease in the local relapse rate and, in the former, by increased survival [1e4]. Postoperative radiotherapy, however, is associated with some complications that may affect patient quality of life and possibly survival. This review summarises the contemporary knowledge on morbidity and mortality related to breast-cancer radiotherapy, and provides possible means to decrease the incidence and severity of complications. As cardiovascular toxicity is covered by a separate paper in this issue, it will not be addressed here.
Pulmonary Complications Pulmonary complications of radiotherapy are usually divided into early (radiation pneumonitis) and late (lung fibrosis) [5,6]. Both are confined to radiation portals: anterolateral peripheral lung after breast or chest wall irradiation, or lung apex after irradiation of the supraclavicular area [6]. Like all forms of diffuse alveolar damage, radiation lung injury is divided into three sequential pathologic phases: exudative, organising or proliferative and chronic fibrotic [7]. Radiation lung damage results from the combined effect of two interrelated mechanisms. The first includes microcapillary vascular damage leading to ischaemic tissue injury and fibrotic healing, and the second includes damage to type I and II pneumocytes in the presence of increased vascular permeability, leading to altered surfactant production, atelectasis, reduced ventilation and secondary vascular atrophy [8,9]. It is 0936-6555/06/180229C07 $35.00/0
suggested that, pathophysiologically, radiation pneumonitis resembles acute respiratory distress syndrome, resulting from tumour necrosis factor production [8]. Radiation pneumonitis usually develops 4e12 weeks after completing radiotherapy, and presents as dry cough, dyspnoea and low-grade fever [5,6,10e12]. In most cases, these symptoms are mild and resolve spontaneously, although some women may require corticosteroid treatment [10,13]. In women diagnosed with moderate-grade pneumonitis, the mean reduction in vital capacity is equivalent to loss of three-quarters of the lung lobe [14]. Some repair of early injury (as assessed by perfusion and ventilation assays and computed tomography) may be found 18 months after radiotherapy, but no further improvement is observed at 48 months [15]. Lung fibrosis appears after 6e24 months, usually remains stable after 2 years [6,12] and is accompanied by limited, but irreversible, changes in pulmonary function tests [15,16]. From the functional point of view, the lung represents a parallel structure, but some data suggest differences between radiation sensitivity of superior and inferior parts of the lung, the latter being more sensitive [5,17]. Interestingly, the incidence of radiation pneumonitis seems to correlate with increased radiological lung density in central, but not apical, parts of the lung [11]. The apical damage seems to be less consequential, as these parts are less perfused and ventilated at rest [11]. Chest radiography initially shows a diffuse haze with obscuring of vascular outlines, gradually progressing to patchy consolidation and then coalescing to form relatively sharp edges conforming to treatment portals [6]. Occasionally, small pleural effusions may accompany acute radiation pneumonitis [6]. These lesions may gradually clear and disappear completely or progress to permanent fibrous
ª 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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changes, presenting as well-defined areas of atelectasis with parenchymal distortion, pleural thickening and, in the case of massive involvement, traction bronchiectasis and mediastinal shifting [6]. In the supraclavicular area, these lesions may mimic pulmonary tuberculosis [6]. On computed tomography imaging, the acute exudative phase is represented by ground glass attenuation, homogeneous consolidation or patchy consolidation not conforming to the shape of portals. The following organising (proliferative) phase presents as discrete consolidation conforming to the shape of portals, but not outlining it uniformly. The final chronic fibrotic phase is represented by solid consolidation, which conforms and involves the irradiated portion of the lung [18]. Differential diagnosis of these radiological abnormalities must, among other things, include local recurrence, lymphangitic spread of the tumour and infectious pneumonitis [6]. Only a part of radiological lung changes are accompanied by clinical symptoms [10,12,19]. The incidence of clinically evident radiation pneumonitis in different series ranges from 0% to 31% [5,10,13,20,21]. However, retrospective studies might underestimate low-grade changes [11]. More pronounced injury, requiring steroid treatment, is present in 0e11% of women with breast cancer [10,13]. On radiological examination, lung fibrosis is seen in up to 87% of women [12,22e24]. Although the exact