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British Journal of Radiology (2004) 77, 811-820
© 2004 British Institute of Radiology
doi: 10.1259/bjr/44576710
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Review article

Breast cancer: improving outcome following adjuvant radiotherapy

J A Violet, BSc, MRCP, FRCR and C Harmer, FRCP, FRCR

The Royal Marsden NHS Trust, Fulham Road, London SW3 6JJ, UK


   Abstract
Top
 Abstract
Introduction
 Surgery
 Conventional radiotherapy
 Toxicity
 Modern techniques that reduce...
 Discussion
 Conclusions
 References
 
In the treatment of early breast cancer adjuvant irradiation improves local control following both mastectomy and breast-conserving surgery. For women at high risk of relapse it also increases survival. Breast radiotherapy is usually given using simple planning techniques and serious morbidity is unusual. The greatest concern following adjuvant breast irradiation is of an increase in cardiovascular mortality after 15–20 years. New techniques of breast irradiation including conformal radiotherapy and intensity-modulated radiotherapy (IMRT) have been shown to reduce cardiac and lung irradiation. In addition, improved dosimetry within the breast may improve both local control and cosmesis. To replace current radiotherapy techniques with those requiring more complex planning would demand an increase in resources including both machinery and staff. In this review we outline the indications and benefits of breast radiotherapy along with the planning process. Technical advances are discussed within the context of improving outcome at a time of limited national resources.


   Introduction
Top
 Abstract
 Introduction
Surgery
 Conventional radiotherapy
 Toxicity
 Modern techniques that reduce...
 Discussion
 Conclusions
 References
 
Breast cancer is the most common cancer in women, accounting for one-third of all cases and for one-fifth of cancer deaths in women in the UK. Both treatment and outcome are dependent on stage and histological subtype of tumour, in addition to patient factors including age and menopausal status. Optimal outcomes depend upon early detection, rapid specialist referral and prompt initiation of treatment. Adjuvant breast irradiation forms an integral part of management for the majority of patients with early breast cancer. Although serious morbidity is unusual with conventionally planned radiotherapy, new treatment approaches have been developed with the aim of reducing toxicity.

Improving outcome following breast radiotherapy is likely to result from reducing treatment delay and also by providing the best available radiotherapy technique. In this review we consider the benefits and toxicity of adjuvant breast irradiation together with the likely benefits of improvement in radiotherapy technique.


   Surgery
Top
 Abstract
 Introduction
 Surgery
Conventional radiotherapy
 Toxicity
 Modern techniques that reduce...
 Discussion
 Conclusions
 References
 
Surgery is the definitive treatment for breast cancer comprising either mastectomy or preferably a breast conserving operation, which removes only the tumour with some surrounding tissue. Mastectomy involves removal of the whole breast and either procedure is usually combined with sampling or removal of the axillary lymph nodes. The latter both treats any axillary disease and provides staging information. Following mastectomy an immediate or delayed reconstruction may be performed. Radiotherapy is routinely recommended following breast conserving procedures and often following mastectomy.


   Conventional radiotherapy
Top
 Abstract
 Introduction
 Surgery
 Conventional radiotherapy
Toxicity
 Modern techniques that reduce...
 Discussion
 Conclusions
 References
 
Breast and chest wall irradiation
Conventional radiotherapy is routine in all centres in the UK and decreases three-fold the relative risk of local recurrence. A pair of tangential photon beams are skimmed across the chest wall to cover all remaining breast tissue following breast conservation, or the whole breast bed following mastectomy. A small amount of lung is invariably irradiated but the depth is carefully screened during simulation to ensure a minimum volume is irradiated. The total dose of radiation, established historically and from numerous clinical trials, to achieve locoregional control while keeping complications at an acceptable level is 40–50 Gy given in a conventionally fractionated schedule over a period of 3–5 weeks. Fractionation refers to the delivery of the total radiation dose in a number of separate treatments, typically given 5 days a week until the total dose has been delivered. Adding an electron boost to the tumour bed, as determined from mammographic and surgical information, further reduces the risk of local relapse [1, 2].

Management of regional lymph nodes
In addition to the breast, the irradiated volume may include regional lymphatic node areas, which comprise the axilla, supraclavicular fossa and internal mammary chain. Management of the axilla is generally surgical because of the additional prognostic information that is obtained, although equivalent disease control in the clinically uninvolved axilla may be achieved with radiotherapy [3–5]. Axillary radiotherapy in addition to axillary dissection is usually avoided due to an unacceptable increase in toxicity, but may be indicated where there is gross extracapsular spread of disease or known residual microscopic disease following surgery.

The incidence of isolated supraclavicular fossa (SCF) relapse in patients with early breast cancer treated with SCF radiotherapy is very low (0.5–3%), even with heavily involved axillary nodes [4, 6, 7]. In series that routinely did not irradiate the SCF in pathologically axillary node positive patients, the risk of isolated SCF recurrence was 4.5–7% [8, 9]. In a randomized study the SCF recurrence rates in clinically axillary node positive patients was reduced from 5.8% in those not receiving radiotherapy to 0% in those irradiated [10]. In addition, the Danish Breast Cancer Co-operative Group study of post-mastectomy radiotherapy versus no irradiation reported a reduction in SCF relapse from 6.5% to 1% with the addition of radiotherapy [11]. An increasing number of involved axillary nodes has been associated with a higher rate of SCF relapse [9]. Recent audit of SCF irradiation amongst clinical oncologists in the UK suggests significant variations in its use, with the highest proportion irradiating the SCF only when the axilla is heavily involved. Irradiation of the internal mammary chain (IMC) remains controversial and is not routinely practiced in the UK. However, interest has been rekindled following the publication of trials demonstrating an increase in survival for post-mastectomy patients in whom regional nodal irradiation including the IMC, was included [12, 13]. In both these trials patients were treated with cytotoxic chemotherapy and were randomized to receive or not additional radiotherapy using a five field technique, which included a separate IMC field. Lymphoscintigraphy data have suggested that selected early breast cancers may have high rates of primary lymphatic drainage to the IMC [14]. However, information from early surgical series showed that internal mammary node involvement was uncommon in patients with early stage axillary node negative disease, but rose to 28–52% in patients with advanced primary tumours and positive axillary nodes [15]. Data from sentinel node biopsy studies have demonstrated that even early stage tumours located in the central or inner regions of the breast include primary drainage to the IMC in many cases: in a series of 16 inner or central tumours imaged with lymphscintigraphy, 44% demonstrated drainage to the IMC [14].

What remains unclear however is whether treatment of the IMC containing micrometastatic deposits increases survival. Being an intrathoracic structure not detectable during routine physical examination, IMC relapse (as a prelude to systemic relapse) would also not be apparent with current follow-up protocols.

