Breast Cancer DOI 10.1007/s12282-016-0672-9

SPECIAL FEATURE

Japanese Breast Cancer Society Guidelines 2015

The Japanese Breast Cancer Society Clinical Practice Guideline for radiation treatment of breast cancer, 2015 edition Chikako Yamauchi1 • Kenji Sekiguchi2 • Akihito Nishioka3 • Satoko Arahira4 Michio Yoshimura5 • Etsuyo Ogo6 • Masahiko Oguchi7 • Yoshinori Ito8 • Hirofumi Mukai9



Received: 6 December 2015 / Accepted: 11 December 2015  The Japanese Breast Cancer Society 2016

Introduction



In the 2015 edition, the major revisions were as follows: •





CQ10 (the optimal timing of radiotherapy (RT) after breast surgery) were created by combining the previous version of CQ12 (the optimal timing of RT after breastconserving surgery) and that of CQ10 (the optimal timing of postmastectomy radiation therapy). The previous CQ8 (Contraindication of RT after breastconserving surgery) were updated to CQ12 (Contraindication of RT after breast surgery) with the addition of the description of the contraindication of PMRT. New CQs were described: CQ8-c, CQ11-b, CQ13, CQ14, CQ15-a,b,c,d.

This article is an English digested edition of the Clinical Practice Guideline of Breast Cancer 2015, published by Kanehara & Co., Ltd. Details of recommendation grades were explained in the previous report (Breast Cancer 2015; 22:1–4). & Chikako Yamauchi [email protected] 1

Department of Radiation Oncology, Shiga Medical Center for Adults, 5-4-30 Moriyama Moriyama-shi, Shiga 524-8524, Japan

2

Department of Radiation Oncology, Sonoda-kai Radiation Oncology Clinic, Tokyo, Japan

3

Division of Radiation Therapy, Kochi Health Sciences Center, Kochi, Japan

4

Department of Radiation Oncology, National Cancer Center Hospital East, Chiba, Japan

5

Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, Kyoto, Japan

The recommended grade of CQ4-b (parasternal nodal irradiation after BCS) was changed (from Grade C2 to B, C1).

CQ1. Is radiotherapy (RT) following breastconserving surgery (BCS) recommended for patients with Stage I–II breast cancer? Recommendation RT should be recommended (Grade A). It was found that the rate of local recurrence in the conserved breast was significantly decreased in randomized trials from different areas of the world in a meta-analysis of these clinical trials analyzed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) [1], with the conclusion that postoperative RT is essential. Although there are some differences between each of the identified 6

Department of Radiology, Kurume University School of Medicine, Kurume, Japan

7

Radiation Oncology Department, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

8

Department of Breast Medical Oncology, The Cancer Institute Hospital of The Japanese Foundation for Cancer Research, Tokyo, Japan

9

Department of Oncology/Hematology, National Cancer Center Hospital East, Chiba, Japan

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randomized trials concerning the tumor diameter, extent of surgical resection, dose/fractionation of RT, and chemo/ endocrine therapy, in most of the trials, following resection in patients with tumors not exceeding 4 cm in diameter, the patients were randomized in terms of whether or not they received RT (approximately 50 Gy for the whole breast and an additional 10 Gy for some patients). In the followup period of 5–20 years, a significant decrease in the local recurrence rate was confirmed in the irradiated group [1, 2]. In a meta-analysis of these clinical trials, RT following BCS contributed to a 70 % decrease in the local recurrence rate [1]. Regarding the omission of RT, a one-arm prospective trial performed by the JCRT (Joint Center for Radiotherapy) for patients with a very low risk of local recurrence was identified that did not use RT. However, the trial was stopped due to a high local recurrence rate among patients [3]. Regarding survival, significant differences between patients treated with or without RT following BCS were not identified in any trial. Vinh-Hung et al. demonstrated that if RT was omitted, the relative risk of death was 1.086 (95 % CI 1.003–1.175) in 13 clinical trials performed from 1976 to 2000 [4]. A decrease in the absolute risk of death rate by 3.8 % was observed in a meta-analysis of 17 clinical trials [5]. Some correlation was identified between a reduction in the local recurrence risk of breast cancer and death risk, and it has been estimated that preventing four local recurrences leads to the prevention of one death due to breast cancer [1] [5].

CQ2. What is the appropriate method of RT following BCS? This section evaluates the appropriate method of RT following BCS. CQ2-a. Is whole-breast irradiation recommended as for radiation fields? Recommendation As for radiation fields following BCS, whole-breast irradiation should be recommended (Grade A). For all clinical trials showing the efficacy of RT in breast-conservation treatment (BCT), whole-breast irradiation is employed, and this is considered to be a standard treatment method. CQ2-b. In whole-breast irradiation, is hypofractionated RT recommended as an equivalent treatment compared with conventional fractionation?

