Evidence based radiation oncology: Breast cancer

Radiotherapy and Oncology 84 (2007) 84–101 www.thegreenjournal.com

Educational review

Evidence based radiation oncology: Breast cancer Philip Poortmans* Dr. Bernard Verbeeten Instituut, Radiotherapy, Tilburg, Netherlands

Abstract Purpose: Radiotherapy is, similar to surgery, a local treatment. In the case of breast cancer, it is generally given after conservative or after more extensive, tumour and patient adapted, surgery. The target volumes can be the breast and/or the thoracic wall and/or the regional lymph node areas. The integration and the extent of radiotherapy as part of the comprehensive treatment of the breast cancer patient, including the amount of surgery and the sequencing with the systemic treatments, has to be well discussed with all medical specialists involved in treating breast cancer on a multidisciplinary basis. Guidelines for the appropriate prescription and execution of radiotherapy are of utmost importance. However, individualisation based on the individual patients’ and tumours’ characteristics should always be envisaged. Materials and methods: Based on a review of the literature the level of evidence that is available for the indications for radiotherapy is summarised, as well as the main clinical questions that are unanswered today. An overview of the recent and ongoing clinical trails in breast cancer will highlight some of the current ongoing debates. Conclusions: In the case of breast cancer, radiotherapy, given after as well conservative as extensive risk-adapted surgery, significantly reduces the risk of local and regional recurrences. Especially for patients with an intermediate to high absolute risk for local recurrences, a positive influence on overall survival has been shown, notably when appropriate radiotherapy techniques are used. Most important is that the best results that we can offer to our breast cancer patients for all clinical endpoints (local and regional control; quality of life; cosmetic results; survival) can be obtained by a multidisciplinary and patient-oriented approach, involving all those involved in the treatment of breast cancer patients. c 2007 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 84 (2007) 84–101.



Keywords: Evidence based medicine; Breast cancer; Radiotherapy; Breast-conserving therapy; Postmastectomy radiotherapy; DCIS; Sequence; Elective lymph node irradiation; Locoregional radiotherapy; Review

A. Breast-conserving therapy Introduction As the self-image of women can be influenced significantly by the appearance of the body, the search for less mutilating surgery has been part of several investigations over the last decades. Especially early stage breast cancer patients might be amenable to a breast-conserving approach but even for larger tumours this is under investigation with the combination of primary chemotherapy to reduce the volume of the primary tumour. As stated nearly 20 years ago, mastectomy is not needed for most small tumours and does not improve prognosis for more extensive disease. Therefore, as many as 80% of the patients with invasive breast cancer might benefit from breast-conserving therapy (BCT), offering identical disease control and survival, compared to modified radical mastectomy. In practice, up to 50% of the patients are treated with BCT. This will probably further rise as an increasing proportion of the patients diagnosed with breast cancer



presents with early stage disease, an evolution that is strengthened after the introduction of mass screening for breast cancer.

Treatment Several randomised clinical trials have shown equivalent results after BCT and mastectomy in stage I and II breast cancer [17,46,125,150,155]. The meta-analysis of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) confirmed the equivalence of those two approaches with survival as endpoint and the need for radiotherapy following lumpectomy to reduce the 5-year local recurrence rate from 26% to 7% [39]. The potential impact on local control and treatment complications of giving a higher dose to the primary tumour bed with a boost was investigated in two prospective randomised trials. Both demonstrated that delivering a boost dose to the tumour bed after 50 Gy to the whole breast significantly reduces the local recurrence rate [8,118]. Besides the administration of a boost, age, the presence of CIS, the size of the excised lump, the tumour size and the administration of adjuvant systemic

0167-8140/$ - see front matter c 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2007.06.002

P. Poortmans / Radiotherapy and Oncology 84 (2007) 84–101

treatments turned out to be significant prognostic factors for local control after BCT [4,46,163].

Cosmetic outcome The previous EORTC (European Organisation for Research and Treatment of Cancer) 10801 trial comparing mastectomy with BCT showed that, because of the high radiation dose given, a significant proportion of the patients experienced severe fibrosis that resulted in a poor cosmetic outcome [28,150]. Therefore, special attention to this item was paid to this aspect in the consecutive EORTC ‘‘Boostno-boost’’ 22881/10882 trial. The dose was lowered from 25 to 16 Gy, the rate of fibrosis at as well the whole breast as at the primary tumour site was recorded at each follow up visit and a cosmetic evaluation was carried out with pictures to be taken at randomisation and every 3 years thereafter. The cosmetic results were scored as excellent to good in 86% of the patients receiving no boost and in 71% of the patients receiving a boost [160,161]. Apart from the boost, other independent predictors that negatively affected the cosmetic outcome were the location of the primary tumour in the lower quadrants of the breast, the size of the excision volume, breast infection and/or haematoma, and clinical T2 stage [162]. The boost dose also significantly increased the worst reported grade of fibrosis in both the whole breast and the boost area, especially after longer follow up. It remained, however, of minor or moderate severity in most patients.

Margin status The association between positive resection margins and the risk of local recurrence after BCT has been controversial for many years but, in general, positive surgical margins are an important risk factor for developing a local recurrence after BCT [90]. The optimal resection margin is uncertain. We examined in the framework of the EORTC 22881/10882 trial the interaction between margin status, age and radiation boost dose for predicting local recurrences at 5 years. In a subset of 1724 patients, an institutional central pathology review was carried out. Margin status for this cohort was determined by the distance of invasive tumour from inked surgical margin: negative (no residual tumour or at least 2 mm from the inked margin) in 78% of the patients, close (less than 2 mm from inked margin) in 12%, or positive (inked margin involved) in 3% of patients. The 5-year Kaplan–Meier local recurrence rate for patients with positive, close and negative margins was 16%, 7%, and 5%, respectively (p < 0.030). In conclusion, the shorter the distance of invasive carcinoma from the inked resection margin the greater the risk of local recurrence [74]. Whether this can be completely counterbalanced by increasing the boost dose has not been demonstrated clearly. In the same EORTC trial, patients with a microscopically incomplete lumpectomy (as stated by the local pathologist) were randomised between a boost dose of 10 and 26 Gy, respectively [108]. Some advocate giving a higher boost dose to patients with a focally irradical lumpectomy without further surgery because in those cases only seldom residual tumour can be found in the re-excision specimen [121].

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Lobular carcinoma Infiltrating lobular carcinoma (ILC) is known for its multicentricity and therefore for its association with a higher incidence of irradicality after BCT and an increased risk of conversion to mastectomy compared to patients with invasive ductal carcinoma. Moreover, it is more difficult to be diagnosed because of this diffusely infiltrative growth, which makes it more difficult to be visualised properly [89,100,134,170]. This explains why concerns have been raised about the use of BCT for patients with infiltrating lobular carcinoma. Local recurrence rates after BCT for ILC vary between 2.8% and 13.5% after 5 years [20,25,62,79,100,104,123,127,129,134,168]. Most studies reported equal local recurrence rates after ILC and infiltrating ductal carcinoma (IDC). Tumour-positive excision margins were found more in patients with ILC than in those with IDC by several authors [84,89,134,168,170]. In a very recent population based study on BCT for ILC including 416 patients, the 5- and 8year local recurrence risk was 3.5% and 6.4%, respectively, despite margin involvement in 29% of the patients after lumpectomy and still 17% when the re-excision was taken into account. In both the univariate and the multivariate analyses, no influence of the surgical margins on the local recurrence risk was found [147]. So in summary, despite the higher risk of an incomplete tumour excision, patients with lobular cancer do not have a higher local recurrence risk after BCT than patients with ductal cancer and should be offered this treatment even after a (focally) microscopically incomplete tumour excision [25,127,134,135].

BCT for young patients Young age is demonstrated to being an unfavourable prognostic factor for local control after breast-conserving therapy [4,8,40,163]. In the EORTC 22881/10882 trial young age appeared to be the single independent significant factor related to local recurrence. The analysis at 5 years showed that for patients 35 years of age or less the addition of a boost resulted in a reduction of the 5-year local recurrence rate from 26% to 8.5%, while for patients older than 60 years this reduction was only from 3.9% to 2.1%. At a longer median follow up of 77.4 months, the paramount importance of age as an independent prognostic factor for the local recurrence risk was confirmed. However, with only 16 more months of follow up compared to the original publication, one of the other major conclusions already changed as it was shown that the relative reduction in local recurrence rate was constant over all age groups (hazard ratio 0.55) [4]. Of course, the absolute reduction in local recurrence rate as a result of a boost of 16 Gy remained much larger for younger patients due to their higher baseline recurrence risk. This result might influence current treatment guidelines by shifting the upper age limit for giving a boost from 50 years upwards, preferably after evaluation of subgroups based on the 10-year update that will soon be published. Of importance is that, according to the consensus at that time, much less patients in the older trials received adjuvant systemic treatment as is advised nowadays. The influence of chemotherapy and hormonal treatment on local

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control is demonstrated by the EORTC trial with an about 35% reduction in the local recurrence rate, as well as in a recent population based review involving 758 patients up to 40 years of age treated with BCT that showed a 53% reduction [4,148]. Concluding, the issue of young age as an independent prognostic factor for local control in BCT is clearly solved. However, the discussion whether young age should be considered as a contraindication to BCT for young patients is still open [151]. Based on the recent evidence, it should probably not be a contraindication in itself but be properly discussed with the patients on an individual base. Current arguments sustaining the use of BCT are the increasing use of adjuvant systemic treatment based on age as a risk factor (with a positive effect on local control as well) and the uncertainty whether a local recurrence after BCT represents the same threat to the patient for long-term survival as other recurrences. Recently, a new trial examining the influence of a further increase of the boost dose to 26 Gy for patients up to 50 years of age started in The Netherlands. The cosmetic outcome, which is known to be dose-dependent, will be carefully monitored. In this trial, translational research including micro-array analysis of the tumour and proteomics will be conducted to search for possible predictive factors for the various endpoints.

Treatment in the elderly Treatment for elderly patients with cancer is a matter of debate in several disease sites. In a series of 636 patients, Hughes et al. compared tamoxifen to tamoxifen and whole breast irradiation for patients 70 years of age or older with early stage oestrogen receptor positive breast cancer. The 5 year locoregional recurrence rate was 4% and 1%, respectively (p < 0.001) [67]. In a similar randomised trial accruing 769 patients of 50 years of age or older, Fyles et al. obtained 5 year locoregional recurrence rates of 7.7 versus 0.6%, respectively (p < 0.001) [52]. In the accompanying editorial, Smith and Ross stated that whole breast irradiation might not always be necessary for all women undergoing BCT for early stage breast cancer. They noted however that patient selection remains difficult, that late recurrences might be a concern (in the series of Fyles, after 8 years of follow up, the difference was already 15.2% versus 3.6% in favour of radiotherapy for the patients with a good prognosis) and that the value of more recent hormonal treatment is not known yet [136]. Amongst the several other arguments in favour of radiotherapy is first of all the continuously growing life expectancy with women of 80 years of age in many countries now having a further life expectancy of more than 10 years. In view of the risk for late recurrences, this further hampers patient selection. Secondly, when omitting radiotherapy and in view of the long-term results, it might be very difficult to stop the hormonal treatment after e.g. 5 years. This will undoubtedly increase the risk for toxicity and the financial costs, especially when more recent hormonal treatments are being used. Finally, the patient will be even older at the time of a local recurrence, often occurring some years after primary diagnosis, and uncon-

trolled local disease is a devastating experience to a patient and to all others involved in caring for her. Based on these arguments, the standard approach should remain to offer optimal local treatment also to elderly patients with early stage low risk breast cancer, on the condition that they are fit enough for this treatment and that they have an estimated life expectancy of P5 years. This can consist of BCT without any systemic treatment, which remains up to now the approach with the highest cost/effectiveness ratio.