The strongest support for the use of IMC irradiation comes from the Institut Gustave-Roussy. On multivariate analysis of 1195 patients treated over a 20 year period, IMC irradiation was independently associated with a reduction in the risk of distant metastasis (p=0.02) for patients with medial or central primary tumours and positive axillary lymph nodes [16]. In the 607 patients with tumours lateral to the areola, there was no clear benefit from IMC treatment. In addition patients with early stage medial tumours have a lower survival rate than their counterparts with laterally placed tumours. One study looking at 2396 patients treated with breast conservation and radiotherapy revealed a 30% increase in distant metastasis for medial or centrally arising tumours compared with laterally placed tumours [17]. However another large retrospective review demonstrated no significant benefit from IMC irradiation [15] and concerns remain with respect to long-term cardiac morbidity from its use, although this is likely to be technique dependent. The Stockholm post-mastectomy trial revealed an increase in ischaemic heart disease in left-sided breast cancers treated with photons but not in patients who received electron treatment of the left chest wall and IMC [18].

Given the possible benefit with IMC irradiation in certain subsets of patients three ongoing prospective randomized studies are addressing the role of locoregional irradiation. A European Organisation for Research and Treatment of Cancer (EORTC) study is randomizing patients with positive axillary nodes or centrally located tumours to treatment with or without IMC and SCF irradiation. The National Cancer Institute of Canada study randomizes axillary node positive patients to breast irradiation with or without ipsilateral SCF, axillary and IMC irradiation. Finally, the South West Oncology Group study is randomizing patients with 1–3 positive axillary nodes to observation or chest wall plus IMC and SCF irradiation following systemic therapy.

Adjuvant radiotherapy to the intact breast
Adjuvant radiotherapy significantly reduces local relapse rates following breast-conserving surgery. This has been analysed in four prospective studies [19–22]; none showed any difference in survival as a result of the local treatment chosen (Table 1Go).


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  		Table 1. Local recurrence rates following mastectomy and breast conserving surgery for invasive breast cancer

 
Data from the NSABP B-06 study [20], which analysed the largest number of patients, indicated that adding radiotherapy to breast-conserving surgery in high-risk patients reduced the rate of local relapse from 35% to 10%. Benefit is also seen in patients with early stage disease: looking only at patients with small node negative tumours, a reduction in local recurrence rate from 24% to 8.5% (p=0.0001) was seen with the addition of radiotherapy [21].

Post-mastectomy radiotherapy
Following mastectomy adjuvant radiotherapy to the chest wall is also associated with reduced local relapse rates. A recent review of seven key early trials conducted in the UK, USA, Norway and Sweden evaluating post-mastectomy radiotherapy in the absence of adjuvant chemotherapy showed a threefold decrease in locoregional recurrence [23]. It has also been demonstrated that in high-risk patients radiotherapy including regional nodal irradiation may be associated with improved survival. Both the Danish and British Columbia trials have revealed a moderate and statistically significant improvement in survival of a magnitude similar to that seen with adjuvant systemic chemotherapy or hormonal therapy [24, 25]. Re-analysis of the data from the Norwegian and Swedish post-mastectomy trials has been performed. Subgroups of patients have been stratified according to the risk of loco-regional recurrence according to axillary nodal status. A significant benefit from radiation in patients with positive axillary nodes was found for distant recurrence and overall survival [26]. The Swedish trial [27] revealed a highly significant fivefold decrease in risk of local recurrence in node-positive patients and radiotherapy also decreased the risk of distant dissemination. Increased local control also reduced the likelihood of distant relapse. A more recent meta-analysis of 18 randomized trials, comparing locoregional radiation therapy after surgery with surgery alone in women with node-positive breast cancer who also received systemic chemotherapy [28] revealed a decrease in overall mortality (odds ratio 0.83, 95% CI 0.74–0.94, p=0.004). Overall, in high-risk breast cancer patients, an improvement in survival of 8–10% is seen with the addition of modern conventional radiotherapy.

Ductal carcinoma in situ
Before the introduction of mammography less than 3% of newly diagnosed breast cancers were ductal carcinoma in situ (DCIS); following the introduction of mammographic screening DCIS now comprises 15–20% of all screen detected breast cancers. Traditional management of DCIS comprised mastectomy, which although effective was probably over-treatment for many lesions. Several randomized trials have now demonstrated that breast conservation for invasive cancer is a safe alternative to mastectomy [19–22]. As a result, breast-conserving surgery has increasingly been offered as an alternative to mastectomy in patients with DCIS, although there are no randomized studies directly comparing breast conserving surgery with mastectomy. With regard to adjuvant radiotherapy, several large prospective randomized trials have demonstrated a reduction in the subsequent incidence of both DCIS and invasive cancer with the addition of radiotherapy [29–31] and the results are summarized in Table 2Go.


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  		Table 2. Relative risk reduction of disease relapse following the addition of adjuvant radiotherapy to breast conserving surgery for DCIS

 
Despite this evidence widespread adoption of post-operative radiotherapy following local excision of DCIS remains controversial. Work by a number of groups, including the National Surgical Adjuvant Breast Project (NSABP), have indicated that pathological evaluation of the excised tumour for nuclear grade, necrosis, size and margin width is important in predicting recurrence and identifying which patients are likely to benefit from post-operative radiotherapy [32]. In addition a quantitative algorithm based on tumour size, margin width and histological classification has been developed as a prognostic index to aid in decision making [33]; more recent evidence suggests that the excision margin may be the most important factor determining the risk of recurrence [34]. As yet however a group of patients who would not benefit from adjuvant radiation remains to be clearly defined.


   Toxicity
Top
 Abstract
 Introduction
 Surgery
 Conventional radiotherapy
 Toxicity
Modern techniques that reduce...
 Discussion
 Conclusions
 References
 
Early
Immediate side effects during adjuvant breast irradiation comprise skin soreness, fatigue and occasionally nausea. Skin toxicity is usually mild and transient with symptoms settling completely within a few weeks of completion of treatment. Radiation pneumonitis (a clinical syndrome of cough, fever and/or shortness of breath accompanied by radiographic changes consistent with a non-infectious infiltrate) is uncommon following adjuvant breast irradiation. One study of 201 patients receiving post-operative radiotherapy to the chest wall involved reconstruction of the inner contour of the chest wall onto the radiation plan and showed that the incidence of radiation pneumonitis rose exponentially with an increase in irradiated volume [35]. The amount of lung irradiated from a SCF or IMC field must also be considered. In one prospective study using high resolution CT, serial morphological changes of lung injury were documented in 30 patients undergoing 3 field (SCF and tangential chest wall) irradiation following breast conserving surgery or mastectomy [36]. In this study there was evidence of lung injury in 90% of women at 1 month and in all patients at 3 months. However, although lung changes were seen in areas of lung irradiated by both tangential fields and SCF fields, only SCF irradiation was significantly correlated with functional impairment as assessed by forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). Respiratory symptoms were experienced by 19 patients, but in all cases were mild and had resolved spontaneously after 6 months.

In a retrospective analysis of 1624 women treated with conservative surgery and adjuvant breast irradiation at a single institution, the overall incidence of symptomatic radiation pneumonitis was only 1% at a median follow-up of 77 months, although this increased to 3% with the addition of a supraclavicular field. Administering concomitant chemotherapy with SCF irradiation lead to radiation pneumonitis in 8.8% [37]. The impact of a third field on the incidence of radiation pneumonitis remains controversial. It has been argued that tangential fields have a greater effect than the nodal fields [35] but also that fibrosis in the upper zones would be less likely to lead to result in symptoms, given that the region is of small volume and pulmonary blood flow is least at the apices [38]. Using CT data however it has been calculated that in a lung of total volume 1346 ml, the estimated volume of lung in the SCF field is 300 ml compared with only 48 ml for the tangential breast fields [39].