tolerance of normal lung tissue is not known, radiation lung damage is rarely seen below 20 Gy, whereas it is common in areas receiving 30e40 Gy, and almost inevitable over 40 Gy [6,10]. The probability of lung damage is related to total dose, fractionation and irradiated lung volume [5,6,10,12]. The effect of other factors is less clear [10,11,13]. Suggested variables include age, performance status, the use of chemotherapy, tamoxifen (or both), smoking, preexisting reduced lung function, co-existing heart disease and short overall treatment time [5,10e13,23,25e27]. The data on the effect of high-dose chemotherapy are contradictory, whereas concomitant paclitaxel was reported to increase the risk of pneumonitis [10]. The difference in the risk of radiation injury among particular studies is predominantly related to various radiotherapy techniques and irradiated volumes. Locoregional radiotherapy, in particular, including the internal mammary chain, is generally associated with significantly higher risk [10,12,13,28]. A good predictor of lung complications of breast or chest wall only irradiation is central lung distance, with values less than 2e3 cm considered safe [13,14,29e31]. More fibrosis is usually seen in patients receiving radiotherapy with single en face electron field [11]. Improved lung protection may be achieved by use of individual bolus to even out localised differences in chest wall thickness [10,23]. Other approaches include treatment at deep inspiration [32] and the use of conformal threedimensional planning [29], although the value of the latter for breast or chest wall only irradiation is disputable [10]. A rare syndrome related to lung irradiation, and for unknown reasons obviously limited almost exclusively to women with breast cancer, is bronchiolitis obliteransorganising pneumonia [33,34]. It can be described as bilateral lymphocytic alveolitis, and is believed to occur
as a result of immunological reactions mediated by lymphocytes [33,34]. Radiological abnormalities include diffuse haze progressing into patchy alveolar infiltrates with air bronchograms [34]. A migratory pattern of dense alveolar infiltrates is characteristic, with lesions originating usually from the irradiated area and spreading to both lungs [34]. Symptoms include cough, dyspnoea, fever, asthenia and weight loss, and respond well to corticosteroid treatment, although high recurrence rate is observed at treatment discontinuation, often requiring long-term lowdose steroid treatment [34]. The prognosis of bronchiolitis obliterans-organising pneumonia is excellent, with virtually no progressive or chronic fibrosis [34].
Second Malignancies The data on the incidence of second malignancies in breastcancer survivors are contradictory. Most studies do not report a large increase in the risk of second primary malignancies among women receiving radiotherapy for breast cancer compared with women who do not receive radiotherapy or with the general population [24,35e37]. This general statement applies to contralateral breast cancer and to non-breast tumours [35,38]. It is noteworthy, however, that most studies had limited power to detect a relatively small increase in incidence [39]. Ten- and 15-year cumulative incidences of all second tumours in women receiving radiotherapy for breast cancer are in the range of 16e19%, with a similar proportion of contralateral breast cancer and other tumours [35,37,40,41]. Among the latter, as in the general population, the most common are skin, endometrial, colorectal and pancreatic cancers [40]. However, some tumours seem to occur with relatively higher frequency [38]. These include ovarian (standardised incidence ratio [SIR] 2.0), renal (SIR 2.5), uterine (SIR 1.9) and lung cancers, leukaemias (SIR 3.1), malignant melanomas (SIR 2.7) and sarcomas (SIR 13) [37,42]. A proportion of these cases may be a result of misclassification of metastatic disease. Some of these malignancies may be related to interaction between radiation and genetic factors [42,43]. Indeed, in some series, the use of radiotherapy was related to an overall increase in the risk of second tumours [42,44], whereas others demonstrated no effect [24,45]. For example, breastcancer radiotherapy increases the risk of leukaemias and lymphomas, but not of thyroid cancer [42,46]. The increased risk is observed predominantly in women diagnosed with breast cancer at a young age [37,42]. Several studies have reported an increased risk of contralateral breast cancer, with [47] or without radiotherapy [40,48] in young women, although, in the SEER (Surveillance Epidemiology and End Results) data, increased risk was observed over the age of 55 years, and was not related to radiotherapy [41]. The data from other studies are conflicting [38]. Of the six randomised studies comparing radiotherapy with no radiotherapy, one showed increased risk in the irradiated group, two a trend towards increase, and three a decreased incidence of contralateral breast cancer [38]. Among retrospective cohort