Conclusion A substantial proportion of the patients with invasive breast cancer can benefit from BCT, offering identical disease control and survival compared to modified radical mastectomy. For breast-conserving therapy, the upper limit for local recurrences is considered to be 1% per year. Up to now, no subset of breast cancer patients could be defined with an acceptable low risk for local recurrence after surgical removal of the tumour only. Therefore, radiotherapy to the breast is an integral part of BCT. Especially in patients below 40 years of age, local recurrences still exceed 1% a year even after a boost.

Key points (with level of evidence if applicable): • BCT offers equal results as compared to mastectomy in appropriately selected patients (1a). • The majority of breast cancer patients can be offered BCT. • After lumpectomy, postoperative radiotherapy is always required (1a). • Their exists a dose–effect relationship that is independent of age (1b). • As young age is an independent risk factor for local relapses, especially younger patients benefit from a boost dose (1b). • The higher local recurrence risk for younger patients is much reduced if adjuvant systemic treatment is given (2a). • As margins are an important prognostic factor for local control, a microscopically complete lumpectomy should be aimed at (1a). • Patients with infiltrating lobular carcinoma are eligible for BCT, even if the resection margins are not microscopically complete (2b). Unresolved questions and controversies: • The best approach to offer patients after a microscopically incomplete lumpectomy is not clear. • Patient subgroups, with a low risk for a local relapse after surgery alone or after a lower dose/ smaller volume of radiotherapy, still need to be properly defined. • The integration of adjuvant systemic treatment with surgery and radiotherapy to optimise local control needs to be worked out.

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B. Regional and post mastectomy radiotherapy Introduction The discussion of regional radiotherapy applies to as well patients treated with BCT as after mastectomy. Because of the fact that thoracic wall irradiation in itself was never studied thoroughly, it cannot be separated clearly from post-mastectomy radiotherapy as a whole. Therefore it is included in this chapter as well. The importance of regional lymph node involvement as a determinant of the prognosis of breast cancer patients is well known. The risk for lymph node invasion depends on a number of prognostic factors including tumour diameter, grade and the location within the breast. The risk of axillary lymph node invasion varies between 5% for T1G1 tumours up to more than 50% for T3 tumours [116]. Supraclavicular lymph node invasion increases with the number of involved axillary lymph nodes, to more than 15% for patients with tumour stage N2a. For the internal mammary lymph node area, the risk of invasion varies between 3% for early stage tumours located upper outer in the breast up to 65% for lower inner located tumours with axillary lymph node involvement [156]. Most of the lymph node involvement is limited to microscopical tumour deposits with clinically enlarged lymph nodes being often a sign of locally advanced breast cancer. The treatment of the regional lymph nodes has been a matter of debate for many years already [13,18,32,34,53, 61,96,97,103,113,122,130,138,166]. On one hand, lymph node invasion could be considered merely as a prognostic factor with axillary surgery serving only for diagnostic purposes but on the other hand regional treatment might not only have an influence on the quality of life by reducing the locoregional relapse rate but as well have a positive influence on long-term survival. The recent update of the meta-analysis, performed by the EBCTCG, of the randomised clinical trials that investigated the influence of local treatments for localised breast cancer on local recurrence and survival clearly demonstrated that radiotherapy produces a similar proportional reduction of about 70% in the rate of locoregional recurrences in all patients, irrespective of age, tumour characteristics or the administration of systemic therapy [39]. Therefore, the absolute improvement in local control depends mainly on the baseline risk, with the highest gain for patients with a high risk for developing a local recurrence. Based on this, most consensus reports and guidelines recommend regional and post-mastectomy radiotherapy (PMRT) for patients with 4 or more invaded axillary lymph nodes, T3 and T4 tumour stage and invasion of the pectoral muscle or the surgical margins. About 3/4 of the locoregional recurrences occur within 5 years after the initial treatment. This meta-analysis also demonstrated that one breast cancer death during the 15 years after randomisation will be avoided for every four local recurrences at 5 years that are prevented. Therefore, a gain in local control obtained with postoperative radiotherapy of 20% at 5 years will result in an improvement in overall survival at 15 years of 5%. However, this meta-analysis also showed

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that there was, at least with some of the older radiotherapy regimens, a significant excess incidence of contralateral breast cancer and a significant increase in non-breast-cancer mortality in irradiated women. The excess mortality was mainly from heart disease and lung cancer. This late toxicity did not yet completely fade out even 15 years after randomisation. Therefore, the long-term net effect of radiotherapy will be strongly influenced by the individual risk factors of the patient and by the quality of the radiotherapy by limiting the irradiation of the organs in the vicinity of the breast and of the regional lymphatic areas. The role of post-mastectomy and of regional radiotherapy for patients with early stage breast cancer (T1–T2, N0–N1a, M0) is less clearly defined. Theoretically, exactly those patients might benefit most from eradicating locoregional disease on long-term survival because of their anticipated lower probability of spread beyond the regional lymph nodes [72,159]. The cut-off point of 4 involved axillary lymph nodes is thoroughly challenged by a recent paper from Overgaard et al. [98,105]. Based on the wellknown DBCG (Danish Breast Cancer Cooperative Group) trials [96,97], they demonstrate that the number of involved nodes should not be used as a threshold to advice PMRT. This adds to the growing level of evidence that PMRT should be offered to all patients with involved axillary lymph nodes. In fact, already the 2000 update, published in 2005, of the EBCTCG meta-analysis showed a similar effect of radiotherapy on local recurrence rate and survival in favour of PMRT irrespective of the number of involved lymph nodes [39]. Moreover, this result became even more pronounced and significant in the 2005 update, not yet published. Therefore, sufficient evidence seems to be available for a new shift towards more aggressive locoregional treatment in breast cancer and to adapt the treatment guidelines accordingly. Further evidence will be obtained from several well-designed large prospective randomised clinical trials, like EORTC 22922/10925, NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) MA20 and SFRO (Socie ¸´te ´ Franc aise de Radiothe ´rapie Oncologique) CMI, that examined the thin line between advantages and side effects of post-mastectomy and of regional radiotherapy for early breast cancer patients. This will allow us to fine-tune the indications and target volumes for locoregional radiotherapy for patients with early stage breast cancer after mastectomy as well as for regional radiotherapy in the framework of BCT for the patients of today who are treated with improved surgical techniques, more efficient systemic treatments and highly sophisticated radiotherapy. However, a large number of patients and a long follow up (at least 10 years) will be needed to definitely resolve these current clinical questions [83,119,146]. Notwithstanding this, there exist still sufficient arguments to sustain the conduct of current trails like intergroup SUPREMO (Selective Use of Postoperative Radiotherapy after Mastectomy) that randomises patients with 1–3 involved lymph nodes, and pT2pN0 tumours with grade 3 tumours and/or lymphovascular invasion between chest wall irradiation and follow up, irrespective of regional radiotherapy. Until these results become available, patients with 1–3

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involved axillary lymph nodes should be offered PMRT, at least to the chest wall and the supraclavicular lymph node area. Similarly, pN1a patients should be offered at least supraclavicular irradiation also in the framework of BCT. Recent work on novel prognostic indicators, including micro-array analysis of the tumour genes and proteomics, opens new pathways to be explored that will probably lead to a completely new way of determining the individual patients’ prognosis and thereby aid in the judgement of the balance between benefits and side effects of as well locoregional as systemic treatments [23,149,153,154].

Axillary lymph node irradiation Du et al. demonstrated, based on the SEER (Surveillance, Epidemiology and End Results) database, that breast cancer related mortality was increased by a factor of 1.76 if the axilla was not treated at all. They also showed that the results of surgery alone, radiotherapy alone or both combined were identical [36]. Strom et al. confirmed that the risk of a local relapse in the low-mid axilla after surgery alone is only 3% actuarial at 10 years, independent from the extent of the axillary involvement [139]. Postoperative axillary radiotherapy more than doubles the risk for arm oedema and other symptoms related to axillary fibrosis [81]. Generally accepted indications for axillary radiotherapy are invasion of the sentinel node without further axillary surgery; those cases where the surgeon states that axillary clearance was not complete; axillary surgery not performed according to the basic oncological principles and in the case of consolidating radiotherapy after primary systemic treatment for locally advanced breast cancer where no surgery is performed. Currently, most of the patients will undergo a sentinel node procedure. In the case of invasion of this node, a complete axillary clearance will generally follow although some prefer radiotherapy. A prospective randomised EORTC trial, AMAROS (Adjuvant Management of the Axilla, Radiotherapy of Surgery), is ongoing to examine the best approach for patients with sentinel node invasion [69]. The results of this trial will be available only in a couple of years and until then, surgical axillary clearance remains the standard approach for patients with invasion of the sentinel node.

Supraclavicular lymph node irradiation The risk of microscopical invasion of the supraclavicular lymph nodes is highly influenced by the number of involved axillary nodes. With 4 or more nodes invaded and especially when level 3 of the axilla is invaded, the risk exceeds 15–20% [139]. Side effects of supraclavicular radiotherapy can be expected at the level of the lungs (the upper part lying behind the supraclavicular lymph node area, even more with the use of a table wedge) but also at the level of the blood vessels and nerves at the base of the neck. With appropriate techniques and a daily dose limited to 2 Gy, the risk for side effects remains low for doses up to 50 Gy. The supraclavicular lymph node area is often considered as being part of one lymph node area together with the

internal mammary lymph node chain. The value of elective radiotherapy of this combined lymph node area was examined in EORTC trial 22922/10925 that completed its accrual in January 2004 but of which we will only have the results after 2010 [146].

Internal mammary lymph node irradiation Invasion of the internal mammary chain (IMC) varies between 3% and 65%, depending on the tumour stage and the position of the primary tumour in the breast [44,51]. A clinically apparent invasion of these nodes is, however, only 2%. An old trial that compared radical mastectomy with extended radical mastectomy including the resection of the IMC nodes demonstrated that the more extended approach did not improve the outcome of the patients but led to a higher level of toxicity [156]. As for the role of radiotherapy, no trial included enough patients and has sufficient follow up to evaluate definitively the value of IMC irradiation. Kaija and Mauna published in 1995 a small trial including 270 patients treated with breastconserving therapy with a follow up of only 2.7 years. Toxicity was comparable in both treatment arms [75]. Romestaing et al. presented but did not yet definitively analyse and publish the result of a French trial randomising 1281 patients after mastectomy. After a follow up of 5.4 years, no difference between both treatment arms was seen, including for toxicity [119]. Stemmer et al. evaluated 100 high risk patients participating in a prospective phase II trial evaluating high dose chemotherapy. Due to the temporarily unavailability of electrons, the IMC was not treated during part of the trial. With a follow up of 6.4 years, the disease free survival and overall survival were found to be significantly better for those patients who received IMC radiotherapy [137].