With respect to chest wall irradiation alone, one study analysed 140 patients. No case of radiation pneumonitis was seen in patients in whom less than 3.35 cm lung was measured at the central axis of the simulation film, with all cases of radiation pneumonitis occurring in patients with more than 4 cm of lung irradiated, suggesting that the central lung depth is a reasonable guide to risk [40]. Radiation pneumonitis is therefore an uncommon complication following radiotherapy for breast cancer but minimizing risk will result from reducing lung volumes irradiated by careful screening of the mid field depth of chest wall tangents, and avoidance of both SCF field and concomitant chemotherapy.

Late radiation effects
Cardiac toxicity
Although a range of effects may be seen in cardiac tissue following irradiation including pericarditis, pancarditis, functional valvular or conduction defects, it is primarily increase in ischaemic heart disease that is of concern following adjuvant breast irradiation [41]. Endothelial damage following radiation has been shown to lead to fibroblastic proliferation and enhanced atherosclerosis. Contemporary treatment for left-sided breast cancer delivers a substantial radiation dose to the left anterior descending coronary artery as this lies within or near to the target volume [42]. Conventional radiotherapy following mastectomy has been associated with an increased risk of non-cancer death, in particular late cardiac death, 10–15 years following treatment [18, 43–47]. Data from 54 617 patients in the Swedish Cancer Registry [47] demonstrated an increased risk of death due to myocardial infarction for patients with left-sided compared with right-sided tumours, presumably a result of cardiac irradiation (relative risk (RR) 1.09 with 95% CI 1.02–1.17). Another population-based analysis of 206 523 women in the surveillance, epidemiology and end results (SEER) database revealed that the overall relative risk for fatal myocardial infarction in women with left-sided breast cancer was increased by 17% compared with right-sided tumours [45] although this result was barely statistically significant (odds ratio 1.17, 95% CI 1.01–1.36). However, the relative risk for fatal myocardial infarction in patients aged less than 60 years among patients with left-sided tumours was significantly increased compared with right-sided cases (RR 1.98; 95% CI 1.31–2.97). Meta-analysis of 36 randomized studies of surgery alone (mastectomy or lumpectomy) versus surgery with radiation performed between 1945 and 1985 showed no clear difference in overall survival at 10 years [43]. Radiation was associated with a reduced risk of death due to breast cancer (odds ratio 0.94, 95% CI 0.88–1.00, p=0.03). However, an increase in non-breast cancer deaths was seen in patients who received radiation (odds ratio 1.24, 95% CI 1.09–1.42, p=0.002). Retrospective analysis of the Stockholm and Oslo trials, which evaluated mastectomy with radiation and was included in this meta-analysis, showed that the increase in non-breast cancer deaths was due to an increase in cardiac mortality, confined to those patients receiving the highest myocardial doses, i.e. those patients treated with tangential fields for left-sided tumours. No increase in ischaemic heart disease was seen in patients with right-sided tumours or those treated with electrons [18].

It has been argued that the increase in cardiac mortality seen in the older studies relates to use of out of date irradiation methods, e.g. orthovoltage radiation, the use of large fraction sizes and the lack of standardized treatment techniques [48]. It has been suggested therefore that improvements in contemporary radiation techniques may have already reduced the likelihood of cardiac toxicity; two recent studies have failed to demonstrate any increase in cardiac morbidity, although one of these utilized electron fields to irradiate the chest wall, a less commonly used technique known to be associated with reduced myocardial irradiation [49, 50]. A more recent update from the Swedish Cancer Registry has now been reported [51]. In this cohort study of 90 000 women mortality from cardiovascular disease was again higher in women with left sided tumours, with the increased risk primarily seen after more than 10 years (mortality ratio 1.1 CI 1.03–1.18). However, most of the late cardiovascular deaths involved women treated for breast cancer in the 1970s and the cardiovascular risk ratio for women treated in the 1980s, although still increased at 1.11, was associated with a wide 95% confidence interval (0.95–1.29). The authors concluded that the cardiovascular hazard from radiotherapy in the 1970s and 1980s remains uncertain.

Even with modern techniques a portion of the myocardium is still irradiated within the tangential fields and receives a minimum of 50% of the dose prescribed to the primary target volume [42, 52]. In a small prospective study using a modern technique, at least part of the myocardium received at least 85–95% of the total radiation dose. Using myocardial perfusion scintigraphy half of those treated had evidence of new fixed scintigraphic defects, indicating regional hypoperfusion secondary to microvascular damage, although the long-term consequences of such changes remains unclear [52]. Another recent CT based study looking at 100 consecutive patients receiving tangential photon fields to the left breast has shown that although the mean irradiated heart volume receiving 50% of the breast dose was only 5.7%, this rose to 11.9% in those with the largest volumes [53].

Lymphoedema
Management of the axilla in breast cancer comprises either surgical dissection or the administration of axillary radiotherapy and lymphoedema represents a potentially serious complication of either approach. The incidence and severity of arm lymphoedema are related to the extent of axillary surgery and the type of breast surgery; both are markedly increased by the addition of axillary radiotherapy. One retrospective review analysed 6000 patients treated over 23 years with over 1400 cases of lymphoedema (defined as greater than or equal to 2 cm difference in arm circumference). A steady decline in lymphoedema incidence was seen coincident with the transition to more conservative surgery and the omission of axillary radiotherapy in the breast conservation group [54]. With each type of surgical procedure (whether radical mastectomy, modified radical mastectomy, or breast conservation) addition of radiotherapy increased the risk of lymphoedema. Single-modality treatment of the axilla by either surgery or radiation is associated with only a low incidence of arm oedema, although the combination of axillary irradiation therapy with axillary dissection increases the risk of arm oedema from 2–10% to 13–18% [54–56]. Axillary recurrence following adequate axillary surgery is so infrequent (0–2%) that routine axillary radiotherapy is not generally indicated [4]. However, the axillary failure rate following inadequate axillary surgery is higher [57] and radiotherapy may be indicated with known residual gross disease or gross extracapsular extension, although evidence of benefit is scant [4, 5]. When axillary radiotherapy is indicated following axillary surgery it has been suggested that the dose should be limited to 45–50 Gy conventionally fractionated because there is no indication of a dose response above this level [5] and there is an increased risk of complications [58].

Brachial plexopathy
This serious late complication of supraclavicular nodal irradiation is fortunately rare. In the Royal Marsden Hospital series [59] 449 breast cancer patients treated with post-operative radiation to the breast and regional lymphatics between 1982 and 1984 were followed for 3–5.5 years. The diagnosis of brachial plexus injury was made clinically, with CT used to distinguish tumour recurrence. When a dose of 54 Gy in 30 fractions over 6 weeks was delivered, the incidence of symptomatic brachial plexus injury was only 1.0%, in contrast to 5.9% with the larger fraction size of 45 Gy in 15 fractions over 6 weeks (p=0.09). A fraction size of greater than 2 Gy is now rarely prescribed for nodal treatment. The incidence of neuropathy is also dependent upon total dose [60, 61] and technique. Serious brachial plexus toxicity has also been seen in the past as a result of matchline overdosing to breast tangential fields [62, 63]. A variety of methods are now routinely employed to avoid this including incorporation of a gap between beams, half beam blocking, couch twist and use of isocentric techniques [64].

