| | Radiotherapy for invasive breast cancer: Guidelines for clinical practice from the French expert review board of Nice/Saint-Paul de VenceAccepted 10 June 2010. published online 08 July 2010.
Corrected Proof Abstract PurposeWhile new strategies for the treatment of invasive breast cancer (BC) are emerging, radiotherapy (RT) modalities are still under debate. The French expert review board of Nice-Saint-Paul de Vence was asked firstly to conduct a qualitative evidence-based systematic review and then to establish clinical practice guidelines for the use of post operative RT in invasive BC. Methods and materialsA search to identify eligible studies was undertaken using the Medline® database. All phase III randomized trials and systematic reviews evaluating the role and modalities of RT in invasive BC were included, together with some noncontrolled studies if no randomized trials were identified. The quality and clinical relevance of the studies were evaluated to determine the level of evidence. ResultsThe maximum delay between surgery and RT should ≤8 weeks when chemotherapy (CT) is not indicated. This should not exceed 24 weeks when adjuvant CT is administered. Whole breast RT delivering 50 Gy in 25 fractions followed by a boost of 10–16Gy remains the standard of care after conservative surgery (CS). In the elderly population, for certain cases presenting comorbidities associated with a limited life expectancy, RT indication (even hypofractioned) and boost delivery may be unnecessary in the light of an unfavourable risk/benefit ratio. RT technique and indications should not vary in case of neoadjuvant CT followed by CS. After total mastectomy, RT should be indicated in N+ and in N− patients with high risk of local recurrence. The experts recommend to initiate tamoxifen at the end of RT, while aromatase inhibitors could be administered either concomitantly or sequentially with RT. There is no consistent data to delay (or suspend) trastuzumab administration during RT. As for all patients, in case of concurrent RT-trastuzumab administration, reduction of cardiac tissues exposure is highly recommended. After breast reconstruction, RT should be delivered as after standard CS without boost. ConclusionDue to significant variations in practice in the treatment of patients with BC, our group aimed to provide guidelines for clinical practice. The systematic review of the literature formed the basis of our evidence-based recommendations; however expert agreements were necessary on those subjects that are still under debate. Our group will update these guidelines every 4 years, taking in consideration new advances in technology, new drugs administration, biologic tools and innovative therapeutic options. 1. Introduction  Breast cancer (BC) is the most frequent female cancer in France. In the last two decades, the incidence of breast cancer has increased, although mortality has decreased [1]. In the context of a multidisciplinary approach, the indications for post operative radiotherapy (RT) and its modalities require clear and practical guidelines, some of these being still under debate. The French group of breast cancer experts of Nice–Saint-Paul de Vence was established in 2005. In the second edition of the Nice–Saint-Paul de Vence Guidelines of 2007, a radiation oncology group, including radiation oncologists from the public and private sectors, professional associations, and teaching societies was created to elaborate French practical guidelines for RT in invasive BC [2]. The main objectives were to conduct a systematic review of the literature and to evaluate the level of evidence of available data to respond to the most important questions selected by the expert review board for modern RT delivery in invasive BC. 2. Methods and materials 2.1. Selection of studies and interventions The systematic review focused on post operative RT for patients with invasive non-metastatic adenocarcinomas. All studies that included patients with recurrent disease or metastases at diagnosis were excluded. Studies focusing on RT after neoadjuvant treatments or immediate breast reconstruction were selected for special consideration. The interventions were detailed as: (i) the optimal delay between surgery and RT; (ii) RT indications and modalities after breast conservation; (iii) RT indications and modalities after total mastectomy; (iv) indications and modalities of the RT to the nodes; (v) rationale and practical use of combined RT with adjuvant systemic drugs; and (vi) RT indications and modalities after neoadjuvant chemotherapy (CT) and/or after immediate breast reconstruction. 2.2. Search strategy A search to identify eligible studies was undertaken using the Medline® database (from 1980). Additional websites of organisations developing and/or evaluating systematic reviews, meta-analyses, and/or therapeutic guidelines, such as the Cochrane Database of Systematic Review and the Cancer Care Ontario's Program in Evidence-Based Care, were also consulted. The Medline® search was updated recently before final submission of the manuscript. 