Thoracic wall irradiation The thoracic wall is nearly always included in the combination of target volumes in the case of PMRT. Whereas in BCT an extensive intraductal component is related to the risk for local recurrence, this is not the case after mastectomy. However, shared risk factors include lymphovascular invasion and high tumour grade [158]. Generally accepted indications for radiotherapy of exclusively the thoracic wall are tumoural invasion of the surgical margins and invasion of the pectoral muscle. A less commonly known and accepted indication is the case of invasive lobular carcinoma after mastectomy, independent of the tumour stage. The combined analysis of the EORTC 10801 and DBCG 82TM trials demonstrated that, for this patient category, the local recurrence rate after mastectomy without radiotherapy was 18% at 10 years, compared to only 10% for patients who were treated with a breast-conserving approach [150,158]. The skin itself is not a part of the target volume, with the exception of the case of locally advanced breast cancer, especially when skin infiltration was present (tumour stage T4b–T4d).

P. Poortmans / Radiotherapy and Oncology 84 (2007) 84–101

Table 1 Risk categories for locoregional relapses after mastectomy and axillary clearance Risk category

Low

Intermediate

High

Risk Tumour stage Number of Ax LN+ Grade Vascular invasion Histology

<10% T1–2 0 1–2

10–20% T1–2 1–3 3 + Lobular

>20% T3–4 >3

Ductal

Ax LN+: involved axillary lymph nodes.

Summary In Table 1, a division in three risk categories for locoregional relapse after mastectomy and axillary clearance is shown. Based on this, Table 2 is a proposed summary of the indications for radiotherapy for the different target volumes.

Conclusion In breast cancer, radiotherapy reduces the locoregional relapse rate by 70%. The indication for postoperative radiotherapy and the definition of the target volumes depend highly on the prognostic factors and the surgical procedure. For high risk patients, as well as for intermediate risk patients, radiotherapy will increase long-term survival, on the condition that appropriate radiotherapy techniques are being used. The most important is that the best results will be obtained at all levels, including local control, quality of life, cosmetic results and survival with a multidisciplinary approach that is highly patient oriented. Key points (with level of evidence if applicable): Attaining maximal initial locoregional tumour control is necessary to achieve the highest possible ultimate survival rate. . . but above all, do not harm the patient! • Radiotherapy reduces the in-field recurrences by 70% (1a). • For every 4 locoregional recurrences prevented at 5 years, 1 life at 15 years will be saved (1a). • PMRT and regional RT is a generally accepted standard from tumour stage pT3 and/or pN2a on (1a). • There are enough data available to advise this also to patients from pN1a stage on (1a). • The indications for PMRT and regional RT are independent from the amount of surgery and the administration of adjuvant systemic treatments (1a). • The target volumes are under discussion, but quite some arguments exist for comprehensive locoregional RT. • There exists, after proper surgery, no indication for irradiation of the axilla (2a). Unresolved questions and controversies: • The role of thoracic wall irradiation in intermediate risk patients is under investigation by the SUPREMOtrial. • The role of radiotherapy of the internal mammary lymph nodes will be revealed after 2010 by the results from several prospective trials.

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Table 2 Indication for irradiation of the different target volumes after mastectomy and axillary clearance as well as for regional RT in the framework of BCT Risk category

Low

Intermediate

High

Thoracic wall Supraclavicular Internal mammary Axilla

No? No? No No

Yes? Yes? Yes? No

Yes Yes Yes? No

Yes: evidence and generally accepted; Yes?: evidence but not generally accepted; No?: limited evidence, however advocated by some authors; No: no evidence.

C. Ductal carcinoma in situ Introduction The incidence of ductal carcinoma in situ (DCIS) of the breast has increased considerably after the introduction of population based mammography screening [42]. If left untreated after biopsy, up to over 70% of patients with DCIS, irrespective of grade, will develop recurrent DCIS or invasive cancer at long-term follow up [124]. The goal of local treatment is primarily the prevention of local failures and in particular progression to invasive breast cancer. Death related to DCIS is rare, regardless of whether mastectomy or BCT is performed, but prevention of invasive cancer with its possible ultimate adverse effect on survival is particularly important [43]. Many patients, especially in the era of mass screening, present with small and often not palpable lesions which are amenable to a breast-conserving approach similar to invasive breast cancer.

Treatment Three major randomised trials evaluated the role of radiotherapy after lumpectomy for DCIS, in one of them combined with an evaluation of the possible role of tamoxifen. In a fourth trial, tamoxifen was evaluated after lumpectomy and radiotherapy (Table 3). In the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-17 trial, the overall local recurrence rate for patients treated with excision alone was 31.7% in contrast to 15.7% for patients with additional radiotherapy at 10.7 years of follow up. Initially, the reduction was more marked for invasive recurrences but at longer follow up this differential effect diminished. The presence of comedonecrosis and to a lesser extent of close/involved resection margins were independent negative prognostic markers [47,49]. In the EORTC 10853 trial, at 10.5 years of follow up, 26% of patients with excision only versus 15% of patients with additional radiotherapy experienced local failure. The relative reduction was similar for invasive and in situ recurrences. Young age, symptomatic detection of the lesion, cibriform or solid growth pattern and close/involved margins were all independent risk factors for local recurrence. The effect of radiotherapy was similar in all patient subgroups [15]. In the UKCCCR (UK Coordinating Committee on Cancer Research) DCIS trial, the addition of breast radiotherapy after wide local excision leads to a significant reduction of the local recurrence rate

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Table 3 Summary of the 4 major trials in BCT for DCIS Trial

Treatment

n

FU years

Positive margins

LR-DCIS

LR-invasive

EORTC 10853 [15]

– RT

1010

10.5

0 22

14 7

13 8

NSABPB-17 [47,49]

– RT

818

10.7

0 17

14.6 8.0

16.8 7.7

NSABP B-24 [48,49]

RT RT+TAM

1804

6.8

25 n.r.

5.8 5.0

5.3 2.6

UKCCCR DCIS [65]

No RT RT No TAM TAM

1701

4.4

0 n.r.

7 3 9 6

6 3 4 5

All patients underwent a lumpectomy; RT, postoperative radiotherapy; TAM, adjuvant tamoxifen; n, numbers of patients; FU, duration of follow-up in months; positive margins: includes close and uncertain margins, upper number is as randomised, lower number is result of central review, n.r., not reported; LR, ipsilateral breast relapse.

for patients receiving radiotherapy (14% without vs 6% with radiotherapy) at 53 months of follow up, with a similar relative reduction for invasive and in situ recurrences. Tamoxifen reduced the local recurrence rate of DCIS but had no effect on the occurrence of invasive breast relapses. No interaction between radiotherapy and tamoxifen was seen [65]. The findings of the analysis of the NSABP B-24 trial showed through 6.8 years of follow up that tamoxifen reduced the overall risk for all breast cancer events, particularly in invasive breast cancer [48,49]. Overall, the risk of recurrence in the ipsilateral breast was reduced by about 50% in the radiotherapy arms in all three trials. The effect varied somewhat for the relative reduction in invasive and in situ cancer, respectively, between the trials. The general interpretation of the results of the different trials is, however, hampered by the differences in the proportion of patients with involved resection margins and of the method of detection and by the different methods for calculating time of follow up. The value of tamoxifen could not unequivocally be demonstrated [48,65]. Also in other studies, risk factors for local recurrence after BCT were identified, similar to BCT for patients with invasive breast cancer: in particular young age and margin status but also other risk factors such as tumour grade, the presence of comedonecrosis and the presence of a clinically detectable lump [15,16,29,133,157]. Overall, no subgroup could be defined that did not show a clear benefit from radiotherapy after lumpectomy [15]. The radiotherapy dose used in the randomised studies was 50 Gy to the whole breast. Most recurrences of DCIS or invasive cancer occur at the primary site. Whether patients with DCIS, especially young patients, will benefit from boost irradiation similar to the BCT for invasive breast cancer, was the subject of a retrospective study of the Rare Cancer Network. Data on a total of 373 patients below the age of 45 at diagnosis and treated with a lumpectomy for DCIS were collected and evaluated. After a median follow up of 72 months 15% developed a local failure, consisting in about half of them of invasive breast cancer. The 10-year local relapse-free survival was 46% in the no-radiotherapy group, 72% in the whole breast irradiation only group, and 86% in the radiotherapy

with a boost group (p < 0.0001). In the multivariable analysis, age, margin status and radiotherapy were significant predictors for local relapse-free survival. The authors conclude that, especially for young patients, whole breast irradiation followed by a boost should be advised for BCT for DCIS [94]. However, to properly assess the value of an additional boost dose following breast-conserving surgery and postoperative radiotherapy, a rigorous quality assurance programme needs to be applied to all aspects of treatment, including the surgical, radiotherapeutic, radiological and pathological details. This is to ensure that differences in recurrence of DCIS and development of invasive cancer are not due to inadequate surgery, radiotherapy or radiological/pathological assessment.

Summary Many similarities exist between invasive and in situ breast cancer as far as it concerns local tumour behaviour after treatment. The local recurrence rate is, similar to invasive breast cancer, too high after lumpectomy alone. After lumpectomy, radiotherapy halves the risk for local recurrence to about 1% a year (in half of them DCIS and in the other half invasive cancer) with a disease specific survival identical to mastectomy at nearly 100%. Age and margins are the most significant prognostic factors for local recurrence. Therefore, we should aim with our treatment at tumour-free resection margins and in the case of very extensive DCIS, a mastectomy should be considered. Especially in younger patients, the administration of a boost to the primary tumour bed could be advised based on the probable dose–effect relation and similar to invasive breast cancer. About half of the local recurrences are invasive breast cancer. Nevertheless, overall survival up to 15 years of follow up will not be significantly influenced by the treatment offered to the patients. Also because of the extremely low risk for metastases and death due to DCIS, the role of adjuvant hormonal treatment is not yet well defined for patients treated with BCT for DCIS. For all of these reasons, effective local treatment to minimise the risk for developing a local recurrence should be prescribed.

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Key points (with level of evidence if applicable): Many parallels do seem to exist between DCIS and invasive breast cancer. • DCIS is a local disease and should primarily be treated with local approaches only. • BCT offers an acceptable local control rate for many patients with DCIS (1b). • After lumpectomy, postoperative radiotherapy is always required (1b). • No influence on survival from the treatment can be detected (1b). • Their exists a probable dose–effect relationship (4). • As young age is an independent risk factor for local relapses, especially younger patients might benefit from a boost dose (4). • As margins are an important prognostic factor for local control, a microscopically complete lumpectomy should be aimed at (1b). Unresolved questions and controversies: • Patient subgroups, with a low risk for a local relapse with surgery alone or with a lower dose/smaller volume of radiotherapy, still need to be properly defined. • The role of adjuvant systemic treatment, if any, needs to be evaluated.

D. Sequence of radiotherapy and adjuvant systemic treatment Introduction Results of the Early Breast Cancer Trialists’ Collaborative Group meta-analysis have shown clearly that adjuvant chemotherapy improves breast cancer specific survival (and overall survival) in early breast cancer patients [38]. Recently, the results of three studies demonstrated that distant metastases free survival significantly improved in patients with HER2-neu positive breast cancers when trastuzumab was added to chemotherapy [101,120]. However, these trials simultaneously showed that the risk for cardiac toxicity was significantly increased in patients treated with trastuzumab. The importance of obtaining locoregional control with appropriate surgery and radiotherapy on long-term survival has been demonstrated clearly [39,116,140]. From all this it is concluded that after lumpectomy whole breast irradiation (with or without a boost) is indicated. Patients bearing a high risk of locoregional recurrent disease (after lumpectomy or ablative surgery) are to be treated with irradiation to the breast or chest wall and to the regional lymph node areas. Late treatment-related morbidity of PMRT and CMF chemotherapy versus CMF chemotherapy alone appears not to differ significantly in the Danish studies [61]. These findings, that more recent radiotherapy techniques have a less pronounced effect on late toxicity, were confirmed by Giordano et al. in a large study comprising 27,283 irradiated breast cancer patients [54]. They calculated that with each succeeding year after 1979, the hazard of death from ischemic heart disease for women with left-sided versus those with right-sided disease declined by 6% and ultimately disappeared.