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and caseecontrol studies, increased risk was shown in two, a trend for increased risk in five and decreased risk in another five studies [38]. No study, however, showed an increase in the relative incidence of tumours appearing in the medial part of the breast (i.e. in the area of higher scatter dose, where the carcinogenic effect of radiation is expected to be more pronounced) [38]. As the carcinogenic effect of radiation on breast tissue was shown in many studies [38,49], it is reasonable to make every effort to limit the doses of incidental irradiation. Conventional tangential fields result in a substantial dose absorbed by contralateral breast (average 2e5 Gy) [38,47,50]. The amount of scatter radiation is dependent on distance from field edge in the medial beam, use of SSD (source skin distance) (as opposite to isocentric) technique, use of multiple fields and non-alignment of deep field edges, use of wedges, half beam blocks (or both) [38,50]. Significant lowering of scatter may be achieved by replacing some of these accessories by dynamic wedges and asymmetric jaws [38]. Dose to the opposite breast is also increased by irradiation of internal mammary chain [38]. In relation to the opposite breast dose, it is thus recommended to apply the ALARA (as low as reasonably achievable) strategy. This may partly be accomplished by the use of wedges in lateral field and by shielding the opposite breast [38]. Introduction of conformal three-dimensional radiotherapy allows for a decrease in radiation exposure of normal tissues, whereas the use of intensity-modulated radiotherapy may significantly increase the doses to normal tissues (including opposite breast) [38,39]. The total body dose is expected to be two to three times higher, predominantly owing to the increased number of beams used, as well increased leakage radiation (resulting from increased ‘beam on’ times) [39]. Intensity-modulated radiotherapy may therefore increase the incidence of second tumours in 10-year survivors; this will predominantly include tumours resulting from low exposure, such as leukaemias and carcinomas [39]. Better discrimination of high-dose volume may, however, decrease the incidence of tumours related to high radiation exposure, such as sarcomas [39]. Another factor strongly associated with increased risk of contralateral breast cancer is family history [38,40] and, in particular, a presence of BRCA1 or BRCA2 mutations [38]. As protein products of BRCA1 and BRCA2 interact with repair of double strand breaks, it has been suggested that these patients may be particularly vulnerable even to small radiation doses [38]. Another tumour of confirmed relationship to radiation exposure is lung cancer. Three large studies confirmed a significantly increased incidence of ipsilateral (compared with contralateral) lung cancer after irradiation for breast cancer [49,51e53]. In most studies, this increase was related to post-mastectomy and not to post-lumpectomy radiotherapy [52,53]. Increased risk was observed in smokers and non-smokers, but the exposure to both agents (radiation and smoking) seemed to have a multiplicative effect (relative risk 32.7) [49,51]. Tumours with the largest relative increase of incidence in breast-cancer survivors are soft-tissue sarcomas (SIR 13)
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[42]. Women exposed to radiotherapy harbour over a fourfold relative risk of sarcomas compared with women not exposed to radiotherapy [42]. Radiation-related soft-tissue tumours appear after a mean latency of 10e12 years [43,54]. In the Swedish Cancer Registry study, 63% of these tumours occurring in breast-cancer survivors were located within the breast and ipsilateral arm, and over one-third were angiosarcomas [43]. This accounted for 20% of all angiosarcomas registered, whereas other soft-tissue sarcomas in breast-cancer survivors constituted only 2% of all tumours of this type [43]. Most angiosarcomas developed in the vicinity of the breast, particularly within the lymphoedematous arm (StewarteTreves syndrome) [43]. Angiosarcoma may also develop within the skin of the conserved breast [43,55]. The risk of developing soft-tissue sarcomas other than angiosarcomas is related to integral radiation dose, although the risk decreased above a certain dose threshold, which is compatible with cell sterilisation at high doses. Risk of angiosarcomas is not directly related to history of irradiation, but correlates strongly with presence of lymphoedema, which in turn is often induced or aggravated by radiotherapy [43]. Overall, however, the risk of developing radiation-induced sarcomas is small, comparable to mortality due to anaesthesia [56].