2.3. Selection of eligible studies Eligible studies were meta-analyses, systematic reviews, and phase III randomized trials. In the absence of such trials, some phase II or retrospective studies were selected. Study selection was based on the abstract or the full paper (if the abstract was insufficiently detailed). All the experts of the working group participated in the initial selection and discussed all selected abstracts. 2.4. Data extraction and quality assessment Clinical and methodological data were extracted using pre-specified data collection forms. Four explicit criteria were used to assess the validity, relevance, and consistency of the results, as well as the quality of the methodology according to the type of study. Each expert of the working group independently evaluated each selected paper. Disagreements were resolved by discussion to reach a consensus (“expert agreement”). 2.5. Synthesis of the evidence Data synthesis of relevant studies was performed considering both efficacy and toxicity outcomes for each intervention. Conclusions for each intervention were quoted by the working group according to the FNCLCC grading system of level of evidence, based on the methodology, quality of the study, and coherence of the results with other available data [3]. 3. Results 3.1. Optimal delay from surgery to radiotherapy 3.1.1. Eligible studies There is a lack of randomized data on this issue. The group of experts decided to rely only on retrospective studies having more than 1000 patients (Table 1). We have thus excluded six studies having between 400 and 673 patients. On the basis of retrospective data, we have recommended varying delays, depending on the therapeutic sequence whether or not adjuvant CT is included [3]. 3.1.2. Indications Absence of indication for CT: A maximum delay of 8 weeks is recommended between surgery and loco-regional RT (level 3 grade C) particularly for patients with high risk of recurrence. Indication for CT: Standard fractionated RT should start after the end of chemotherapy. However, the maximum delay between surgery and RT should be between 20 and 24 weeks (level 3, grade C). 3.2. RT indications and modalities after breast conservation RT indication after conservative surgery is compulsory. It reduces the risk of relapse in all patient sub-groups whatever the extent of partial surgery. 3.2.1. Eligible studies The group of experts has retained only phase III trials and meta-analyses for these recommendations. Practical recommendations are defined for RT indication to the whole breast (then for the boost to the tumour bed) and for the modalities for practical and technical issues. 3.2.2. Indications of whole breast RT and boost to the tumour bed In the 15-year update of the meta-analysis of the Early Breast Cancer Trialists Collaborative Group, the advantage in terms of local control at 15 years translates into a 6% improvement in survival [4]. Whole breast RT should be systematic after breast conserving surgery (level 1, grade A). The total dose should be equal or equivalent to 50Gy in 25 fractions over 5 weeks. Nevertheless, the issue of fractionation of RT of the whole breast remains a subject of discussion. Trials testing different hypofractionation schemes have reported non-significant varying results at 5 years [5], [6], [7]. The Canadian trial is more mature in terms of follow-up. The recent update showed that, with 12 years hindsight, the local relapse rates were identical in the two arms [5] (Table 2). In the elderly population, certain particular cases presenting comorbidities associated with a limited life expectancy, RT indication (even hypofractioned) may be unnecessary in the light of an unfavourable risk/benefit ratio (expert agreement). Following whole breast irradiation, it is recommended to deliver a boost of 10–16Gy to the tumour bed. Three randomized trials have shown the importance of an increase in the dose to the tumour bed in order to improve local control [8], [9], [10], [11], [12] (level 1, grade A). The updated results of the EORTC trial [11] have confirmed this advantage for patients of all ranges of ages, including those over 60 years of age. For older patients (>70 years) the decision to deliver the boost should be discussed taking in consideration the tumour size, extent of surgical margins and a possible presence of a large extensive in situ component and grade (expert agreement). The surgical clips marking the original tumour bed should indicate the borders of the excision particularly in the case of remodelling. The number of surgical clips can vary, but a minimum of three is recommended (expert agreement). Practical recommendations and quality assurance (expert agreement): The quality of RT begins with the methodology adopted for establishing its indication. In spite of the formal character of the indication of RT, after a conservative surgery, the decision should be endorsed within the framework of a multidisciplinary consultation meeting (MCM). A pre-treatment consultation prior to a decision on the management of the patient forms part of “Good Clinical Practice”. The radiation-oncologist should ensure the definition of volumes to be treated and dose prescription. The RT quality should, in all cases, match certain strict technical criteria. The treatment modality, as well as the possible secondary side effects, should be clearly explained to the patient and recorded during and after RT. 3.3. RT indications and modalities after total mastectomy 3.3.1. Eligible studies The group of experts has retained only phase III trials and meta-analyses for these recommendations. Practical recommendations are established for the indications of RT to the chest wall and nodes. The modalities for practical issues and quality assurance are identical to those described in the previous chapter. 