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From the above we can conclude that both radiotherapy and chemotherapy contribute to an increased overall survival rate. However, the sequencing of both treatment modalities remains a matter of debate, with differing treatment policies between various countries and even within each country between various centres.

Timing of radiotherapy Postponement of radiotherapy leads to an increased incidence of locoregional recurrences, as was observed in a systematic review [66]. The authors noted that the 5-year local recurrence rate was significantly higher in patients treated with adjuvant radiotherapy more than 8 weeks after surgery, compared with those who started treatment within 8 weeks of surgery (OR 1.6). They noted also that radiotherapy given after completion of adjuvant chemotherapy resulted in a higher local recurrence rate compared to patients who received early onset radiotherapy (OR 2.3). In a comprehensive review dealing with prospective and retrospective studies in BCT it appeared that early initiation of radiotherapy might be of benefit to patients with positive, close or unknown microscopic margins, whereas those with wider tumour free margin widths did not benefit clearly [114]. In a single large (n = 7800) retrospective study it was suggested that delaying the initiation of RT for 20–26 weeks after surgery is associated with a decreased survival after BCT [88].

Timing of chemotherapy In a theoretical analysis of the integration of chemotherapy, radiation therapy and surgery, it was suggested that patients with a larger systemic tumour burden would have a more favourable outcome when chemotherapy preceded radiotherapy [9]. Postponement by more than 20 days of chemotherapy in oestrogen-receptor negative patients carries the risk of an increased incidence of distant metastases according to Colleoni et al. (Hazard Ratio 0.49) [27]. In another study however, Shannon et al. observed no significant difference [131]. Only one small randomised trial in BCT has been published where radiotherapy followed by chemotherapy was compared to chemotherapy followed by radiotherapy. Initially it appeared that CTRT led to more local recurrences, whereas RTCT led to more distant metastases, but at longer follow up, this difference disappeared completely [11,115]. Moreover, this trial never showed any survival benefit for either sequence. At the first analysis, the difference in distant and regional failures (as first event) between the treatment arms existed only in the subset of patients with >3 axillary lymph node metastases and not for patients with 1–3 positive nodes [114]. This observation was also made in a non-randomised study for patients with early stage disease with either 1–3 or >3 positive nodes [22]. In an editorial accompanying a report of a retrospective study on the timing of radiotherapy in the prospective randomised trial CALGB 9344 that evaluated three dose levels of anthracyclines and the addition of paclitaxel, Bellon and Harris concluded that with the available evidence radiotherapy should be given after completion of all chemotherapy [12,126]. However, they confirmed, based on their previous experience, that one should remain cautious in the subset of patients with close surgical margins. They postulated that

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not only more effective systemic therapy might better eliminate systemic micrometastases, but that it might also be more successful at decreasing the local tumour burden, up to now not (yet) to a level that might obviate the need for radiotherapy. They suggest that the risk of locoregional relapses, both with and without radiotherapy, will need to be re-examined as systemic therapy becomes more effective. At the same time, they state that it could even be possible that more effective systemic therapy might even further increase the utility of postmastectomy radiotherapy. These and other findings suggest that effective systemic therapies might be more successful in treating systemic involvement than in eradicating locoregional disease. Possible explanations for this include among others a more important locoregional microscopic disease burden than elsewhere in the body, a diminished blood flow and a relative hypoxia in the postoperative region.

Combined radiotherapy and chemotherapy As the effectiveness of radiotherapy and chemotherapy for eradicating all clonogenic cancer cells diminishes with an increasing tumoural burden, ideally both treatment modalities should start as soon as possible. Theoretically, the best way to achieve this goal is to administer adjuvant radiotherapy and chemotherapy concurrently. Quite a lot of concerns are opposing this approach. First of all, more acute toxicity can be anticipated from simultaneous administration of radiotherapy and chemotherapy [45,114]. Severe chemotherapy-related acute side-effects might even lead to an interruption of the radiotherapy course, which is highly unwarranted [55,71,86]. A decreased cosmetic outcome after BCT has been reported in a number of studies [1,5,33,37,80,141]. Finally, based on preclinical studies, more (late) cardiac toxicity might be anticipated after concurrent administration of irradiation and anthracyclines [30]. This observation was confirmed in a clinical study comprising patients with left sided breast cancer and radiotherapy. A 4-fold increased risk of cardiac events after anthracyclin containing chemotherapy (>450 mg/m2) regimens was observed. Of note, cardiac events occurred as long as 10 years after treatment [31,132]. Conflicting data on the combined toxicity of adjuvant systemic treatment including docetaxel and trastuzumab with radiotherapy administered together are reported, possibly due to a lack of long term follow up but maybe also due to the influence of the age at treatment with a reported high risk of toxicity encountered in childhood cancer [56,142].

fied a gap in our knowledge regarding the modern treatment of breast cancer and that this important question should be answered with the most rigorous design possible [167]. Specifically concerning the sequencing of chemotherapy and tamoxifen, it was noted that tamoxifen should start after the completion of chemotherapy [3].

Summary Whereas most systemic treatments have been shown to result in a decreased locoregional relapse rate, the absolute risk remains too high to obviate the need for optimal locoregional treatments. The reported results on dose-dense regimens and the use of newer systemic agents do not add substantially to the risk reduction above that achieved with standard chemotherapy. If radiotherapy and chemotherapy are not to be given concurrently, they have to be administered sequentially. The question which modality should be given first, radiotherapy or chemotherapy, remains unanswered. Several attempts to address this in a properly designed randomised clinical trial failed. With the evidence that is available up to now, adjuvant hormonal treatment should start after completion of chemotherapy whereas no firm recommendations on its sequence with radiotherapy can be given. Key points (with level of evidence if applicable): The best results for all clinical endpoints can be obtained by an optimal combination of surgery, systemic treatment and radiotherapy. This might be considered as a plea for dedicated breast clinics. • Adjuvant systemic treatment has a positive effect on survival (1a). • The influence of adjuvant systemic treatment on locoregional control is existing but not large enough to obviate the use of radiotherapy (1a). • Both adjuvant systemic treatment as radiotherapy should be started as soon as possible after surgery (2a). • Combined chemotherapy and radiotherapy leads to a higher risk of especially late toxicity: the sequential administration is therefore preferred (2b). • The sequence can be discussed on a patient per patient base depending on the type (especially the duration) of treatment and the individual patients’ risk factors. Unresolved questions and controversies: • The most appropriate sequence of radiotherapy, chemotherapy and hormonal treatment might very well remain to stay unknown. . .

Timing of hormonal treatment In some but not all in vitro studies, breast cancer cell lines incubated in TAM were shown to have a lower radiosensitivity [128,165]. Several authors reported an increased toxicity at the level of cosmetic outcome, pulmonary fibrosis or subcutaneous fibrosis if tamoxifen was administered concomitantly with radiotherapy [6,14,164]. Despite these concerns, based on a number of small (147–234 patients) studies, the data of three retrospective studies suggest that giving tamoxifen concurrently with radiation therapy does not impair treatment results [2,58,102]. Whelan and Levine stated however, in the accompanying editorial, that those studies have identi-

E. Technical aspects and quality assurance Breast-conserving therapy The most used technique for the irradiation of the whole breast is by 2 tangential photon fields. Due to the change in the shape and the volume of the breast in all directions, this often results in a rather inhomogeneous dose distribution. With the use of a wedge filter, dose homogeneity can be

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improved in a 2D level of planning but this does not improve the inhomogeneity caused by the presence of the lung underlying the breast or in craniocaudal direction. For this, 3D planning based on a CT-scan of the breast is necessary. In this respect, Donovan et al. conducted a prospective trial to investigate the influence of optimisation of dose homogeneity on late adverse effects after BCT [35]. Patients were randomised between standard 2D and 3D IMRT radiotherapy. With the latter technique, based on either physical compensators or step-and-shoot MLC segmented fields, they minimised dose inhomogeneity in the breast significantly with a sharp decrease in the percentage of the breast volume receiving >105% of the prescribed dose. Of great importance is that they were able to associate this to the change in breast appearance during follow up as scored by photographic and by clinical assessment. Up to now, this did not influence the patients’ self-assessment. The fact however that a relatively small variation in dose homogeneity influences the cosmetic outcome indicates that we are very close to the edge of the occurrence of side effects. These results confirm the sensitivity of late normal tissue effects to fraction size, in agreement with a fairly low a/b value of 3–4, as was derived form an earlier trial conducted in the UK where 3 different fractionation schedules for whole breast irradiation were compared [169]. This should especially be taken into account in the design of schedules using hypofractionation, which have been introduced in some departments to reduce the burden of the treatment to as well the patients as, especially, the busy radiotherapy departments, the latter highly depending on the countries’ organisation of health care. Because of the supposed smaller therapeutic window between side effects and tumour control with larger fraction sizes, the importance of an optimal dose delivery might even be more critical than with conventional dose fractionation. The conclusion of the authors that 3D dose planning should be routinely implemented in this group of patients can therefore be called justified. In the EORTC 22881/10882 trial, we also investigated the potential impact of the different boost techniques on local control and on fibrosis after breast-conserving therapy. A total of 2661 patients was randomised to receive a boost dose of 16 Gy. The choice of the boost technique was left to the treating investigator. Sixty-three percent of the patients received a boost dose with fast electrons, 28% with photon beams and 9% with interstitial brachytherapy. At 5 years, local recurrences were seen in 74 of the 1635 patients who received an electron boost (4,8%), in 28 of the 753 patients who received a photon boost (4.0%) and in 6 of the 225 patients after an interstitial boost (2.5%). The grade of fibrosis in the whole breast as well as at the primary tumour bed, as scored by the treating radiation oncologist, was similar in the three groups. The median boosted volume was smallest with the interstitial technique (60 cc), more than twice as large with an electron boost (144 cc) and nearly 5 times as large with photons (288 cc). The overall treatment time was considerably longer in the group of patients treated with brachytherapy (54 versus 48 days): whereas the external boost started for most patients without any delay following whole breast irradiation, a median delay of 18 days was noted between the end of external beam irradiation and the administration of the interstitial boost. In conclusion, no significant differences could be found between the three boost techniques [107].

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Accelerated partial breast irradiation (APBI) should, for the time being, still be considered as an investigational approach to post-lumpectomy radiation for early breast cancer. Clear advantages of this treatment modality are the highly reduced overall duration of the treatment and the smaller treated volume. The mean concerns however include the possible higher recurrence risk, the increased risk of local fibrosis due to the focally intensified treatment schedule, the lack of pathological criteria that are available at time of treatment and the limited possibility for individual dosimetry, which is depending on the technique that is used. Several applicable treatment techniques are currently available, including the interstitial implant brachytherapy, devices that are positioned in the lumpectomy cavity like the intrabeam device by Zeiss and the MammoSite applicator, intra-operative RT and external beam partial breast irradiation generally using 3D conformal or IMRT [85,95]. Respiratory movements are only a concern for the latter technique [93]. The oncological community should remain cautious to resist to the pressure that is sometimes posed upon them by as well patients driven by desires for a short-course treatment as by commercial companies. Only after the results of the ongoing prospective phase 3 trials (GEC-ESTRO, NSABP B39-RTOG 0413, IRMA and several others) become available for analysis, we will be able to evaluate its proper value based on solid evidence and be able to select the patient group that can possibly benefit from this appealing treatment modality. In the meantime, we should offer this treatment modality only in the framework of clinical trials, no matter how heavy current debates might be [10,91,92].