Second primary malignancy
The rate of second malignancies following adjuvant radiotherapy is extremely low. Sarcomas in the treated field are rare, with the long-term risk only 0.2% at 10 years [65]. One report suggests an increase in contralateral breast cancer for women younger than 45 years of age who have received chest wall irradiation after mastectomy [66]. Techniques to minimize the radiation dose to the contralateral breast are therefore used to keep this risk as low as possible [67].

Cosmesis
Following breast-conserving surgery and adjuvant irradiation, long-term sequelae also include fibrosis of breast tissue and skin changes, which detract from the final cosmetic result. Factors affecting this include breast size, extent of surgical excision, dose and fractionation of radiation, as well as dose homogeneity within the irradiated volume. In one retrospective study looking at 458 patients significant independent factors for excellent cosmetic outcome were a smaller volume of surgical excision (p=0.0001) appropriate scar orientation (p=0.0034) and whole breast radiotherapy dose less than or equal to 50 Gy. Poorer cosmetic outcome was also associated with age greater than 60 years and Black race [68]. Another study of 285 patients on multivariate analysis found that only higher dose per fraction and higher boost dose affected cosmesis [69]. A recent EORTC trial utilizing standardized treatment protocols assessed treatment, patient and tumour factors influencing cosmetic outcome in 731 patients [70]. Significant factors that worsened cosmesis according to panel evaluation included an inferior tumour location, large excision volume, presence of post-operative complications and use of a tumour bed boost. In addition according to digitizer measurement, increased nipple asymmetry appeared to be related to central/superior tumour location, large excision volume, increased pathological tumour size and radiation dose in homogeneity. The latter has been also proposed as a factor resulting in the poorer cosmetic outcome in patients with a large breast size [71, 72].


   Modern techniques that reduce morbidity
Top
 Abstract
 Introduction
 Surgery
 Conventional radiotherapy
 Toxicity
 Modern techniques that reduce...
Discussion
 Conclusions
 References
 
Reducing dose inhomogeneity across the treatment volume
Significant dose inhomogeneity across the target volume is common in conventionally planned radiotherapy to the intact breast. Tangential parallel opposed fields which skim across the chest wall are used with medial and lateral wedges to improve dose distribution in the central transverse plane, this being assumed to model the dosimetry in other parts of the irradiated volume. However, dose inhomogeneity results from the continuous change in shape of the breast in multiple planes and the effect of low-density lung, which is always included in the treatment volume. Several studies have demonstrated significant dose inhomogeneity as large as 15–20% in the superior and inferior regions of the breast from such techniques [73–75]. In addition, the medial and lateral aspects of the breast may be exposed to higher doses of radiation due to lower attenuation of lung. Areas of relative under-dosage will theoretically increase the risk of local relapse and areas of overdose will be associated with increased acute and late toxicity. One approach that has been shown to improve homogeneity has been the use of CT planning and tissue compensators [76–78]. In one study comparing three-dimensional (3D) conformal planning using multiple contours and tissue compensators to those using a single contour and simple wedges, dosimetric improvements were achieved reducing hot spots within the irradiated volume [76]. Endpoints of the study were comparison of the volumes receiving greater than 105% and 110% of the reference dose; significant improvements were seen in 58%. A concern with physical tissue compensators however is a loss of skin sparing and increased scatter dose to the contralateral breast [79]. Currently available intensity-modulated radiotherapy (IMRT) techniques irradiating the breast using a conventional tangential beam arrangement have also been shown to improve dose homogeneity in a number of studies [80–84]. In the study by Kestin et al [82] improvement in dose homogeneity was accompanied by minimal acute skin toxicity for patients with varying breast sizes. In another study looking at 281 patients treated with IMRT skin toxicity was minimal with only 1% of the treated patients developing grade III toxicity; in 95 patients available for cosmetic evaluation at 12 months, no skin telangiectasia or significant fibrosis was seen [85]. It is interesting to note that the static multileaf collimator IMRT technique used in this study was possible without significant increase in either planning time or treatment time (median less than 10 min).

Reducing adjacent normal tissue irradiation
As described above one major concern regarding late effects of adjuvant irradiation is the increased risk of cardiac death related to irradiation of the heart. One CT based study has demonstrated a significant reduction in cardiac irradiation achieved by simple respiratory manoeuvres during radiotherapy [86]. In this study the volume of myocardium irradiated was measured during normal quiet inspiration and following deep inspiration, using conventionally planned tangential fields. Patients who held their breath following deep inspiration removed a significant proportion of myocardium from the treated volume and in 47% the entire myocardium was excluded. Simple cardiac shielding has also been shown to reduce heart volumes irradiated during conventional planned radiotherapy, as has the use of IMRT [87, 88]. In a planning study comparing standard wedged versus intensity-modulated tangential beams, significant reduction in the dose to critical structures was achieved using IMRT. The dose from the IMRT plan encompassing 20% of the coronary artery region decreased by 25% for patients treated to the left breast and the ipsilateral lung volume receiving more than 46 Gy decreased by 31%. Such improvements were also associated with improved dose homogeneity throughout the target volume [87].

Internal mammary node irradiation
Irradiation of the IMC is technically challenging using conventional methods as its inclusion creates an irregular concave volume, which is difficult to irradiate adequately without delivering a significant dose to the heart, especially on the left [89–91]. Use of deep tangential fields covers the IMC effectively but increases significantly the dose received by the heart. Use of tangential fields with an abutting oblique electron field reduces the cardiac dose, but can be obtained only at the expense of dose inhomogeneity, particularly along the match line of the medial tangential photon field. Planning studies suggest a high dose region of the order of 10–20% and a dose variability of up to 40% [89, 90]. Another approach has been to selectively target the superior IMC where most lymphatic spread is thought to occur and use partly split tangents to cover the breast plus superior IMC with a block to shield the heart [92]. Such an approach improves dose homogeneity while reducing the dose to the heart. For such difficult volumes IMRT has been shown to offer the possibility of good target volume coverage whilst reducing irradiation of surrounding normal tissues [93].

Over the last few years there have been significant advances in delivery of radiotherapy including 3D conformal planning, IMRT and precise treatment verification. Despite this little change has occurred in any radiotherapy centres. These innovations are now available to improve breast radiotherapy and many of these could be achieved without significant increase in either planning or delivery time.

Dose and fractionation
An increasing problem facing British clinical oncologists is the increasing demand for radiotherapy due to the increase in breast conserving surgery. Reviews of radiotherapy practice show considerable variation in dose, fractionation and volumes irradiated [94, 95]. It is generally accepted that fraction sizes significantly over 2 Gy may lead to increased late side effects depending on the tissue, volume irradiated and total dose. 40 Gy in 15 fractions is an alternative schedule that has been in use for many years in both the UK and Canada [95]. Retrospective studies and the interim results of one randomized trial suggest that it produces similar clinical effects to 50 Gy in 25 fractions, which is the preferred schedule in North America and mainland Europe [96, 97]. In an attempt to address this variation in practice and the pressures on workload in the UK, the START (Standardization of Radiotherapy) trial was launched to test the effects of schedules using fraction sizes larger than 2 Gy. Endpoints are assessment of normal tissue response, locoregional tumour control, quality of life and economics. However, concerns regarding large fraction size and technique have been expressed following the serious (though rare) cases of brachial plexus neuropathy. There are some data that larger fraction sizes may be associated with a poorer cosmetic result and an increased incidence of late sequelae [69].