3.3.2. Indications of chest wall RT Post-mastectomy radiotherapy (PMRT) has shown an absolute overall survival benefit of about 10% in pre- or post-menopausal node positive (N+) patients [4], [13], [14], [15], [16]. Thus, the indications for PMRT are clearly established for the T3–T4 patients and for those presenting with nodal involvement (level 1, grade A). In node negative patients, RT should be indicated on the basis of the existence of one or more risk factors for local relapse, described by the working group as: age less than 40 years, size ≥pT3, grade III, multifocality, lymphovascular and/or muscular and/or cutaneous invasion (expert agreement). These factors have been also reported as independent factors in retrospective studies [17], [18]. In clinical practice, notwithstanding associated comorbidities, the tumour volume (≥T3) and/or nodal involvement (≥4 positive nodes) are generally situations where the indication is clear. RT will include the chest wall, internal mammary chain (IMC) and ipsilateral supra clavicular areas. Apart from cases with insufficient lymph node dissection, irradiation of the axilla should not be carried out systematically. 3.4. Indications and modalities of nodal irradiation 3.4.1. Eligible studies Available data relate to the indication (or not) for irradiation of the IMC for tumours of the internal and central quadrants. The group of experts has retained the update of the French phase III trial [9]. In addition, these recommendations are based on the hypothesis that the dissection of the axilla is considered as sufficient (>7 nodes dissected) (expert agreement). 3.4.2. Practical recommendations according to the nodal status Recommendations for N+ patients: The supra- and sub-clavicular and the IMC nodes should be systematically irradiated to a dose of 46–50Gy using conventional fractionation (2Gy per fraction) through an alternate mixed photon–electron beams. IMC RT is particularly indicated in patients with internal-central node positive patients and those with >4N+. Recommendations for isolated cells and axillary micrometastases: In tumours located in the external quadrants, systematic irradiation of the nodal areas is not recommended. In tumours located in the internal and central quadrants, indications are identical to those for node negative cases (expert agreement). Recommendations for N− patients: The indication for nodal RT is discussed in the section for tumours of the internal and central quadrants. In this case, the indication should be modulated according to the tumour size, patient's age and associated comorbidities as well as consideration to the risk/benefit ratio. Table 3 shows the risk of invasion according to prognostic factors (Table 3) [19]. When supra clavicular and IMC RT is to be given, then it should be performed according to the same modalities as for node positive cases. For tumours in the external quadrants, nodal RT should not be given. Recommendations for RT to the axilla: In the N− patients irradiation of the axilla is not justified. The other cases should be discussed in the MCM on a case by case basis: -Positive sentinel node without axillary dissection. -Sufficient axillary dissection (≥7 nodes removed): in case of massive invasion with consideration of the nodal ratio (number of positive nodes/total number of nodes removed). -Insufficient axillary dissection (<7 nodes removed): N+: take into account the nodal ratio of positive nodes/total number of nodes removed. The number of nodes with extracapsular extension should not count in the decision-making process. N−: take into account the total number of nodes dissected and other local and general prognostic factors. 3.5. Rationale and practical use of combined RT with adjuvant systemic drugs 3.5.1. Eligible studies In this chapter, we will address the possible associations of RT with chemotherapy (CT) in the adjuvant setting. For CT, the results of randomized trials are available, even if the drugs used no longer constitute the standard of treatment. On the contrary, only a few retrospective data on hormonotherapy and trastuzumab have been reported. 3.5.2. Association of RT with tamoxifen There are no randomized trials that compare sequential with concomitant RT with tamoxifen (TAM). Three publications have reported the results of retrospective comparisons between a concomitant and a sequential delivery of RT and TAM [20], [21], [22]. No difference in terms of disease control or survival was found between these two schemes. In clinical practice, given the absence of difference in carcinologic efficiency between a concomitant and sequential administration, the group of experts has recommended the start of TAM at the end of RT (level 3, grade C). 