Regional and post mastectomy radiotherapy General Thanks to the anatomical information obtained with a planning-CT-scan, the treatment plan for every individual patient can be highly adapted [41]. Ideally, a radiotherapy department should have several radiotherapy techniques for every set of target volumes so that the most optimal can be chosen based on the anatomical data and the resulting dose distribution. A problem is that most radiotherapy departments do not routinely delineate the target volumes, which is essential to obtain a high level of individualisation and for comparing different treatment plans [110]. For as well the breast as the thoracic wall and for the boost volume of the primary tumour bed, neither the target volume definition nor the appropriate imaging modalities are standardised. In contrast with this, the lymphatic nodal areas are reasonably well defined. The improvement of the (semi-) automatic treatment delivery facilities of the modern linear accelerators allows delivery of multiple segmented fields using the MLC collimator in a reliable and very fast way.

Thoracic wall Most radiotherapy departments have a set-up protocol for thoracic wall irradiation, most often with 2 tangential fields. About 1/4 of the radiotherapy departments use one or more electron fields with an energy adapted to the individual patients’ anatomy [82,111,112]. While many still use

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conventional simulation and treatment planning, the use of CT based planning and virtual simulation is increasing rapidly. This allows adapting the treatment fields 3-dimensionally to the individual patient in order to optimise the coverage of the target volume and to limit the dose to the heart and the lungs. As current electron beams have a less pronounced effect on the skin, patients with a very curved thoracic wall can be offered a skin-sparing treatment with for example a 5-field electron technique which delivers a homogeneous dose to the thoracic wall with much less burden to the underlying lungs and heart than with tangential photon fields.

Supraclavicular lymph node area The supraclavicular irradiation field matches the thoracic wall fields and sometimes also the axillary and/or the internal mammary fields. To obtain a homogeneous dose distribution, an appropriate solution is to position the isocentre at or close to the junction between the supraclavicular and the thoracic wall fields and using asymmetric fields, whenever appropriate tailored with the MLC. This also facilitates the use of (semi)automated set-up at the treatment machine. To limit the dose at the spinal cord, oesophagus and trachea the gantry can be angled 10–15. Especially when the internal mammary chain is irradiated with electrons, it is important to avoid zones of over- or underdose at the junction with the supraclavicular field. As can be done for the thoracic wall when it is irradiated with electrons, the dose homogeneity can be improved by varying on alternate days the position of the junction between the different fields over 1–2 cm, which can be done easily when the isocentre of the photon fields is situated in that region.

Axillary lymph node area For axillary irradiation, to obtain a homogeneous dose distribution, a small posterior field is often added to the wide anterior field that also includes the supraclavicular lymph node area. To avoid overdosing the anterior part of the axilla, several technical solutions have been proposed like a fixed isocentre between the supraclavicular and axillary regions allowing for a homogeneous dose distribution by using the asymmetric collimation and MLC tools of the linear accelerator.

Internal mammary lymph node area The Quality Assurance programme of EORTC trial 22922/ 10925 demonstrated that several appropriate techniques are being used for irradiating the IMC [82,111,112]. Most radiotherapy departments use the so-called standard technique with a combined supraclavicular and IMC photon field joined to the radiotherapy fields for the breast and/or the thoracic wall. Part of the IMC dose is delivered with electrons. The inconvenience of this technique is the under- or overdose at the level of the junction of the different fields, which is influenced by the use of an overlap or not between the fields and by the individual anatomy of the patient. Several departments therefore developed modifications to improve the dose homogeneity. Important hereby is that this should be adapted to the individual patients’ anatomy and notably to the thickness of the thoracic wall and to the position of the primary tumour within the breast. About one-quarter of the departments that participated in the EORTC trial developed a highly individualised CT based treatment technique [82]. The dose homogeneity is improved when compared to the standard treatment technique,

however at the cost of a somewhat larger amount of lung tissue. After two years of FU, side effects are nearly equal for all patients, whether or not irradiated on the IMC and independent of the treatment technique [59].

Prevention of late side effects While old trials demonstrated an increase in long-term non-breast cancer related deaths due to cardiovascular and/or pulmonary problems, more recent trials did not confirm this [61,63]. The risk of late cardiac morbidity and mortality is also related to the anatomic sites of radiotherapy for breast cancer, with left sided breast cancer, the use of an anterior field to treat the internal mammary lymph nodes and an increasing area of an anterior left breast boost field as risk factors [99]. To avoid irradiating normal tissues while at the same time covering appropriately the target volumes, 3D conformal radiotherapy is currently being introduced by many departments. On top of this, IMRT (Intensity Modulated Radiotherapy) and IGRT (Image Guided Radiotherapy) solutions are being investigated to tailor the high dose region to the target volumes, while limiting the dose to the normal tissues in their neighbourhood [68]. This can also be obtained with the use of the deep breath hold technique [76,77]. Especially for patients with a specific anatomy that makes it difficult to limit the dose to lungs and heart, gated radiotherapy might offer solutions in the near future. Moreover, as we are faced with an increasing frequency of patients with larger breasts, often due to a high BMI, we need to be able to offer our patients a treatment technique that is adapted to the individual patients’ anatomy. For patients with pendulous breasts, the prone position with an adaptation to the treatment table might offer an excellent solution [21]. Several of those techniques can be used at the same time for dose intensity modulation like in the simultaneous integrated boost that has recently been introduced into the clinic to improve treatment delivery in the case of a photon boost [70,145]. While implementing those new techniques, we have to keep in mind that the amount of normal tissue which is irradiated to a low dose (especially the contralateral breast in young patients) should not be increased to a level that will lead to a rise in the secondary cancer risk at long term [19,24,26,50, 87,143]. Based on an evaluation of the dose distribution to the contralateral breast for locoregional radiotherapy to the thoracic wall and the supraclavicular and axillary lymph node areas, Johansen et al. advised to evaluate field arrangements also in view of the dose to the contralateral breast [73]. Forward-planned IMRT techniques and techniques that mix step-and-shoot IMRT with open fields have been proposed as a class solution by several authors, on one hand because of the time constraints and simplicity, but on the other hand because the much lower dose outside of the treatment volume than with ‘‘conventional’’ inverse IMRT techniques. For the sake of individualisation of the treatment set-up however, we should routinely delineate as well the target volumes as the organs at risk to allow a conformal delivery of the treatment with maximal shielding of especially heart and lungs. Apart from technical improvements, irradiated breast cancer patients should also be monitored for other risk factors like cardiac diseases and secondary cancers including smoking [64].

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Quality assurance The EORTC 10801 trial, run in the 1980s and comparing mastectomy with BCT, demonstrated that major differences in local control were observed between the treating institutes that could not be explained by patient selection [150]. Therefore, and based on other experiences, an intensive quality assurance (QA) programme was set-up in the framework of the EORTC 22881/10882 trial to ensure that the treatment was delivered in a standard fashion in all centres. This consisted of a dummy run procedure to check dose prescriptions and dose calculations and of on-site visits [7,57,60,106,152]. At the time of the analysis, no significant variation in local control rate existed between the participating centres. The paramount importance of performing comprehensive QA, adapted to each trial, has been confirmed in several other EORTC trials as well [78,109]. Also in daily practice, proper preparation and execution of treatment are very important and proper QA measures should be put into place routinely. Among these, portal image verification of treatment set-up should be considered as a minimum. Newer measures, such as the use of magnetic sensors to facilitate the implementation and use of the (moderately) deep breath hold technique in combination with dynamic MLC compensation deserve, attention [117].

Conclusion With the introduction of highly individualised new treatment techniques, more conformal coverage of the target volumes and improved shielding of the organs at risk become available, adapted to the every single patient. However, very long-time follow up is necessary to definitely demonstrate that these improvements in treatment techniques will indeed diminish this risk for long-term toxicity and avoid an excess in non-breast cancer related mortality. A warning should be included that the introduction of target volume delineation does not lead to, after adding the appropriate margins for CTV and PTV, considerably larger irradiated volumes compared to those that are used today. Not only is there any clinical reason to increase the irradiated volume, but it probably will lead to an increase in acute and late toxicity. Key points • Optimal treatment techniques are required to optimally cover the target volumes while limiting the dose to the neighbouring tissues. • Radiotherapy departments should be able to offer several technical treatment approaches for different indications, target volumes and patient related factors. Unresolved questions and controversies: • Much remains to learn about target volume definition and delineation, especially for the breast and the thoracic wall but also for the lymph node areas! • Several trials are ongoing to define the possible place of partial breast irradiation. • Participation in clinical trials including a strong translational research component should be highly encouraged to collect data that will make us able to better predict the clinical outcome than we can now, based on the well-established clinical risk factors.

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Recommended reading References [8,15,32,38,39,43,46,49,54,66,105,109,114, 136,139,140,158,166].

Acknowledgements I express my gratitude to many colleagues and collaborators with whom I worked together in the framework of clinical trials in breast cancer, especially Walter van den Bogaert, Harry Bartelink, Jean-Claude Horiot, Henk Struikmans, Bernard Davis, Vassilis Kouloulias, Fatma Ataman, Elena Musat, Laurence Collette, Marianne Pierart, Marleen Van der Hulst, Vernon Vlaun and many others whose names I cannot all mention here. Furthermore, I want to thank the authors who published their work in this field and the patients who participated in the clinical research.