One study has suggested that larger fraction sizes may be associated with an increase in brachial plexopathy but this did not reach statistical significance [59]. As a result many oncologists prefer to use 2 Gy per fraction the SCF and axilla, although a hypofractionated regimen to these nodal areas is permissible within the START trial.


   Discussion
Top
 Abstract
 Introduction
 Surgery
 Conventional radiotherapy
 Toxicity
 Modern techniques that reduce...
 Discussion
Conclusions
 References
 
In early breast cancer the benefits of adjuvant radiotherapy include improved local control and survival. The toxicity of adjuvant radiotherapy is acceptable using conventional techniques with a low risk of serious long-term sequelae. In particular the risk of serious long-term cardiac morbidity is probably much less than previously. Further reductions in cardiac irradiation may be achieved by the use of simple cardiac shielding and breathing techniques. More complex planning techniques such as 3D conformal radiotherapy and IMRT; in addition to reducing lung and cardiac irradiation, also improves target volume dosimetry and reduce acute skin toxicity. A better cosmetic outcome and further improvement in local control are anticipated.

The British Association of Surgical Oncology guidelines state that for patients treated by breast conserving surgery and post-operative radiotherapy, the time interval between the two should not exceed 4 weeks. The Canadian consensus document recommended that all women who undergo breast-conserving surgery should commence irradiation not later than 12 weeks following surgery [98]. In the UK, the recommended time interval between breast-conserving surgery and post-operative radiation should not exceed 20 working days, except for clinical reasons [99]. From 2005 the National Cancer Plan target for England is for all patients with cancer to start treatment within 1 month of diagnosis. At present this target is not achieved by the majority of centres in the UK. Currently delay can be upwards of 6 weeks for planning and starting radical treatment.

The levels of radiotherapy equipment, staffing and training required that will allow delivery of an optimal service in the UK has recently been reported [100]. Although in 1997 it was proposed under the National Cancer Plan to increase the number of linear accelerators per million population to 4.2 by 2004, due to the increased demand for radiotherapy this is well below what is needed now. In 1998 28% of patients had to wait longer than 4 weeks to start potentially curative radical radiotherapy, in 2002 81% of patients waited longer than 4 weeks. It is known that delay in commencing treatment can result in disease progression and compromise the probability of cure [101–104]. One retrospective study of 653 patients with early stage node negative breast cancer treated by breast-conserving surgery and radiotherapy alone demonstrated no increase in local relapse rates by delaying radiotherapy up to 8 weeks [105]. However, the recent meta-analysis of 15 000 patients confirmed that delay in starting radiotherapy was associated with a significant increase in local relapse rate. This increase was seen when radiotherapy was delayed beyond 8 weeks following surgery (odds ratio 1.62, 95% CI 1.21–2.16) corresponding to an increase in local recurrence rate from 5.8% to 9.1% at 5 years [106]. In patients also receiving adjuvant chemotherapy, a delay in radiotherapy of greater than 6 months from diagnosis is associated with both increase in local relapse rate and increase in distant relapse with a reduced overall survival [107].

Conformal radiotherapy is already considered to be the standard modern treatment in many centres in Europe and North America, but is currently not widely available. Additional resources are needed for staff with specialized training to ensure that its implementation and that of IMRT is both accurate and safe [42].


   Conclusions
Top
 Abstract
 Introduction
 Surgery
 Conventional radiotherapy
 Toxicity
 Modern techniques that reduce...
 Discussion
 Conclusions
References
 
The considerable benefits of conventional adjuvant breast radiotherapy in terms of local control and survival may be diminished with long waiting times for treatment currently seen in the UK. More treatment machines together with the physicists and radiographers to staff them are urgently needed. Improvement will be realised only if staff and machines are trained and capable of delivering high quality radiotherapy. Greater homogeneity of dose distribution as well as reduced cardiac and lung irradiation are possible with modern techniques. Further improvements in local control and survival can also be anticipated.


   Footnotes
 
Address correspondence to Dr John A Violet, Department of Oncology, Royal Free Hospital, Rowland Hill Street, London NW5 2PF, UK. Back

Received for publication May 23, 2003. Revision received April 26, 2004. Accepted for publication June 22, 2004.


   References
Top
 Abstract
 Introduction
 Surgery
 Conventional radiotherapy
 Toxicity
 Modern techniques that reduce...
 Discussion
 Conclusions
 References
 