3.5.3. Association of radiotherapy with aromatase inhibitors Third generation aromatase inhibitors (AI) (Anastrozole, Letrozole, Exemestane) are widely used in post-menopausal patients since the publication of the results of several randomized trials. The only available data on severe toxicity after sequential vs. concomitant delivery of Letrozole-RT are those reported in the French COHORT study. At 2 years, there was no difference in terms of acute toxicity between the two arms. However, intrinsically radiosensitive patients had significantly higher probability for cutaneous toxicity [23]. In the absence of other mature data on these molecules, the group of experts concluded that AI may be delivered either concomitantly or sequentially (level 2, grade B). 3.5.4. Association of radiotherapy with chemotherapy Recently, randomized phase III trials [24], [25], [26] which compared a sequential to a concomitant CT have been published. These studies have used mitoxantrone [25], [26] or methotrexate [24], which is no longer recommended for use in the adjuvant setting. The new molecules such as taxanes have been evaluated in combination with RT. However, this association has shown a significant increase in radiation pneumonitis [27], [28]. Finally, the group of experts does not recommend the practice of any concomitant CT-RT schemes outside trials (expert agreement). 3.5.5. Association of radiotherapy with trastuzumab There is no randomized study that raises the issue of sequencing of RT and trastuzumab. Thus, for BC overexpressing HER2, the impact of a late administration and/or interruption of trastuzumab during the 5–7 weeks of irradiation is not yet known. In clinical practice, given the efficacy demonstrated with adjuvant trastuzumab in HER2-positive BC patients [29], [30], [31] and the absence of severe toxicity when nodal RT is limited, it is recommended to continue trastuzumab (every 3 weeks) during irradiation on condition that the cardiac volume is as limited as possible. This occurs with the absence of systematic irradiation of the IMC or the optimisation of the technique if indicated. In addition, given the relatively long half-life of trastuzumab (of the order of 4–6 weeks), the interruption may be considered as insignificant (expert agreement). 3.6. RT after neoadjuvant CT and/or after immediate breast reconstruction We have distinguished two particular situations where RT has obtained agreement among experts: -whole breast RT or PMRT after neoadjuvant chemotherapy; -RT after immediate breast reconstruction. 3.6.1. Radiotherapy after neoadjuvant chemotherapy Whatever the type of surgery and the response to neoadjuvant CT, the RT indication should be taken into consideration by considering the initial tumour criteria. The indications are identical to those described in the adjuvant situation. There is no exception to the rule for RT after conservative surgery (expert agreement). RT to the nodal areas should be systematic for N+ patients and for tumours located in the central or internal quadrants. For patients that have node negative status after CT, the initial nodal and tumour status must be taken into consideration, and the risk/benefit relationship of a more or less extended irradiation must be considered (experts agreement). 3.6.2. Radiotherapy after immediate breast reconstruction The RT indications and technique are similar to those of RT after standard conservative surgery. All decisions should be endorsed within the framework of an MCM. The dose delivered to the reconstructed breast (whatever the type of reconstruction) should be between 45 and 50.4Gy in 28 fractions (1.8–2Gy/fraction). The techniques and constraints are those defined previously. However, there is no indication for a boost dose due to the fact that in most cases it is impossible to locate the initial tumour site (expert agreement). 4. Discussion 4.1. Optimal delay from surgery to RT Optimal delay should be always discussed according to adjuvant CT indication. This is discussed in Section 4.5.2. A delay in post operative RT delivery can be due to various factors, i.e. the lack of available equipment and personnel, thus leading to long waiting lists, even in some developed countries. It has been reported from a Canadian experience that RT could be delayed in a proportion of patients as high as 54% [32]. Since RT is expected to be more efficient? if the residual tumour burden is less, a long interval after breast surgery could theoretically lead to an increased residual tumour growth and, eventually, to poorer results [33]. RT delay could theoretically be harmful in terms of tumour regrowth. It is not surprising that, due to obvious ethical limitations, the existing knowledge regarding RT delay after surgery is limited due to the lack of randomized trials. In a recent review of the literature, Tsoutsou et al. concluded that, in the absence of indication for CT, a delay of more than 8–12 weeks between surgery and RT could be harmful in terms of local control of the disease [34]. Buchholz et al. described the only study that resulted in a decrease in overall survival when RT administration was delayed due to the administration of CT first [35]. In another study updated by Bellon et al., no significant survival differences between patients assigned after conservative breast surgery to receive 12 weeks CT before RT vs. RT first followed by CT was found. However, this study does not have enough statistical power to rule out a clinically important survival benefit for either sequence [3]. In general, no robust evidence exists to suggest any impact of any particular sequence on overall survival. RT administration after CT does not result in decreased survival in most of the studies. However, RT should be administered within 7 months after surgery. The data resulting from studies that have involved more than 1000 patients have also supported this conclusion with delays ranging between 5 and 14 weeks (Table 1). 