Appendix. Summary of the UICC TNM Classification, 6th edition, 2002 [144] A. Clinical classification T = primary tumour: T0: No evidence of primary tumour Tis: Carcinoma in situ T1: Tumour 62.0 cm T1mic: 60.1 cm T1a: >0.1 cm–60.5 cm T1b: >0.5 cm–61.0 cm T1c: >1.0 cm–62.0 cm T2: Tumour >2.0 cm–65.0 cm T3: Tumour >5.0 cm T4: Tumour of any size with: T4a: Extension to chest wall T4b: Oedema or ulceration of the skin, or satellite skin nodules confined to the breast T4c: Both 4a and 4 b T4d: Inflammatory carcinoma N = regional lymph nodes: N0: No regional lymph node metastasis N1: Metastasis in movable ipsilateral axillary lymph node(s) N2a: Metastasis in axillary lymph node(s) fixed to one another or to other structures N2b: Metastasis only in clinically apparent internal mammary lymph nodes and in the absence of clinically evident axillary lymph node metastasis N3a: Metastasis in infraclavicular lymph node(s) N3b: Metastasis in internal mammary and axillary lymph node(s) N3c: Metastasis in supraclavicular lymph node(s) M = distant metastasis: M0: No distant metastasis M1: Distant metastasis

B. Pathological classification pT = primary tumour: The pT categories correspond to the T categories.

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pN = regional lymph nodes: pN0: No regional lymph node metastasis, including only isolated tumour cells 6 0.2 mm pN1mi: Micrometastasis, >0.2 mm–62.0 mm pN1a: Metastasis in 1–3 axillary lymph node(s), including at least one >2 mm pN1b: Metastasis in internal mammary lymph nodes detected only by sentinel node dissection pN1c: Metastasis in 1–3 axillary lymph nodes and in internal mammary lymph nodes detected only by sentinel node dissection pN2a: Metastasis in 4–9 axillary lymph nodes including at least one >2 mm pN2b: Metastasis in clinically apparent internal mammary lymph node(s)in the absence of axillary lymph node metastasis pN3a: Metastasis in P10 axillary lymph nodes (at least one >2 mm)or metastasis in infraclavicular lymph nodes pN3b: Metastasis in clinically apparent internal mammary lymph nodes in the presence of positive axillary lymph node(s); or metastasis in >3 axillary lymph nodes and in internal mammary lymph nodes detected only by sentinel node dissection pN3c: Metastasis in supraclavicular lymph node(s) pM = distant metastasis: The pM categories correspond to the M categories. * Philip Poortmans, Dr. Bernard Verbeeten Instituut, PO Box 90120, 5000 LA Tilburg, Netherlands. E-mail address: [email protected] Received 25 January 2007; received in revised form 30 May 2007; accepted 2 June 2007; Available online 27 June 2007

References [1] Abner AL, Recht A, Vicini FA, et al. Cosmetic results after surgery, chemotherapy, and radiation therapy for early breast cancer. Int J Radiat Oncol Biol Phys 1991;21:331–8. [2] Ahn PH, Vu HT, Lannin D, et al. Sequence of radiotherapy with tamoxifen in conservatively managed breast cancer does not affect local relapse rates. J Clin Oncol 2005;23:17–23. [3] Albain K, Green SJ, Ravdin PM, et al. Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol 2002;21:37a. [4] Antonini N, Jones H, Horiot JC, et al. Effect of age and radiation dose on local control after breast conserving treatment: EORTC Trial 22881-10882. Radiother Oncol 2007;82:265–71. [5] Aristizabal SA, Miller RC, Schlichtemeier AL, Jones SE, Boone MLM. Adriamycin-irradiation cutaneous complications. Int J Radiat Oncol Biol Phys 1977;2:325–31. [6] Azria D, Gourgou S, Sozzi WJ, et al. Concommitant use of tamoxifen with radiotherapy enhances subcutaneous breast fibrosis in hypersensitive patients. Br J Cancer 2004;91: 1251–60.

[7] Bartelink H, Garavaglia G, Johansson KA, et al. Quality assurance in conservative treatment of early breast cancer. Report on a consensus meeting of the EORTC radiotherapy and breast cancer cooperative groups and the EUSOMA. Radiother Oncol 1991;22:323–6. [8] Bartelink H, Horiot JC, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001;345:1378–87. [9] Beil DR, Wein LM. Sequencing surgery, radiotherapy and chemotherapy: insights from a mathematical analysis. Breast Cancer Res Treat 2002;74:279–86. [10] Belkace ´mi Y, Vicini F. High-dose brachytherapy using MammoSite applicator: ‘‘Our doubts are traitors, And makes us lose the good we oft might win, By fearing to attempt!’’. Radiother Oncol 2007;82:354–5. [11] Bellon JR, Come SE, Gelman RS, et al. Sequencing of chemotherapy and radiation therapy in early-stage breast cancer: updated results of a prospective randomized trial. J Clin Oncol 2005;23:1934–40. [12] Bellon JR, Harris JR. Chemotherapy and radiation therapy for breast cancer: What is the optimal sequence? J Clin Oncol 2005;23:5–7 [editorial]. [13] Bellon JR, Harris JR. What extent of radiation therapy is standard? Breast 2005;14:532–40. [14] Bentzen S, Skoczylas J, Overgaard M, et al. Radiotherapyrelated lung fibrosis enhanced by tamoxifen. J Natl Cancer Inst 1996;88:918–22. [15] Bijker N, Meijnen P, Peterse JL, et al. Breast conserving treatment with or without radiotherapy in ductal carcinomain-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853 – a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol 2006;24:3381–7. [16] Bijker N, Peterse JL, Duchateau L, et al. Risk factors for recurrence and metastasis after breast conserving therapy for ductal carcinoma in situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853. J Clin Oncol 2001;19:2263–71. [17] Blichert-Toft M, Rose C, Andersen JA, et al. Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative Group. J Natl Cancer Inst Monogr 1992:19–25. [18] Boice Jr JD, Harvey EB, Blettner M, Stovall M, Flannery JT. Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med 1992;326:781–5. [19] Borghero YO, Salehpour M, McNeese MD, et al. Multileaf field-in-field forward-planned intensity-modulated dose compensation for whole-breast irradiation is associated with reduced contralateral breast dose: a phantom model comparison. Radiother Oncol 2007;82:324–8. [20] Bouvet M, Ollila DW, Hunt KK, et al. Role of conservation therapy for invasive lobular carcinoma of the breast. Ann Surg Oncol 1997;4:650–4. [21] Buijsen J, Jager JJ, Bovendeerd J, et al. Prone breast irradiation for pendulous breasts. Radiother Oncol 2007;82:337–40. [22] Buzdar AU, Smith TL, Powl KC. Effect of timing of initiation of adjuvant chemotherapy and disease free survival in breast cancer. Breast Cancer Res Treat 1998;2:163–9. [23] Chang HY, Nuyten DS, Sneddon JB, et al. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc Natl Acad Sci USA 2005;102:3738–43.

P. Poortmans / Radiotherapy and Oncology 84 (2007) 84–101 [24] Chui CS, Hong L, McCormick B. Intensity-modulated radiotherapy technique for three-field breast treatment. Int J Radiat Oncol Biol Phys 2005;62:1217–23. [25] Chung MA, Cole B, Wanebo HJ, Bland KI, Chang HR. Optimal surgical treatment of invasive lobular carcinoma of the breast. Ann Surg Oncol 1997;4:545–50. [26] Coles CE, Moody AM, Wilson CB, Burnet NG. Reduction of radiotherapy-induced late complications in early breast cancer: the role of intensity-modulated radiation therapy and partial breast irradiation. Part II – Radiotherapy strategies to reduce radiation-induced late effects. Clin Oncol (R Coll Radiol) 2005;17:98–110. [27] Colleoni M, Bonetti M, Coate AS, et al. Early start of adjuvant chemotherapy may improve treatment outcome for premenopausal breast cancer patients with tumors not expressing estrogen receptors. J Clin Oncol 2000;18:584–90. [28] Curran D, Van Dongen JP, Aaronson NK, et al. Quality of life of early-stage breast cancer patients treated with radical mastectomy or breast –conserving procedures: results of EORTC trial 10801. Eur J Cancer 1998;34:307–14. [29] Cutuli B, Cohen-Solal-le Nir C, de Lafontan B, et al. Breastconserving therapy for ductal carcinoma in situ of the breast: the French Cancer Centers’ experience. Int J Radiat Oncol Biol Phys 2002;53:868–79. [30] Dalloz F, Maingon P, Cottin Y, Briot F, Horiot JC, Rochette L. Effects of combined irradiation and doxorubicin treatment on cardiac function and antioxidant defenses in the rat. Free Radic Biol Med 1999;26:785–800. [31] Dalton WS, Brooks RJ, Jones SE, et al. Breast cancer adjuvant therapy trials at the Arizona Cancer Center using adriamycin and cyclophosphamide. In: Samon ES, editor. Adjuvant therapy of cancer V. Orlando: Grune and Stratton; 1987. p. 263–9. [32] Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300 000 women in US SEER cancer registries. Lancet Oncol 2005;6:557–65. [33] Denham JW, Hamilton CS, Christie D, et al. Simultaneous adjuvant radiation therapy and chemotherapy in high-risk breast cancer – toxicity and dose modification: a transtasman radiation oncology group multi-institution study. Int J Radiat Oncol Biol Phys 1995;31:305–13. [34] 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;98:1362–8. [35] Donovan E, Bleakley N, Denholm E, et al. Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy. Radiother Oncol 2007;82:254–64. [36] Du X, Freeman JL, Nattibger AB, Goodwin JS. Survival of women after breast conserving surgery for early stage breast cancer. Breast Cancer Res Treat 2002;72:23–31. [37] Dubey A, Recht A, Come SE, et al. Concurrent CMF and radiation therapy for early stage breast cancer: results of a pilot study. Int J Radiat Oncol Biol Phys 1999;45:877–84. [38] Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687–717. [39] Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50] [51]

[52]

[53]

[54]

[55]

97

year survival: an overview of the randomised trials. Lancet 2005;366:2087–106. Elkhuizen PH, van de Vijver MJ, Hermans J, Zonderland HM, van de Velde CJ, Leer JW. Local recurrence after breastconserving therapy for invasive breast cancer: high incidence in young patients and association with poor survival. Int J Radiat Oncol Biol Phys 1998;40:859–67. Ernst MF, Voogd AC, Coebergh JWW, Poortmans PM, Roukema JA. Using loco-regional recurrence as an indicator of the quality of breast cancer treatment. Eur J Cancer 2004;40:487–93. Ernster VL, Barclay J, Kerlikowske K, Grady D, Henderson C. Incidence of and treatment for ductal carcinoma in situ of the breast. JAMA 1996;275:913–8. Ernster VL, Barclay J, Kerlikowske K, Wilkie H, BallardBarbash R. Mortality among women with ductal carcinoma in situ of the breast in the population-based surveillance, epidemiology and end results program. Arch Intern Med 2000;160:953–8. Farrus B, Vidal-Sicart S, Velasco M, et al. Incidence of internal mammary node metastases after a sentinel lymph node technique in breast cancer and its implication in the radiotherapy plan. Int J Radiat Oncol Biol Phys 2004;60:715–21. Fiets WE, Helvoirt van RP, Nortier JWR, Tweel van der I, Struikmans H. Acute toxicity of concurrent adjuvant radiotherapy and chemotherapy (CMF versus AC) in breast cancer: a prospective comparative study. Eur J Cancer 2003;39:1081–8. Fisher B, Anderson S, Bryant J, et al. Twenty-year followup of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233–41. Fisher ER, Dignam J, Tan-Chiu E, 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. Fisher B, Dignam J, Wolmark N. Tamoxifen in the treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomized controlled trial. Lancet 1999;353:1993–2000. Fisher B, Land S, Mamounas E, et al. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience. Semin Oncol 2001;28:400–18. Fogliata A, Nicolini G, Alber M, et al. IMRT for breast. A planning study. Radiother Oncol 2005;76:300–10. Freedman GM, Fowble BL, Nicolau N, 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. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without Breast Irradiation in Women 50 Years of Age or Older with Early Breast Cancer. N Engl J Med 2004;351:963–70. Gagliardi G, Lax I, Soderstrom S, Gyenes G, Rutqvist LE. Prediction of excess risk of long-term cardiac mortality after radiotherapy of stage I breast cancer. Radiother Oncol 1998;46:63–71. Giordano SH, Kuo YF, Freeman JL, Buchholz TA, Hortobagyi GN, Goodwin JS. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 2005;97:419–24. Groome PA, O’Sullivan B, Mackillop WJ, et al. Compromised local control due to treatment interruptions and late treatment breaks in early glottic cancer: population-based out-