  1. Bartelink H, Horiot JC, Poortmans P, Struikmans H, Van den Bogaert W, Barillot I, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. New Engl J Med 2001;345:1378–87.[Abstract/Free Full Text]
  2. Romestaing P, Lehingue Y, Carrie C, Coquard R, Montbarbon X, Ardiet JM, et al. Role of a 10-Gy boost in the conservative treatment of early breast cancer: results of a randomized clinical trial in Lyon, France. J Clin Oncol 1997;15:963–8.[Abstract/Free Full Text]
  3. Falk SJ. Radiotherapy and the management of the axilla in early breast cancer. Br J Surg 1994;82:1277–81.
  4. Recht A, Pierce S, Abner A, Vicini FA, Osteen RT, Love SM, et al. Regional nodal failure after conservative surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol 1991;11:1536–44.
  5. Recht A, Houlihan MJ. Axillary lymph nodes and breast cancer. Cancer 1995;76:1491–512.[CrossRef][Medline]
  6. Halverson KJ, Taylor ME, Perez CA, Garcia DM, Myerson R, Philpott G, et al. Regional nodal management and patterns of failure following conservative surgery and radiation therapy for stage I and II breast cancer. Int J Radiat Oncol Biol Phys 1993;26:593–9.[Medline]
  7. Hoskin PJ, Rajan B, Ebbs S, Tait D, Milan S, Yarnold JR. Selective avoidance of lymphatic radiotherapy in the conservative management of early breast cancer. Radiother Oncol 1992;25:83–8.[CrossRef][Medline]
  8. Fairlamb DJ, Machin D. Prophylactic supraclavicular fossa radiotherapy in early breast cancer: is it worthwhile? Clin Oncol 1994;6:227–31.[CrossRef]
  9. Fisher BJ, Perera FE, Cooke AL, Opeitum A, Venkatesan V, Dar AR, et al. Long-term follow-up of axillary node-positive breast cancer patients receiving adjuvant systemic therapy alone: patterns of recurrence. Int J Radiat Oncol Biol Phys 1997;38:541–50.[CrossRef][Medline]
  10. Fisher BJ, Redmond C, Fisher ER, et al. Ten year results of a randomised clinical trial comparing radical mastectomy to total mastectomy with or without radiation. New Engl J Med 1985;312:674–81.[Abstract]
  11. Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999;353:1641–8.[CrossRef][Medline]
  12. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high risk pre-menopausal women with breast cancer who receive adjuvant chemotherapy. New Engl J Med 1997;337:949–55.[Abstract/Free Full Text]
  13. Ragaz J, Jackson SM. Adjuvant radiotherapy and chemotherapy in node-positive pre-menopausal women with breast cancer. New Engl J Med 1997;337:956–62.[Abstract/Free Full Text]
  14. Uren RF, Howman-Giles RB, Thompson JF, et al. Mammary lymphoscintigraphy in breast cancer. J Nuclear Med 1995;36:1775–80.[Abstract/Free Full Text]
  15. Freedman GM, Fowble BL, Nicolaou N, Sigurdson ER, Torosian MH, Boraas MC, et al. Should internal mammary lymph nodes in breast cancer be a target for the radiation oncologist? Int J Radiat Oncol Biol Phys 2000;46:805–14.[CrossRef][Medline]
  16. Le M, Arriagada R, Vathaire F, et al. Can internal mammary chain treatment decrease the risk of death for patients with medial breast cancer and positive lymph nodes? Cancer 1990;66:2213–318.[CrossRef]
  17. Zucali R, Luigi M, Ettore M, et al. Early breast cancer: evaluation of the prognostic role of the site of the primary tumour. J Clin Oncol 1998;16:1363–6.[Abstract/Free Full Text]
  18. Rutqvist LE, Lax I, Fornander T, Johansson H. Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer. Int J Radiat Oncol Biol Phys 1992;22:887–96.[Medline]
  19. Clark RM, McCulloch PB, Levine MN, Lipa M, Wilkinson RH, Mahoney LJ, et al. Randomized clinical trial to assess the effectiveness of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer. J Natl Cancer Inst 1992;84:683–9.[Abstract/Free Full Text]
  20. Fisher B, Anderson S, Redmond CK, Wolmark N, Wickerham DL, Cronin WM. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. New Engl J Med 1995;333:1456–61.[Abstract/Free Full Text]
  21. Liljegren G, Holmberg L, Bergh J, Lindgren A, Tabar L, Nordgren H, et al. 10-Year results after sector resection with or without postoperative radiotherapy for stage I breast cancer: a randomized trial. J Clin Oncol 1999;17:2326–33.[Abstract/Free Full Text]
  22. Veronesi U, Salvadori B, Luini A, Greco M, Saccozzi R, del Vecchio M, et al. Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials on 1,973 patients. Eur J Cancer 1995;31A:1574–9.
  23. Arriagada R, Rutqvist LE, Le MG. Postmastectomy radiotherapy: randomized trials. Semin Radiat Oncol 1999;9:275–86.[CrossRef][Medline]
  24. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. New Engl J Med 1997;337:949–55.
  25. Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positivie premenopausal women with breast cancer. New Engl J Med 1997;337:956–62.
  26. Auquier A, Rutqvist LE, Host H, Rotstein S, Arriagada R. Post-mastectomy megavoltage radiotherapy: the Oslo and Stockholm trials. Eur J Cancer 1992;28:433–7.
  27. Arriagada R, Rutqvist LE, Mattsson A, Kramar A, Rotstein S. Adequate locoregional treatment for early breast cancer may prevent secondary dissemination. J Clin Oncol 1995;13:2869–78.[Abstract]
  28. Whelan TJ, Julian J, Wright J, Jadad AR, Levine ML. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000;18:1220–9.[Abstract/Free Full Text]
  29. Fisher B, Dignam J, Wolmark N, Mamounas E, Costantino J, Poller W, et al. Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 1998;16:441–52.[Abstract]
  30. Julien JP, Bijker N, Fentiman IS, Peterse JL, Delledonne V, Rouanet P, et al. Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet 2000;355:528–33.[CrossRef][Medline]
  31. UKCCR DCIS working party. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast treated in the UK, Australia, and New Zealand: randomised controlled trial. Lancet 2003;362:95–102.
  32. Fisher ER, Dignam J, Tan-Chiu E, Costantino J, Fisher B, Paik S, et al. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer 1999;86:429–38.[CrossRef][Medline]
  33. Silverstein MJ, Lagios MD, Craig PH, et al. A prognostic index for ductal carcinoma in situ of the breast. Cancer 1996;77:2267–74.[CrossRef][Medline]
  34. Silverstein MJ, Lagios MD, Groshen S, Waisman JR, Lewinsky BS, Martino S, et al. The influence of margin width on local control of ductal carcinoma in situ of the breast. New Engl J Med 1999;340:1455–61.[Abstract/Free Full Text]
  35. Rothwell RI, Kelly SA, Joslin CAF. Radiation pneumonitis in patients treated for breast cancer. Radiother Oncol 1985;4:9–14.[Medline]
  36. Ooi GC, Kwong KN, Chan KN, Ngan H, Lock DTW, Lam WK, et al. Serial HRCT lung changes after 3-field radiation treatment of breast cancer. Clin Radiol 2000;55:817–24.[CrossRef][Medline]
  37. Lingos TI, Recht A, Vicini F, Abner A, Silver B, Harris JR. Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 1991;21:355–60.[Medline]
  38. Polansky SM, Ravin CE, Prosnitz LR. Pulmonary changes after primary irradiation for early breast cancer. Am J Radiol 1980;134:101–5.[Abstract]
  39. Kaufman J, Gunn W, Hartz AJ, Fischer M, Hoffman R, Schlueter DP, et al. The pathophysiologic and roentgenologic effects of chest irradiation in breast carcinoma. Int J Radiat Oncol Biol Phys 1986;12:887–93.[Medline]