4.2. Indications of whole breast RT plus tumour bed boost Whole breast RT remains the standard of care after conservative surgery. The question that remains unsolved relates to the possibility of individualizing sub-populations where this standard treatment would be questioned. One of the future challenges will be to evaluate the possibility for tumour biology in contributing to the personalisation of RT. In a study from British Columbia by Truong et al. [36] involving 4836 patients, data showed a significant increase in the rate of local recurrence (from 3% to 9%) and decrease in the overall survival rate from 90% to 72% and specific survival rate from 94% to 91% for groups with and without RT respectively. Risk factors for recurrence after conservative treatment have been integrated in a predictive model that estimates the relative risks (RR) of recurrence for each group (5-year age interval, margin status, emboli, size of tumour, grade, and use of TAM or CT) [37]. However, these prognostic factors have been established based on studies that used therapies which have considerably evolved over time and in a context of limited knowledge of tumour biology. One of the future questions will be to define the exact place that tumour biology could take in the determination of indications and/or the definition of RT volumes. Indeed, new classifications determination may be useful to tailor treatment according to local or distant risk of metastasis [38], [39], [40], [41], [42]. This could be also useful in elderly patients to discriminate sub-populations that have very low risk of recurrence and may not need RT delivery. The large French retrospective study reported excellent local control in elderly patients ≥70 years treated conservatively with RT [43]. On the other hand, the tumour bed definition is a crucial step for a high quality of RT. For this purpose, we recommend at least 3 clips for tumour bed definition. This number has been reported recently advocated by French teams as an important parameter that allows an increased accurancy of the tumour bed delineation [44], [45]. 4.3. RT indications and modalities after total mastectomy In node positive BC patients, PMRT increases overall survival by about 10 % [4], [13], [14], [15], [16]. In the update at 20 years of the Vancouver trial, this gain was found for the whole population and in the sub-groups of patients who had involvement of 4 or more positive nodes [16]. The benefit in terms of survival is also observed in all sub-groups of the meta-analysis. Thus, RT indication is not a subject of debate. Conversely, the debate is important is sub-groups of N− patients. The rationale for indicating PMRT in N− patients is generally based on the presence of local recurrence risk factors. In the Danish trials, the independent factors influencing survival were: large tumour size, high number of involved nodes +/− extracapsular extent, nodal relapse (supra- or sub-clavicular), less than 2 years interval before the first relapse [15]. In our group, the recommendations in N− patients were based on the existence of one or more risk factors for local recurrence such as age (less than 40 years), tumour size (≥pT3), grade III, multifocality, lymphovascular and/or muscular and/or cutaneous invasion [17], [18]. Thus, we included the particular cases of T3N0. In this population there is a lack of information and conflicting data. For example, in the USA the majority of practising radiation oncologists recommends PMRT for these tumours [46] because of the lack of recommendations from the American Society of Clinical Oncology [47]. In the study from Taghian et al. [48] the 10-year recurrence rates were different according to systemic therapy administration (7%) or not (16%). The authors concluded that, in the context of systemic therapy, isolated recurrence rates as first events is lower then 6%. This rate is low enough that the benefit from routine PMRT might not outweigh its potential adverse effects. As for intermediate risk patients (with 1–3N+), the lack of randomized trials in T3N0, cannot allow a systematic omission of PMRT. 4.4. IMC and supra clavicular radiotherapy The practice of nodal RT is characterised by great heterogeneity according to teams and continents as has been reported in a survey published by Taghian et al. [49]. Following total mastectomy and for limited (1–3 positive nodes) and extensive (more than 3 positive nodes) nodal involvement, the IMC was irradiated by 59% and 64% of French and Belgian