Shoulder and Arm Complications Shoulder and arm complications are among the most troublesome sequelae of breast-cancer treatment [25,57,58]. Some arm problems are estimated to occur in up to 90% of women with breast cancer [58,59]. Most important complications include arm lymphoedema, brachial plexus neuropathy and impaired shoulder mobility [25,57]. These morbidities often appear together and, to some extent, share common pathogenic elements (e.g. neural damage leads to restricted mobility, which in turn may aggravate lymphoedema) [25,58,60]. These complications may be related to muscular and subcutaneous fibrosis or to vascular injury [25]. All of these symptoms influence the ability to carry out common daily activities [57]. They may lead to change in clothing habits or may require job change [22]. The gross effect in particular women is, however, the product of severity of symptoms and individual’s ability to cope [25].
Lymphoedema Lymphoedema is considered a most significant complication of locoregional treatment of breast cancer [61]. It may result in significant psychological and functional morbidity, and markedly worsens quality of life [20,62]. Once established, in most cases it cannot be cured. It is thus essential to prevent or minimise this condition [63]. Chronic lymphoedema is often associated with skin changes, the socalled ‘brawny oedema’ [63]. In most women, it is also accompanied by pain, numbness and shoulder stiffness [58]. It may also predispose to development of cellulitis and limits the arm mobility [20,25,57].
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The pathogenesis of lymphoedema includes radiationinduced fibrosis, causing venous and lymphatic vessel obstruction and lymphocyte depletion with fatty replacement and local fibrosis [25]. These factors strongly interact with surgery, possibly due to reduced lymphatic regeneration after surgical interruption [25]. The contribution of haemodynamic factors is also relevant [25]. The incidence of lymphoedema in particular studies varied greatly between 4% and 39% [20,57,61,64]. This is partially due to different definitions of increased arm dimensions: volume increase greater than 200 ml, circumference increase greater than 2 cm or increase of diameter greater than 5% [20,63,64]. The median latency is usually in the range of 1.5e4 years [20,25,61,65]. As lymphoedema may develop as many as 10 years after radiotherapy, its observed incidence depends also on the length and completeness of follow-up [61,63]. The risk of lymphoedema is mainly related to the treatment applied [64]. The risk after surgery only varies between 1% and 30% [20,25,63], and depends primarily on the extent of lymph-node dissection [20,22,25,58,61,64]. Radiotherapy to the axilla considerably increases incidence and severity of this complication, with relative risk ratio reaching 4.6 [20,57,61,64]. It is estimated that these two treatment modalities contribute to the development of lymphoedema to a similar degree [57]. The effect of radiotherapy is highly dependent on the size of dose per fraction (low a/b value). The doseeresponse relationship is strongly affected by surgery and, similarly to other late end points, is very steep (which translates to large effects of small changes of fractionation and dose distribution) [25]. Concomitant use of tamoxifen or chemotherapy may increase the risk of lymphoedema [25,63], although a bias associated with the selection of patients with more advanced disease cannot be excluded [61]. Other risk factors can be divided into patient-related and disease-related factors. The first group includes obesity, older age, lower education, history of hypertension and infection or inflammatory process within the arm [20,22,25,58,61,63,64]. Disease-related factors include stage and, in particular, pathological nodal (N) status [61,63]. The mechanism involved here may be lymphostasis secondary to malignant involvement of lymphatic channels and scarring caused by successful eradication of disease [61]. It is hoped that widespread use of the sentinel node technique will significantly decrease the risk of lymphoedema [25]. Ongoing studies are testing whether full lymph-node dissection in node-positive patients can be replaced by axillary radiotherapy (European Organisation for Research and Treatment of Cancer ‘‘After Mapping of the Axilla: Radiotherapy Or Surgery’’ EORTC AMAROS study). On the other hand, the need for nodal irradiation after adequate lymph-node dissection is questionable [64,66].