98

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

EB RT in breast cancer comes study supporting need for intensified treatment schedules. Int J Radiat Oncol Biol Phys 2006;64:1002–12. Guldner L, Haddy N, Pein F, et al. Radiation dose and long term risk of cardiac pathology following radiotherapy and anthracyclin for a childhood cancer. Radiother Oncol 2006;81:47–56. Hamers HP, Johansson KA, Venselaar JLM, De Brouwer P, Hansson U, D Moudi C. Entrance and exit TL-dosimetry in the conservative treatment of breast cancer: a pilot study for the EORTC Radiotherapy Cooperative Group. Radiother Oncol 1991;22:280–4. Harris EE, Christensen VJ, Hwang WT, Fox K, Solin LJ. Impact of concurrent versus sequential tamoxifen with radiation therapy in early-stage breast cancer patients undergoing breast conservation treatment. J Clin Oncol 2005;23:11–6. Heimsoth IM, Poortmans P, Collette L, et al. Radiation technique per patient compared to the radiation policy per institute and early toxicity in the EORTC trial 22922/10925 investigating the role of internal mammary and medial supraclavicular (IM–MS) lymph node chain irradiation in stage I to III breast cancer. Radiother Oncol 2006;81 [abstract 93]. Heukelom S, Lanson JH, Van Tienhoven G, Mijnheer BJ. In vivo dosimetry during tangential breast treatment. Radiother Oncol 1991;22:169–279. Højris I, Overgaard M, Christensen JJ, Overgaard J. Morbidity and mortality of ischemic heart disease in high-risk breastcancer patients after adjuvant post-mastectomy systemic treatment with or without radiotherapy: analysis of DBCG 82b and 82c randomised trials. Lancet 1999;354:1425–30. Holland PA, Shah A, Howell A, et al. Lobular carcinoma of the breast can be managed by breast-conserving therapy. Br J Surg 1995;82:1364–6. Hooning MJ, Aleman BM, van Rosmalen AJ, Kuenen MA, Klijn JG, van Leeuwen FE. Cause-specific mortality in long-term survivors of breast cancer: a 25-year follow-up study. Int J Radiat Oncol Biol Phys 2006;64:1081–91. Hooning MJ, Botma A, Aleman BM, et al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst 2007;99:365–75. Houghton J, George WD, Cuzick J, et al. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia and New Zealand: randomized controlled trial. Lancet 2003;362:95–102. Huang J, Barbera L, Brouwers M, Browman G, Mackillop WJ. Does delay in starting treatment affect the outcomes of radiotherapy? A systematic review. J Clin Oncol 2003;21:555–63. Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus Tamoxifen with or without Irradiation in Women 70 Years of Age or Older with Early Breast Cancer. N Engl J Med 2004;351:971–7. Hurkmans CW, Borger JH, Bos LJ, et al. Cardiac and lung complication probabilities after breast cancer irradiation. Radiother Oncol 2000;55:145–51. Hurkmans CW, Borger JH, Rutgers EJ, van Tienhoven G. Quality assurance of axillary radiotherapy in the EORTC AMAROS trial 10981/22023: the dummy run. Radiother Oncol 2003;68:233–40. Hurkmans CW, Meijer GJ, van Vliet-Vroegindeweij C, van der Sangen MJ, Cassee J. High-dose simultaneously integrated breast boost using intensity-modulated radiotherapy and inverse optimization. Int J Radiat Oncol Biol Phys 2006;66:923–30. Isaac N, Panzarella T, Lau A, et al. Concurrent cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy and radiotherapy for breast carcinoma: a well tolerated adjuvant regimen. Cancer 2002;95:696–703.

[72] Janni W, Dimpfl T, Braun S, et al. Radiotherapy of the chest wall following mastectomy for early-stage breast cancer: impact on local recurrence and overall survival. Int J Radiat Oncol Biol Phys 2000;48:967–75. [73] Johansen S, Olsen DR, Danielsen T, Malinen E. Contralateral breast doses following radiotherapy of the breast and regional lymph nodes: measurements and treatment planning calculations. Radiother Oncol 2007;82:332–6. [74] Jones HA, Antonini N, Hart G, et al. Significance of margins of excision on breast cancer recurrence. Eur J Cancer 2004;147 [abstract 316]. [75] Kaija H, Mauna P. Tangential breast irradiation with or without internal mammary chain irradiation: results of a randomized trial. Radiother Oncol 1995;36:172–6. [76] Korreman SS, Pedersen AN, Nøttrup TJ, Specht L, Nystro ¨m H. Breathing adapted radiotherapy for breast cancer: comparison of free breathing gating with the breath-hold technique. Radiother Oncol 2005;76:311–8. [77] Korreman SS, Pedersen AN, Josipovic ´ M, et al. Cardiac and pulmonary complication probabilities for breast cancer patients after routine end-inspiration gated radiotherapy. Radiother Oncol 2006;80:257–62. [78] Kouloulias VE, Poortmans PM, Bernier J, et al. The quality assurance programme of the Radiotherapy Group of the European Organization for Research and Treatment of Cancer (EORTC): a critical appraisal of 20 years of continuous efforts. Eur J Cancer 2003;39:430–7. [79] Kurtz JM, Jacquemier J, Torhorst J, et al. Conservation therapy for breast cancers other than infiltrating ductal carcinoma. Cancer 1989;63:1630–5. [80] Kurtz JM, Mirabell R. Radiation therapy and breast conservation: cosmetic results and complications. Semin Radiat Oncol 1992;2:125–31. [81] Leer JW, Caspers RJ, van Lonkhuijzen LR, et al. Selective avoidance of postoperative locoregional radiotherapy in breast cancer seems to be justified. Eur J Surg 1997;163:815–22. [82] Lievens Y, Poortmans P, Van den Bogaert W. A glance on quality assurance in EORTC study 22922 evaluating techniques for internal mammary and medial supraclavicular lymph node chain irradiation in breast cancer. Radiother Oncol 2001;60:257–65. [83] Lievens Y, Van den Bogaert W. Internal mammary and medial supraclavicular lymph node irradiation: the thin line between advantages and side effects (editorial). Radiother Oncol 2002;65:75–7. [84] Mai KT, Yazdi HM, Isotalo PA. Resection margin status in lumpectomy specimens of infiltrating lobular carcinoma. Breast Cancer Res Treat 2000;60:29–33. [85] Major T, Niehoff P, Kova ´cs G, Fodor J, Polga ´r C. Dosimetric comparisons between high dose rate interstitial and MammoSiteTM balloon brachytherapy for breast cancer. Radiother Oncol 2006;79:321–8. [86] Marks LB, Rosner GL, Prosnitz LR, Ross M, Vredenburgh JJ, Peters WP. The impact of conventional plus high dose chemotherapy with autologous bone marrow transplantation on hematologic toxicity during subsequent localregional radiotherapy for breast cancer. Cancer 1994;74:2964–71. [87] Mayo CS, Urie MM, Fitzgerald TJ. Hybrid IMRT plans – concurrently treating conventional and IMRT beams for improved breast irradiation and reduced planning time. Int J Radiat Oncol Biol Phys 2005;61:922–32. [88] Mikeljevic JS, Haward R, Johnston C, et al. Trends in postoperative radiotherapy delay and the effect on survival in breast cancer patients treated with conservation surgery. Br J Cancer 2004;90:1343–8.

P. Poortmans / Radiotherapy and Oncology 84 (2007) 84–101 [89] Moore MM, Borossa G, Imbrie JZ, et al. Association of infiltrating lobular carcinoma with positive surgical margins after breast-conservation therapy. Ann Surg 2000;231:877–82. [90] Newman LA, Kuerer HM. Advances in breast conservation therapy. J Clin Oncol 2005;23:1685–97. [91] Niehoff P, Polga ´r C, Kova ´cs G. In regard to Belkace ´mi and Vicini: high-dose brachytherapy using the MammoSite applicator ‘‘. . .Give me your hand, and let the subject see, to make them know’’. Radiother Oncol 2007;82:355–6. [92] Niehoff P, Polga ´r C, Ostertag H, et al. Clinical experience with the MammoSite radiation therapy system for brachytherapy of breast cancer: Results from an international phase II trial. Radiother Oncol 2006;79:316–20. [93] Oliver M, Chen J, Wong E, Van Dyk J, Perera F. A treatment planning study comparing whole breast radiation therapy against conformal, IMRT and tomotherapy for accelerated partial breast irradiation. Radiother Oncol 2007;82:317–23. [94] Omlin A, Amichetti M, Azria D, et al. Boost radiotherapy in young women with ductal carcinoma in situ: a multicentre, retrospective study of the Rare Cancer Network. Lancet Oncol 2006;7:652–6. [95] Ott OJ, Hildebrandt G, Po ¨tter R, et al. Accelerated partial breast irradiation with multi-catheter brachytherapy: Local control, side effects and cosmetic outcome for 274 patients. Results of the German–Austrian multi-centre trial. Radiother Oncol 2007;82:281–6. [96] Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949–55. [97] Overgaard M, Jensen M-J, Overgaard J, 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. [98] Overgaard M, Nielsen HM, Overgaard J. Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b & c randomized trials. Radiother Oncol 2007;82:247–53. [99] Paszat LF, Vallis KA, Benk VMA, Groome PA, Mackillop WJ, Wielgosz A. A population-based case-cohort study of the risk of myocardial infarction following radiation therapy for breast cancer. Radiother Oncol 2007;82:294–300. [100] Peiro G, Bornstein BA, Connolly JL, et al. The influence of infiltrating lobular carcinoma on the outcome of patients treated with breast-conserving surgery and radiation therapy. Breast Cancer Res Treat 2000;59:49–54. [101] Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659–72. [102] Pierce LJ, Hutchins LF, Green SR, et al. Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer. J Clin Oncol 2005;23:24–9. [103] Pierce LJ, Richer AS. Postmastectomy radiotherapy: more than locoregional control. J Clin Oncol 1994;12:444–6. [104] Poen JC, Tran L, Juillard G, et al. Conservation therapy for invasive lobular carcinoma of the breast. Cancer 1992;69:2789–95. [105] Poortmans P. A bright future for radiotherapy in breast cancer. Radiother Oncol 2007;82:243–6 [editorial]. [106] Poortmans PM, Ataman F, Davis JB, et al. Quality assurance in the EORTC phase III randomised ‘boost vs. no boost’ trial for breast conserving therapy: comparison of the results of two individual case reviews performed early and late during the accrual period. Radiother Oncol 2005;76:278–84.