practitioners compared to 15% and 24% of American practitioners respectively [49]. The indications for IMC irradiation are not clearly defined for node negative patients or when only a limited number of nodes is involved (particularly with isolated tumour cells or micrometastases). In the recent update of the results of the Lyon trial [9], no difference was observed in terms of control of loco-regional disease or survival between patients that have had IMC RT or not, for inner and central tumours. However, the defenders of systematic RT to the IMC in case of central or internal localisation, in addition to anatomic arguments, suggest that optimising local control by a complete IMC irradiation sterilises the nodal areas to avoid any risk of diffusion from the areas where occult tumour involvement is frequently located. Moreover, the risk of recurrence is probably multiparametric. For Huang et al. [50] a high risk of IMN metastasis is observed in patients: with >4N+, with medial tumour and N+, with T3 tumour and younger than 35 years, with T2 tumour and N+ and patients with T2 and medial tumour. 4.5. Combined RT with adjuvant systemic therapy 4.5.1. Radiation-hormonotherapy The retrospective data from the American trials [20], [21], [22] are encouraging with regard to effectiveness, even though the analysis was not planned. At first sight, the main lesson is that delayed initiation of TAM may not compromise outcome of patients. In terms of toxicity, the results regarding radiation-induced fibrosis by the postoperative concomitant TAM-RT combination are arguable. The three studies [51], [52], [53] that did not show any significant increase in sub-cutaneous fibrosis with a concomitant treatment did not take into consideration the possible important impact of individual radiosensitivity [54]. On the other hand, the methodology used for the evaluation of fibrosis in studies having described the increase in risks of fibrosis in the concomitant scheme is debatable [55], [56]. In all, the essential place taken by AI at the expense of TAM in the adjuvant setting for post-menopausal patients drastically changes the debate on the AI-RT combination. The discussion remains open for post-menopausal patients. Indeed, studies comparing AI and TAM showed a gain of approximately 3%, whatever the molecule used with different tolerance profiles compared to TAM [57]. None of the randomized studies have addressed the issue of the RT-AI sequence. The COHORT study is the only study that questions the sequence with Letrozole; the time lapse is too small to assess the long-term radiation-induced toxicity [23]. 4.5.2. Radiation-chemotherapy The choice of RT and CT sequence, when they are indicated, has been the subject of numerous controversies over the past 15 years, especially due to the potential harmful risk associated with the delay in delivery of RT after the end of the CT [58]. In a review of published trials on 1900 patients, Huang et al. have reported a lower level of efficacy of late RT in terms of local control. The level of local relapse at 5 years was 6% following immediate RT against 16% after a late delivery of RT after CT [59]. In a prospective randomized study on 244 patients, Recht et al. [60] compared early RT following 4 cycles of polychemotherapy to the same CT followed by RT. While at 58 months, the local control was better in the RT-CT arm, no difference in terms of local relapse, survival without metastases and overall survival was observed at 135 months, with a death rate of 28% and 33% in both arms [3]. In the intergroup study, the question was related to the number of cycles administered to node positive patients (n=3170) [61]. The schemes of CT followed by RT consisted either of 4 cycles of adriamycin and cyclosphamide or the same CT followed by 4 cycles of paclitaxel. In the 8 cycle arm, RT was delivered at approximately 6–7 months after surgery. This trial showed an advantage in survival in the 8 cycle arm. In addition, the sub-group analysis of 354 patients included by the CALGB and treated conservatively, showed a significant decrease in terms of local relapse in favour of the 8 cycle arm (9.7% vs. 3.7%) after a median follow-up of 58 months [61]. In the recent randomized phase III trials [24], [25], [26] that compared sequential to concomitant CT-RT, drugs no longer recommended (such as mitoxantrone or methotrexate) have been evaluated. In addition, the concurrent administration of RT and taxanes has shown a significant increase in radiation pneumonitis [27], [28]. These data show that concomitant CT-RT should not be used outside trials. 