  40. Schoeppel S, LaVigne ML, Fraas BA, Herman JS, Cornell RG, Lichter AS. Radiation pneumonitis after treatment with tangential breast fields: a dose volume analysis (Abstr). Proceedings of ESTRO, Den Haag, The Netherlands: 1988.
  41. Gyenes G. Radiation-induced ischemic heart disease in breast cancer—a review. Acta Oncologica 1998;37:241–6.[CrossRef][Medline]
  42. Fuller SA, Haybittle JL, Smith RE, Dobbs HJ. Cardiac doses in post-operative breast irradiation. Radiother Oncol 1992;25:19–24.[CrossRef][Medline]
  43. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 2000;355:1757–70.[CrossRef][Medline]
  44. Cuzick J, Stewart H, Rutqvist L, Houghton J, Edwards R, Redmond C, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 1994;12:447–53.[Abstract]
  45. Paszat LF, Mackillop WJ, Groome PA, Boyd C, Schulze K, Holowaty E. Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. [erratum appears in J Clin Oncol 1999;17:740]. J Clin Oncol 1998;16:2625–31.[Abstract]
  46. Paszat LF, Mackillop WJ, Groome PA, Schulze K, Holowaty E. Mortality from myocardial infarction following postlumpectomy radiotherapy for breast cancer: a population-based study in Ontario, Canada. Int J Radiat Oncol Biol Phys 1999;43:755–62.[CrossRef][Medline]
  47. Rutqvist LE, Johansson H. Mortality by laterality of the primary tumour among 55,000 breast cancer patients from the Swedish Cancer Registry. Br J Cancer 1990;61:866–8.[Medline]
  48. Levitt SH, Fletcher GH. Trials and tribulations: do clinical trials prove that irradiation increases cardiac and secondary cancer mortality in the breast cancer patient? Int J Radiat Oncol Biol Phys 1991;21:523–7.[Medline]
  49. Hojris I, Overgaard M, Christensen JJ, Overgaard J. Morbidity and mortality of ischaemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: analysis of DBCG 82b and 82c randomised trials. Radiotherapy Committee of the Danish Breast Cancer Cooperative Group. Lancet 1999;354:1425–30.[CrossRef][Medline]
  50. Nixon AJ, Manola J, Gelman R, Bornstein B, Abner A, Hetelekidis S, et al. No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques. J Clin Oncol 1998;16:1374–9.[Abstract/Free Full Text]
  51. Darby S, McGale P, Peto R, Granath F, Hall P, Ekbom A. Mortality from cardiovascular disease more than 10 years after radiotherapy for breast cancer: nationwide cohort study of 90 000 Swedish women. BMJ 2001;326:256–7.
  52. Gyenes G, Fornander T, Carlens P, Glas U, Rutqvist LE. Myocardial damage in breast cancer patients treated with adjuvant radiotherapy: a prospective study. Int J Radiat Oncol Biol Phys 1996;36:899–905.[CrossRef][Medline]
  53. Gyenes G, Gagliardi G, Lax I, Fornander T, Rutqvist LE. Evaluation of irradiated heart volumes in stage I breast cancer patients treated with postoperative adjuvant radiotherapy. J Clin Oncol 1997;15:1348–53.[Abstract/Free Full Text]
  54. Meek AG. Breast radiotherapy and lymphedema. Cancer1998;83(12 Suppl American):2788–97.[CrossRef]
  55. Larson D, Weinstein M, Goldberg I, Silver B, Recht A, Cady B, et al. Edema of the arm as a function of the extent of axillary surgery in patients with stage I-II carcinoma of the breast treated with primary radiotherapy. Int J Radiat Oncol Biol Phys 1986;12:1575–82.[Medline]
  56. Swedborg I, Norrefalk JR, Piller NB, Asard C. Lymphoedema post-mastectomy: is elevation alone an effective treatment? Scand J Rehabil Med 1993;25:79–82.[Medline]
  57. Overgaard M, Christiansen JJ, Johansson H, Nybo-Rasumssen A, Brinckner H, Van Der Kooy P, et al. Postmastectomy irradiation in high risk breast cancer patients. Acta Oncologica 1988;27:707–14.[Medline]
  58. Delouch G, Bachelot F, Premont M, Kurtz JM. Conservation treatment of early breast cancer: long term results and complications. Int J Radiat Oncol Biol Phys 1987;13:29–34.[Medline]
  59. Powell S, Cooke J, Parsons C. Radiation-induced brachial plexus injury: follow-up of two different fractionation schedules. Radiother Oncol 1990;18:213–20.[CrossRef][Medline]
  60. Basso-Ricci S, della Costa C, Viganotti G, Ventafridda V, Zanolla R. Report on 42 cases of postirradiation lesions of the brachial plexus and their treatment. Tumori 1980;66:117–22.[Medline]
  61. Pierce SM, Recht A, Lingos TI, Abner A, Vicini F, Silver B, et al. Long-term radiation complications following conservative surgery (CS) and radiation therapy (RT) in patients with early stage breast cancer. Int J Radiat Oncol Biol Phys 1992;23:915–23.[Medline]
  62. 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;48:745–50.[CrossRef][Medline]
  63. 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 2001;52:1207–19.
  64. Landau DB, Laing RW. An audit of indications and techniques for supraclavicular fossa irradiation in early breast cancer in the United Kingdom. Clin Oncol 2000;12:172–8.
  65. Taghian A, de Vathaire F, Terrier P, Le M, Auquier A, Mouriesse H, et al. Long-term risk of sarcoma following radiation treatment for breast cancer. Int J Radiat Oncol Biol Phys 1991;21:361–7.[Medline]
  66. Boice JDJ, Harvey EB, Blettner M, Stovall M, Flannery JT. Cancer in the contralateral breast after radiotherapy for breast cancer. New Engl J Med 1992;326:781–5.[Abstract]
  67. Fraass BA, Roberson PL, Lichter AS. Dose to the contralateral breast due to primary breast irradiation. Int J Radiat Oncol Biol Phys 1985;11:485–97.[Medline]
  68. Taylor ME, Perez CA, Halverson KJ, Kuske RR, Philpott GW, Garcia DM, et al. Factors influencing cosmetic results after conservation therapy for breast cancer. Int J Radiat Oncol Biol Phys 1995;31:753–64.[CrossRef][Medline]
  69. Sarin R, Dinshaw KA, Shrivastava SK, Sharma V, Deore SM. Therapeutic factors influencing the cosmetic outcome and late complications in the conservative management of early breast cancer. Int J Radiat Oncol Biol Phys 1993;27:285–92.[Medline]
  70. Vreiling C, Collette L, Fourquet A, Hoogenraad W, Horiot JC, Jager J, et al. The influence of patient, tumour and treatment factors on the cosmetic result in the EORTC ‘Boost vs no Boost’ trial. Radiother Oncol 2000;55:219–32.[CrossRef][Medline]
  71. Harris JR, Levene MB, Svensson G, Hellman S. Analysis of cosmetic results following primary radiation therapy for stages I and II carcinoma of the breast. Int J Radiat Oncol Biol Phys 1979;5:257–61.[Medline]
  72. Clarke D, Martinez A, Cox RS. Analysis of cosmetic results and complications in patients with stage I and II breast cancer treated by biopsy and irradiation. Int J Radiat Oncol Biol Phys 1983;9:1807–13.[Medline]
  73. Buchholz TA, Gurgoze E, Bice WS, Prestige BR. Dosimetric analysis of intact breast irradiation in off-axis planes. Int J Radiat Oncol Biol Phys 1997;39:261–7.[Medline]
  74. Cheng CW, Das IJ, Stea B. The effect of the number of computerised tomographic slices on dose distributions and evaluation of treatment planning systems for radiation therapy of intact breast. Int J Radiat Oncol Biol Phys 1994;30:183–95.[Medline]