99

[107] Poortmans P, Bartelink H, Horiot JC, et al. The influence of the boost technique on local control in breast conserving treatment in the EORTC ‘‘boost versus no boost’’ randomised trial. Radiother Oncol 2004;72:25–33. [108] Poortmans P, Collette L, Horiot J-C, et al. Impact of the boost dose on local control and survival in patients with early stage breast cancer after a microscopically incomplete lumpectomy: 10 years results of the randomised EORTC boost trial 22881/10882. Radiother Oncol 2006;81 [abstract 54]. [109] Poortmans PM, Davis JB, Ataman F, Bernier J, Horiot JC. The quality assurance programme of the Radiotherapy Group of the European Organisation for Research and Treatment of Cancer: past, present and future. Eur J Surg Oncol 2005;31:667–74. [110] Poortmans P, Kouloulias V, van Tienhoven G, et al. Quality assurance in the EORTC randomized trial 22922/10925 investigating the role of irradiation of the internal mammary and medial supraclavicular lymph node chain works. Strahlenther Onkol 2006;182:576–82. [111] Poortmans P, Kouloulias VE, Venselaar JL, et al. Quality assurance of EORTC trial 22922/10925 investigating the role of internal mammary – medial supraclavicular irradiation in stage I–III breast cancer: the individual case review. Eur J Cancer 2003;39:2035–42. [112] Poortmans PMP, Venselaar JLM, Struikmans H, et al. The potential impact of treatment variations on the results of radiotherapy of the internal mammary lymph node chain: a quality-assurance report on the dummy run of EORTC phase III randomized trial 22922/10925 in stage I–III breast cancer. Int J Radiat Oncol Biol Phys 2001;49:1399–408. [113] Ragaz J, Olivotto IA, Spinelli JJ, et al. Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst 2005;97:116–26. [114] Recht A. Integration of systemic therapy and radiation therapy for patients with early-stage breast cancer treated with conservative surgery. Comprehensive review. Clin Breast Cancer 2003;4:104–13. [115] Recht A, Come SE, Henderson IC, et al. The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 1996;334:1356–61. [116] Recht A, Gray R, Davidson NE, et al. Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: experience of the Eastern Cooperative Oncology Group. J Clin Oncol 1999;17:1689–700. [117] Remouchamps VM, Huyskens DP, Mertens I, et al. The use of magnetic sensors to monitor moderate deep inspiration breath hold during breast irradiation with dynamic MLC compensators. Radiother Oncol 2007;82:341–8. [118] Romestaing P, Lehingue Y, Carrie C, 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. [119] Romestaing P, Ecochard R, Hennequin C, Bosset JF, Maingon P. The role of internal mammary chain irradiation on survival after mastectomy for breast cancer. Results of a phase III SFRO trial. Radiother Oncol 2000;56 [abstract 306]. [120] Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–84. [121] Rutgers EJ, Nortier JW, Tuut MK, et al. Dutch Institute for Healthcare Improvement guideline, ‘‘Treatment of breast cancer’’. Ned Tijdschr Geneeskd 2002;146:2144–51.

100

EB RT in breast cancer

[122] Rutqvist LE, Rose C, Cavallin-Stahl E. A systematic overview of radiation therapy effects in breast cancer. Acta Oncol 2003;42:532–45. [123] Salvadori B, Biganzoli E, Veronesi P, Saccozzi R, Rilke F. Conservative surgery for infiltrating lobular breast carcinoma. Br J Surg 1997;84:106–9. [124] Sanders ME, Schuyler PA, Dupont WD, et al. The natural history of low-grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long term follow up. Cancer 2005;103:2481–4. [125] Sarrazin D, Le MG, Arriagada R, et al. Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 1989;14:177–84. [126] Sartor CI, Peterson BL, Woolf S, et al. Effect of addition of adjuvant paclitaxel on radiotherapy delivery and locoregional control of node positive breast cancer: Cancer and Leukemia Group B 9344. J Clin Oncol 2005;23:30–40. [127] Sastre-Garau X, Jouve M, Asselain B, et al. Infiltrating lobular carcinoma of the breast. Clinicopathologic analysis of 975 cases with reference to data on conservative therapy and metastatic patterns. Cancer 1996;77:113–20. [128] Schmidberger H, Hermann RM, Hess CF, Emons G. Interactions between radiation and endocrine therapy in breast cancer. Endocr Relat Cancer 2003;10:375–88. [129] Schnitt SJ, Connolly JL, Recht A, Silver B, Harris JR. Influence of infiltrating lobular histology on local tumor control in breast cancer patients treated with conservative surgery and radiotherapy. Cancer 1989;64:448–54. [130] Senkus-Konefka E, Jassem J. Complications of breastcancer radiotherapy. Clin Oncol (R Coll Radiol) 2006;18:229–35. [131] Shannon C, Ashley S, Smith IE. Does timing of adjuvant chemotherapy for early breast cancer influence survival? J Clin Oncol 2003;21:3792–7. [132] Shapiro CL, Harrigan-Hardenberg P, Gelman R, et al. Cardiac effects of adjuvant doxorubicin and radiation therapy in node positive breast cancer patients. J Clin Oncol 1998;16:3493–501. [133] Silverstein MJ, Buchanan C. Ductal carcinoma in situ: USC/ Van Nuys Prognostic Index and the impact of margin status. Breast 2003;12:457–71. [134] Silverstein MJ, Lewinsky BS, Waisman JR, et al. Infiltrating lobular carcinoma. Is it different from infiltrating duct carcinoma? Cancer 1994;73:1673–7. [135] Singletary SE, Patel-Parekh L, Bland KI. Treatment trends in early-stage invasive lobular carcinoma: a report from the National Cancer Data Base. Ann Surg 2005;242:281–9. [136] Smith IA, Ross GM. Breast radiotherapy after lumpectomy – no longer always necessary. N Engl J Med 2004;351:1021–3. [137] Stemmer SM, Rizel S, Hardan I, et al. The role of irradiation of the internal mammary lymph nodes in high-risk stage II to IIIA breast cancer patients after high-dose chemotherapy: a prospective sequential nonrandomized study. J Clin Oncol 2003;21:2713–8. [138] Storm HH, Andersson M, Boice Jr JD, et al. Adjuvant radiotherapy and risk of contralateral breast cancer. J Natl Cancer Inst 1992;84:1245–50. [139] Strom EA, Woodward WA, Katz A, et al. Clinical investigation: regional nodal failure patterns in breast cancer patients treated with mastectomy without radiotherapy. Int J Radiat Oncol Biol Phys 2005;63:1508–13. [140] Taghian A, Jeong JH, Mamounas E, et al. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and chemotherapy with or without tamoxifen and without radiotherapy: results from five

[141]

[142] [143] [144] [145]

[146]

[147]

[148]

[149]

[150]

[151]

[152]

[153]

[154]

[155]

[156]

[157]

[158]

[159]

national surgical adjuvant breast and bowel project randomized trials. J Clin Oncol 2004;22:4247–54. Taylor ME, Perez CA, Halverson KJ, et al. Factors influencing cosmetic results after conservation therapy for breast cancer. Int J Radiat Oncol Biol Phys 1995;31:753–64. Theodoulou M, Seidman AD. Cardiac effects of adjuvant therapy for early breast cancer. Semin Oncol 2003;30:730–9. Thilmann C, Zabel A, Nill S, et al. Intensity-modulated radiotherapy of the female breast. Med Dosim 2002;27:79–90. Sobin LH, Wittekind Ch, editors. UICC TNM classification of malignant tumours. Hoboken (NJ): John Wiley & Sons; 2002. van Asselen B, Schwarz M, van Vliet-Vroegindeweij C, Lebesque JV, Mijnheer BJ, Damen EMF. Intensity-modulated radiotherapy of breast cancer using direct aperture optimization. Radiother Oncol 2006;79:162–9. Van den Bogaert W, Struikmans H, Fourquet A, Bartelink H. Internal mammary and medial supraclavicular (IM–MS) lymph node chain irradiation in stage I–III breast cancer. A phase III randomised trial of the EORTC, protocol 22922/10925, May 1996, revision May 1999, Brussels. Van den Broek N, Van der Sangen MJ, Van de Poll-Franse LV, van Beek MW, Nieuwenhuijzen GA, Voogd AC. Margin status and the risk of local recurrence after breast-conserving treatment of lobular breast cancer. Breast Cancer Res Treat, in press (PMID:17115109 [PubMed - as supplied by publisher]). van der Leest M, Evers L, van der Sangen MJC, et al. The safety of breast-conserving therapy in breast cancer patients of 40 years and younger. Cancer 2007;109:1957–64. Van de Vijver MJ, He YD, van’t Veer LJ, et al. A geneexpression signature as a predictor of survival in breast cancer. N Engl J Med 2002;347:1999–2009. van Dongen JA, Voogd AC, Fentiman IS, et al. Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 2000;92:1143–50. van Nes JG, van de Velde CJ. The preferred treatment for young women with breast cancer – mastectomy versus breast conservation. Breast 2006;15:S3–S10. Van Tienhoven G, Van Bree NAM, Mijnheer BJ, Bartelink H. Quality assurance of the EORTC trial 22881/10882: ‘‘assessment of the role of the booster dose in breast conserving therapy’’: the Dummy Run. Radiother Oncol 1991;22:290–8. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Expression profiling predicts outcome in breast cancer. Breast Cancer Res 2003;5:57–8. van’t Veer LJ, Dai HY, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002;415:530–6. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347:1227–32. Veronesi U, Marubini E, Mariani L, Valagussa P, Zucali R. The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial. Eur J Cancer 1999;35:1320–5. Vicini FA, Kestin LL, Goldstein NS, et al. Impact of young age on outcome in patients with ductal carcinoma-in-situ treated with breast-conserving therapy. J Clin Oncol 2000;18:296–306. Voogd AC, Nielsen M, Peterse JL, et al. Differences in risk factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer: pooled results of two large European randomized trials. J Clin Oncol 2001;19:1688–97. Voordeckers M, Van de Steene J, Vinh-Hung V, Storme G. Adjuvant radiotherapy after mastectomy for pT1–pT2 node

P. Poortmans / Radiotherapy and Oncology 84 (2007) 84–101

[160]

[161]

[162]

[163]

[164]

negative (pN0) breast cancer: Is it worth the effort? Radiother Oncol 2003;68:227–31. Vrieling C, Collette L, Bartelink E, et al. Validation of the methods of cosmetic assessment after breast-conserving therapy in the EORTC ‘‘boost versus no boost’’ trial. Int J Radiat Oncol Biol Phys 1999;45:667–76. Vrieling C, Collette L, Fourquet A, et al. The influence of the boost in breast-conserving therapy on cosmetic outcome in the EORTC ‘‘boost versus no boost’’ trial. Int J Radiat Oncol Biol Phys 1999;45:677–85. Vrieling C, Collette L, Fourquet A, et al. The influence of patient, tumor and treatment factors on the cosmetic results after breast-concerving therapy in the EORTC ‘‘boost vs. no boost’’ trial. Radiother Oncol 2000;55:219–32. Vrieling C, Collette L, Fourquet A, et al. Can patient-, treatment- and pathology-related characteristics explain the high local recurrence rate following breast-conserving therapy in young patients? Eur J Cancer 2003;39:932–44. Wazer D, DiPetrillo T, Schmidt-Ullrich R, et al. Factors influencing cosmetic outcome and complication risk after conservative surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol 1992;10:56–363.

101

[165] Wazer D, Tercilla O, Lin P, et al. Modulation in the radiosensitivity of MCF-7 human breast carcinoma cells by 17-estradiol and tamoxifen. Br J Radiol 1989;62:1079–83. [166] 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. [167] Whelan T, Levine M. Radiation therapy and tamoxifen: concurrent or sequential? That is the question. J Clin Oncol 2005;23:1–4 [editorial]. [168] White JR, Gustafson GS, Wimbish K, et al. Conservative surgery and radiation therapy for infiltrating lobular carcinoma of the breast. The role of preoperative mammograms in guiding treatment. Cancer 1994;74:640–7. [169] Yarnold J, Ashton A, Bliss J, et al. Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: long-term results of a randomised trial. Radiother Oncol 2005;75:9–17. [170] Yeatman TJ, Cantor AB, Smith TJ, et al. Tumor biology of infiltrating lobular carcinoma. Implications for management. Ann Surg 1995;222:549–59 [discussion 559–61].