4.5.3. Trastuzumab-RT The administration of trastuzumab in the adjuvant setting brings a significant benefit in survival for patients with tumours overexpressing HER2 [29], [30], [31]. There are currently four retrospective studies published on the cardiotoxicity risk of the adjuvant RT-trastuzumab combination, evaluated by the reduction in LVEF [62], [63], [64], [65]. None of them recommended stopping trastuzumab at the time of RT. In the joint analysis of the North American study [30], nodal irradiation was optional in the B-31 and systematic in cases where more than four nodes were invaded in the N9831. IMC was not irradiated in this trial. The concomitant scheme was well tolerated with no difference in terms of cardiotoxicity between left and right breast RT [63]. We recently reported a significant reduction of grade ≥2 LVEF in patients receiving concomitant RT and weekly trastuzumab. The follow-up is still short to conclude on the impact of reversibility of the LVEF reduction on late cardiotoxicity [62]. In the Scottish and Institut Curie experiences, the concomitant administration of trastuzumab with RT of the IMC does not seem to be deleterious to the heart in the short- or middle-term [64], [65]. However, regarding the short term of follow-up in these published studies and the uncertainties concerning the use of LVEF to predict late cardiac toxicity, it should be recommended to strongly limit the dose to the heart structures when RT of the IMC is delivered [66]. Regarding the other toxicities, Bellon et al. reported a cutaneous toxicity of grade ≥2 in 54% of cases and two interstitial pneumonitis (8%) in 26 patients. In that report the relationship between pneumonits and concurrent association of RT-trastuzumab was not clearly demonstrated [67]. In the French experience, acute grade ≥2 cutaneous and oesophageal toxicities were significantly higher among patients treated with the concomitant IMC RT and weekly trastuzumab [62]. However, the weekly schedule is not currently the standard in the adjuvant setting. In the analysis of the sub-group of patients who received the same scheme in the North American trial (N9831), no difference in terms of cardiac, cutaneous or oesophageal toxicity was noted. However, in this trial where the IMC was not irradiated, it is difficult to come to a conclusion concerning the absence of oesophageal toxicity when the oesophagus was not exposed to RT [63]. Finally, it is fundamental that patients benefit from an optimal treatment with respect to the risk/benefit ratio. At the cardiovascular level, benefit is obtained through a maximum reduction of the volumes of the exposed cardiac tissues in order not to lose the benefit obtained from the evolution of the RT techniques. 4.6. RT after neoadjuvant CT and/or after immediate breast reconstruction Breast reconstruction (BR) procedures, either performed immediately after total mastectomy or delayed until after RT, have significantly increased over the last decades. BR is generally indicated in patients with large tumours that have not sufficiently responded to neoadjuvant CT or when the radiation tumour/breast volume does not permit conservative surgery and in multifocal disease of the breast. The impact of BR on cosmesis and its psychologic aspects has been reported [68]. RT after BR has been suggested as an important factor that increases the risk of complications as compared to non-irradiated patients [69], [70], [71]. However these retrospective studies have not identified RT parameters or predictive factors for reduction of cosmesis. In the hypofractionated schemes, where BR has been delayed after RT, the rate of reconstruction failures seems to be lower than 10% [7], [59]. However, the limited number of patients analysed, the short follow-up and possible biases have to be considered for a cautious use of large dose/fraction in post-BR irradiation. 5. Conclusion Due to some variations in practice among French radiation oncologists in the treatment of patients with invasive non-metastatic breast cancer, the Nice-Saint-Paul de Vence group authorized a task force of breast experts to provide guidelines for radiotherapy indications. The systematic review of the literature was the basis of the evidence-based recommendations, however expert agreements in the subjects that are still under debate were necessary. Our group will update these guidelines every 4 years taking in consideration advances in breast cancer management. In the next update, we will also focus on the particular situations in some countries surrounding mainly the southern border of the mediterranean area, including those having limited RT resources [75]. Conflicts of interest The authors state no actual conflicts of interest. Reviewers Prof. Abraham Kuten, M.D., Head, Department of Oncology, Rambam Medical Center, Haifa, IL-31096, Israel. Dr. Philip Poortmans, M.D., Ph.D., Department of Radiotherapy, Dr. Bernard Verbeeten Institute, PO Box 90129, Tilburg, NL-5000 LA, Netherlands. Acknowledgement The authors would like to thank Frances Godson (Lausanne, Switzerland) for linguistic review of the manuscript. References [1]. [1]Belot A, Grosclaude P, Bossard N, et al. Cancer incidence and mortality in France over the period 1980–2005. Rev Epidemiol Sante Publique. 2008;56:159–175.