  75. Solin LJ, Chu JC, Sontag MR, Brewster L, Cheng E, Doppke K, et al. Three dimensional photon treatment planning of the intact breast. Int J Radiat Oncol Biol Phys 1991;21:193–203.[Medline]
  76. Aref A, Thornton D, Youssef E, He T, Tekyi-Mensah S, Denton L, et al. Dosimetric improvements following 3D planning of tangential breast irradiation. Int J Radiat Oncol Biol Phys 2000;48:1569–74.[CrossRef][Medline]
  77. Carruthers LJ, Redpath AT, Kunkler IH. The use of compensators to optimise the three dimensional dose distribution in radiotherapy of the intact breast. Radiother Oncol 1999;50:291–300.[CrossRef][Medline]
  78. Mayles WP, Yarnold JR, Webb S. Improved dose homogeneity in the breast using tissue compensators. Radiother Oncol 1991;22:248–51.[CrossRef][Medline]
  79. Fontenla DP, Napoli JJ, Hunt M, Fass D, McCormick B, Kutcher GJ. Effects of beam modifiers and immobilization devices on the dose in the build-up region. Int J Radiat Oncol Biol Phys 1994;30:211–9.[Medline]
  80. Donovan EM, Johnson U, Shentall G, Evans PM, Neal AJ, Yarnold JR. Evaluation of compensation in breast radiotherapy: a planning study using multiple static fields. Int J Radiat Oncol Biol Phys 2000;46:671–9.[CrossRef][Medline]
  81. Donovan EM, Bleackley NJ, Evans PM, Reise SF, Yarnold JR. Dose-position and dose-volume histogram analysis of standard wedged and intensity modulated treatments in breast radiotherapy. Br J Radiol 2002;75:967–73.[Abstract/Free Full Text]
  82. Kestin LL, Sharpe MB, Frazier RC, Vicini FA, Yan D, Matter RC, et al. Intensity modulation to improve dose uniformity with tangential breast radiotherapy: initial clinical experience. Int J Radiat Oncol Biol Phys 2000;48:1559–68.[CrossRef][Medline]
  83. Lo YC, Yasuda G, Fitzgerald TJ, Urie MM. Intensity modulation for breast treatment using static multi-leaf collimators. Int J Radiat Oncol Biol Phys 2000;46:187–94.[CrossRef][Medline]
  84. van Asselen B, Raaijmakers CP, Hofman P, Lagendijk JJ. An improved breast irradiation technique using three-dimensional geometric information and intensity modulation. Radiother Oncol 2001;58:341–7.[CrossRef][Medline]
  85. Vicini FA, Sharpe M, Kestin L, Martinez A, Mitchell CK, Wallace MF, et al. Optimizing breast cancer treatment efficacy with intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2001;54:1336–44.
  86. Lu HM, Cash E, Chen MH, Chin L, Manning WJ, Harris J, et al. Reduction of cardiac volume in left-breast treatment fields by respiratory maneuvers: a CT study. Int J Radiat Oncol Biol Phys 2000;47:895–904.[CrossRef][Medline]
  87. Hong L, Hunt M, Chui C, Spirou S, Forster K, Lee H, et al. Intensity modulated tangential beam irradiation of the intact breast. Int J Radiat Oncol Biol Phys 1999;44:1155–64.[CrossRef][Medline]
  88. Landau D, Adams EJ, Webb S, Ross G. Cardiac avoidance in breast radiotherapy: a comparison of simple shielding techniques with intensity-modulated radiotherapy. Radiother Oncol 2001;60:247–55.[CrossRef][Medline]
  89. Hurkmans CW, Saarnak AE, Pieters BR, Borger JH, Bruinvis IA. An improved technique for breast cancer irradiation including the locoregional lymph nodes. Int J Radiat Oncol Biol Phys 2000;47:1421–9.[CrossRef][Medline]
  90. Woudstra E, van der Werf H. Obliquely incident electron beams for irradiation of the internal mammary lymph nodes. Radiother Oncol 1987;10:209–15.[Medline]
  91. Arthur DW, Arnfield MR, Warwicke LA, Morris MM, Zwicker RD. Internal mammary node coverage: an investigation of presently accepted techniques. Int J Radiat Oncol Biol Phys 2000;48:139–46.[Medline]
  92. Marks LB, Hebert ME, Bentel G, Spencer DP, Sherouse GW, Prosnitz LR. To treat or not to treat the internal mammary nodes: a possible compromise. Int J Radiat Oncol Biol Phys 1994;29:903–9.[Medline]
  93. Cho BC, Hurkmans CW, Damen EM, Zijp LJ, Mijnheer BJ. Intensity modulated versus non-intensity modulated radiotherapy in the treatment of the left breast and upper internal mammary lymph node chain: a comparative planning study. Radiother Oncol 2002;62:127–36.[CrossRef][Medline]
  94. Goy JC, Dobbs HJ. Variation in postoperative radiotherapy delivery for patients with screen-detected breast cancer in the south Thames (east) Region. Clin Oncol 1998;10:30–4.[CrossRef]
  95. Yarnold JR, Price P, Steel GG. Non-surgical management of early breast cancer in the United Kingdom: radiotherapy fractionation practices. Clinical Audit Sub-committee of the Faculty of Clinical Oncology, Royal College of Radiologists, and the Joint Council for Clinical Oncology. Clin Oncol 1995;7:223–6.[CrossRef]
  96. Ash DV, Benson EA, Sainsbury JR, Round C, Head C. Seven-year follow-up on 334 patients treated by breast conserving surgery and short course radical postoperative radiotherapy: a report of the Yorkshire Breast Cancer Group. Clin Oncol 1995;7:93–6.
  97. Spooner D. The role of radiotherapy in breast cancer (stage I). A West Midlands Breast Group Prospective Collaborative Study (BR3002). Abstract of the 4th Nottingham International Breast Cancer Conference. Ther Breast 1995;4:231–2.
  98. Canadian Consensus Document. Clinical practice guidelines for care and treatment of breast cancer. CMAJ 1998;3:158.
  99. Barrett-Lee, P. Reducing delays in cancer treatments: some targets. A report of the Joint Council for Clinical Oncology, Royal College of Physicians and Royal College of Radiologists. CMAJ 1993;3:158.
  100. Royal College of Radiologists. Equipment, Workload and Staffing for Radiotherapy in the UK 1997–2002. 2003.
  101. Fortin A, Bairati I, Albert M, Moore L, Allard J, Couture C. Effect of treatment delay on outcome of patients with early stage head and neck carcinoma receiving radical radiotherapy. Int J Radiat Oncol Biol Phys 2002;52:929–36.[CrossRef][Medline]
  102. O'Rourke N, Edwards R. Lung cancer treatment waiting times and tumour growth. Clin Oncol 2000;12:141–4.
  103. O'Sullivan. The influence of delay in the initiation of radiotherapy in carcinoma of the tonsillar region. Int J Radiat Oncol Biol Phys; 1998;42(Suppl):323.
  104. Waaijer A, Terhaard CH, Dehnad H, Hordijk GJ, van Leeuwen MS, Raaymakers CP, et al. Waiting times for radiotherapy: consequences of volume increase for the TCP in oropharyngeal carcinoma. Radiother Oncol 2003;66:271–6.[CrossRef][Medline]
  105. Nixon AJ, Recht A, Neuberg D, Connolly JL, Schnitt S, Abner A, et al. The relationship between the surgery-radiotherapy interval and treatment outcome in patients treated with breast-conserving surgery and radiation therapy without systemic therapy. Int J Radiat Oncol Biol Phys 1994;30:17–21.[Medline]
  106. Huang J, Barbero L, Brouwers M, Browman G, Mackillop WJ. Does delay in starting treatment affect the outcomes of radiotherapy? A systematic review. J Clin Oncol 2003;3:555–63.
  107. Buchholz TA, Austin-Seymour MM, Moe RE, Ellis GK, Livingston RB, Pelton JG, et al. Effect of delay in radiation in the combined modality treatment of breast cancer. Int J Radiat Oncol Biol Phys 1992;26:23–35.



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