Brachial Plexopathy Brachial plexus neuropathy is a relatively rare complication of modern radiotherapy, although, in the past, its incidence was much higher [60,65e69]. It has been predominantly
observed in women treated with high dose per fraction or with overlapping fields [60,68]. The most remarkable data on this complication come from the Umea series, in which, over 30 years after hypofractionated radiotherapy with possible field overlapping, more than 90% of women developed complete paralysis of the arm [67]. The estimated biologically equivalent dose in 2 Gy fractions in these women was 85e92 Gy [65]. Interestingly, the damage continued to progress up to 30 years after radiotherapy [67,68,70]. The latency period for this complication ranges from 1.5 to 10 years (7e14 years for complete paralysis), and is similar for motor and sensory impairment [25,60,65,67,68,70]. The late presentation of damage results from slow turnover of tissues, which attempt cell division many years after injury. Lost tissue is then replaced by fibrosis, leading to formation of dense, inelastic and constricting tissue [67]. Brachial plexus neuropathy is defined as motor or sensory symptoms or physical signs, with or without accompanying pain in a nerve-root distribution in the arm. Neurological manifestations may include paresthesia in the fingers or hands, hypoesthesia, hypoalgesia, disesthesia, paresis, hyporeflexia and muscular atrophy [25,60,67,68,70]. The limb weakness may be selectively distal, global with more marked distal deficits or a complete flaccid paralysis [60]. Most women have abnormal neurophysiology findings: absent sensory nerve action potential, axonal changes, myokymia and prolonged F-waves [60]. Magnetic resonance imaging studies show only soft-tissue fibrosis [60]. Brachial plexopathy is strongly correlated with late fibrosis and muscle atrophy within the shoulder region [60,65]. The damage may encompass the whole plexus or only its lower part [60]. Plexopathy is irreversible [70]. Its incidence depends on total dose, dose per fraction (low a/b value), patient age and concomitant use of chemotherapy [25,64,65,68,70]. Frequently, the toxicity results from unplanned overdosage originating from field overlap caused by changing the woman’s position between treatment fields or from ‘matchline’ problems [25,60,65,67,68]. One of the suggested pathomechanisms of radiationinduced neuropathy is nerve entrapment by radiationinduced fibrosis, chronic oedema, or both [25,67,68]. Another postulated cause was direct damage to neurones or glial cells and ischaemic damage resulting from microvascular injury [25,65,68]. There are probably two phases of radiation-induced neuropathy: the first includes more direct changes in electrophysiology and histochemistry, whereas the second involves fibrotic changes around the nerves and injury of the adjacent vessels [25,71].
Impaired Shoulder Mobility A proportion of women with breast cancer experience some degree of post-surgery shoulder stiffness, which may further be aggravated by the use of axillary radiotherapy [22]. Symptoms usually include reduced flexion, external rotation and abduction, and pain at movement or at rest [25,57]. In some women, this leads to reduced working ability [25].
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Shoulder stiffness is usually caused by fibrosis of the major pectoralis muscle and damage to vasculature or to the joints [25]. Movement range may also be decreased as a result of lymphoedema or neural damage [25]. Symptoms usually appear after a median latency of 4 years [25]. Increased risk of radiation-related impaired shoulder mobility is related to the use of large doses per fraction (low a/b value), older age, use of concomitant systemic treatment, co-existence of subcutaneous fibrosis and degree of movement impairment at the start of radiotherapy [25,72]. To diminish the consequences of shoulder and arm problems, women should be recommended physical exercise programmes [25,64]. However, some women with oedema or neurological deficits may not be able to follow these programmes [25].
Other Complications Less frequently encountered problems after breast-cancer radiotherapy include rib fractures, chronic pain, axillary vein thrombosis and bone necrosis [20,22,65,66,73]. Rib fractures usually involve anterior aspects of third, fourth and fifth rib, are frequently multiple, spontaneous and asymptomatic and may be slow to unite. Bone complications seemed to be particularly common in the orthovoltage era, most probably due to more energy attenuation in bone [74].
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Conclusion Women undergoing radiotherapy for breast cancer should be followed-up lifelong for complications, as these problems tend to appear after long latency periods and damage may be progressive [25,60,70]. Long observation is particularly important before confirming the safety of new (in particular hypofractionated) irradiation schedules and techniques. The injury developing after many years means, however, that these women have survived all these years symptom free, possibly thanks to radiotherapy [25]. Much of the experience on the radiation-induced damage with long latency periods comes from old series, applied obsolete radiotherapy techniques, whereas contemporary treatments seem to be less harmful [25]. The application of modern radiotherapy techniques, including conformal three-dimensional radiotherapy, intensity-modulated radiotherapy, gated, image-guided irradiation, or both, as well as tailored use of radiotherapy, will hopefully further decrease the incidence of complications [75].
_ Author for correspondence: Elzbieta Senkus-Konefka, Department of Oncology and Radiotherapy, Medical University of Gdan ´sk, Dxbinki 7, 80-211 Gdan ´sk, Poland. Tel: C48-58-3492271; Fax: C4858-3492270; E-mail: [email protected]
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