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[75]. [75]Guidelines, minimal requirements and standard of cancer care around the Mediterranean Area: Report from the Collaborative Update ref by : AROME (Association of Radiotherapy and Oncology of the Mediterranean Area) working parties. AROME. Crit Rev Oncol Hematol. 2010 Apr 15. [Epub ahead of print]. Yazid Belkacémi, M.D., Ph.D. is professor of Radiation Oncology at the University of Paris XII and vice-chairman of the Radiation Oncology Depatment at Henri Mondor Hospital (APHP) in Créteil. His research interests and topics include the management of breast and gynecologic cancers, hematologic malignancies, rare cancers and new technology developments in radiation oncology. He is a founding board member and president of AROME (Association of Radiotherapy and Oncology of the Mediterranean arEa, www.aromecancer.org). Alain Fourquet, M.D. is currently head of the Department of Radiation Oncology at the Institut Curie in Paris. His research interests are breast cancer, including technical improvements in the delivery of breast irradiation, ductal carcinoma in situ, the study of long-term outcome after treatment and its consequences on follow-up modalities. He is involved in translational research projects on breast cancer in young women, and ways to improve radiation sensitivity with concurrent chemotherapy and targeted treatments. Bruno Cutuli, M.D. is radiation oncologist at the Courlancy Clinic in Reims, France. He is currently the secretary of the French Society of Senology. His research interests and topics include breast cancer, ductal carcinoma in situ and male breast cancer. Céline Bourgier, M.D., Ph.D. is currently head of the Radiation Breast Unit at the IGR in Villejuif and has a research position in the Radiobiology Laboratory, UPRES EA27-10/IGR, in Villejuif. Her research interests include breast cancer, radiotherapy technical improvement and phase I radiation clinical trials. She is strongly involved in translational research, particularly in radiosensitization and in prevention and treatment of late radiation effects. Michel Hery, M.D. is currently head of the Department of Radiation Oncology at Princesse Grace Hospital of Monaco. His research interests include breast cancer management. He is the chairman of the Monaco Age Oncology and Bienales of Cancerology meetings in Monaco. Gérard Ganem, M.D. is a radiation oncologist at the Jean Bernad Center in Le Mans, France. His main interests are in non Hodgkin's lymphomas, gastro-intestinal and breast cancers. He is director of publication of a French didactic journal since 1992 (www.rpoc.org). Hugo Marsiglia, M.D. is professor of Radiation Oncology at Florence University in Italy. He is currently the medical director of IMO Group, Instituto Madrileno de Oncologia, the first private group of radiation oncology facilities in Spain. He is also consultant in Breast Cancer Radiotherapy at Institut Gustave Roussy (IGR), Villejuif, France. Moise Namer, M.D. is currently consultant at the Centre Azureen de Cancerologie in Mougins, France. He is past head of the Medical Oncology Department at the Anticancer Center Antoine-Lacassagne, Nice, France. Dr Namer's research interests include chemotherapy, hormone therapy, screening for breast cancers and investigation of tumour markers. He is also involved in a number of phase II and phase III clinical trials and is president of a number of medical professional organisations. Dr Namer is founder and organiser of the Breast Cancer course that takes place in Saint Paul de Vence. Joseph Gligorov, M.D. is currently medical oncologist at Tenon Hospital, Paris, France. His main research interests are breast cancer, gynaecological oncology, lung cancer and the investigation of factors that predict patient response to anticancer treatment. He is a co-founder of French St Paul de Vence conference for recommendations on breast cancer treatment, member of the expert board for breast cancer at the French National Institute for Cancer, panellist for the last St Gallen Consensus Conference and ESO Metastatic Breast Cancer Task Force. He is a founding board member and vice-president of AROME (Association of Radiotherapy and Oncology of the Mediterranean arEa, www.aromecancer.org). David Azria, M.D., Ph.D. is a radiation oncologist at the Val d’Aurelle Cancer Institute of Montpellier in France. He is professor in Radiation Oncology at the Faculty of Medicine of Montpellier. He is head of project of translational researches at the laboratory Inserm U896 (Immunotargeting and Radiobiology in Oncology). He is also the coordinator of the Translational Research Committee at the Comprehensive Cancer Centre of Montpellier. His research interests and topics include Immunotargeting in breast and digestive cancers, concurrent hormonoradiotherapy in breast and prostate tumours, predictive tests of normal tissue late effects after radiotherapy. a AP-HP, CHU Henri Mondor, Créteil, Université de Paris XII, France b Institut Curie, Paris, France c Clinique de Courlancy, Reims, France d Institut Gustave Roussy, Villejuif, France e University of Florence, Italy f Centre Hospitalier Princesse Grace. Monaco, France g Centre Jean Bernard, Le Mans, France h Centre Azuréen de Cancérologie, Mougins, France i AP-HP, Hôpital Tenon, Cancer-Est, Paris, France j CRLC Val d’Aurelle, Université Montpellier I, Montpellier, France  Corresponding author at: Service d’Oncologie-Radiothérapie, Hôpital Henri Mondor, 51 av du Maréchal De-Lattre-de Tassigny, 94000 Créteil Cedex, France. Tel.: +33 1 49 81 45 22; fax: +33 1 49 81 25 89.
PII: S1040-8428(10)00142-3 doi:10.1016/j.critrevonc.2010.06.002 © 2010 Published by Elsevier Inc. | |
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