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Recommendation For patients older than 50 years old, with pT1-2N0, without chemotherapy, and with appropriate dose homogeneity, hypofractionated whole-breast irradiation is recommended (Grade B). Recommendation For patients other than those described above, hypofractionation may be carefully considered (Grade C1). Regarding the dose and fractionation for whole-breast irradiation, a total dose of 45–50.4 Gy in 25–28 fractions over a period of 4.5–5.5 weeks has been conventionally used, and the method is considered to be a standard. In a randomized trial performed in Canada, a dose of 42.5 Gy in 16 fractions and a standard dose of 50 Gy in 25 fractions were compared, with no significant differences found in terms of the 10-year local recurrence rate, overall survival rates, or cosmetic results [6]. Moreover, in England, hypofractionated RT showed similar rates of tumor control and normal tissue damage with a standard dose of 50 Gy in 25 fractions in some randomized trials [7, 8]. In a Cochrane review evaluating these clinical trials, it was concluded that although the hypofractionation method for selected patients could reduce acute side effects without increasing local recurrence, longer followup is required for a more complete assessment of the effect of altered fractionation [9]. Based on the findings described above, ASTRO developed a guideline [10] showing that the hypofractionation method is equivalent to the conventional method for patients older than 50 years with pT1-2N0 tumors, without systemic chemotherapy, and with no more than ±7 % dose homogeneity in the central axis plane. The guideline also recommended a dose reduction in cases where the heart is in the primary treatment field to decrease late adverse effects. CQ2-c. Is boost irradiation for the tumor bed recommended following whole-breast irradiation? Recommendation It is recommended as boost irradiation reduces local recurrence rates in the conserved breast (Grade B). In patients with pathologically positive surgical margins, a high rate of local recurrence has been recognized compared with patients with negative surgical margins. Therefore, in many centers, boost irradiation of 10–16 Gy for tumor beds has been employed. In two randomized

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trials [11, 12], a reduction of the local recurrence rate in conserved breasts has been demonstrated for patients with negative surgical margins treated with boost irradiation. In clinical practice in Japan, boost irradiation is commonly used for patients with a high risk of local recurrence. CQ2-d. Is accelerated partial breast irradiation (APBI) recommended as a routine tool? Recommendation No adequate evidence to support APBI exists, so APBI is basically not recommended. It should be performed in a clinical trial setting (Grade C2). Reducing irradiation fields facilitates relatively highdose irradiation with a small fraction in a short period, a method that has been introduced in clinical practice as APBI. There are several methods of APBI, including using interstitial brachytherapy, intracavitary brachytherapy, intraoperative RT, and three-dimensional conformal external beam RT. A randomized trial conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP)/Radiation Therapy Oncology Group (RTOG) has been performed, and whole-breast irradiation is therefore recommended as a standard method until more data are available. APBI using particle beam RT should also be performed in a clinical trial setting. CQ3. Should regional lymph nodes be irradiated in stage I-II breast cancer patients who have undergone BCS? CQ3-a. Should regional lymph nodes be irradiated for patients with 4 or more positive axillary nodes? Recommendation For patients with 4 or more positive axillary nodes, regional lymph nodes should be irradiated (Grade B). For postmastectomy patients with an increased risk of recurrence such as 4 or more positive axillary lymph nodes, a number of randomized clinical trials as well as metaanalyses have shown that chest wall and regional nodal irradiation increases not only local control, but also overall survival (also refer to CQ9). However, little high-level evidence exists regarding those who underwent BCS. Nonetheless, patients with a large number of positive nodes have an increased risk of regional nodal metastasis [13–15], and regional nodal irradiation has been reported to improve loco-regional control [13, 16, 17]. CQ3-b. Should regional lymph nodes be irradiated in patients with 1–3 positive axillary nodes?

Recommendation For patients with 1–3 positive axillary nodes, regional irradiation can be considered (Grade C1). For postmastectomy patients with 1–3 positive axillary lymph nodes, some evidence from meta-analysis exists demonstrating that regional nodal irradiation increases the local control rate and reduces breast cancer-related mortality [18] (also refer to CQ7). In the MA.20 trial [16], node-positive or high-risk nodenegative breast cancer patients who were treated with BCS and adjuvant systemic therapy were randomized to undergo either whole-breast irradiation plus regional nodal irradiation or whole-breast irradiation alone. At the 10-year follow-up, there was no significant between-group difference in overall survival. However, the rates of disease-free survival were 82 % in the nodal-irradiation group and 77 % in the control group (p = 0.01). Patients in the nodalirradiation group exhibited higher rates of grade 2 or greater acute pneumonitis (p = 0.001). In the European Organization for Research and Treatment (EORTC) 22922/10925 trial [17], women who had a centrally or medially located primary tumor, or an externally located tumor with axillary involvement were randomized to undergo either whole-breast or chest wall irradiation in addition to regional nodal irradiation (nodalirradiation group) or whole-breast or thoracic-wall irradiation alone (control group). At 10 years, irradiation of the regional nodes had a marginal effect on overall survival (82 % in the nodal-irradiation group and 81 % in the control group, p = 0.06). The rate of disease-free survival was improved, and breast cancer-related mortality was reduced. On the other hand, the systemic therapies generally performed in these two studies have been replaced in a newly developed regimen known to reduce local recurrence and improve survival. Although these two trials indicate that some patients with 1–3 positive lymph nodes benefit from regional nodal irradiation after axillary dissection, currently employed systemic therapies might further reduce regional nodal recurrence. Therefore, for patients with 1–3 positive lymph nodes, regional nodal irradiation can be considered, particularly for those at higher risk. CQ3-c. Should regional lymph nodes including undissected axilla be irradiated in patients with positive sentinel lymph nodes? Recommendation For patients with micrometastasis in axillary nodes, routine adjuvant axillary RT applied to undissected axilla is not

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recommended when appropriate systemic therapy is available (Grade C2). Recommendation For patients with macrometastasis and an increased risk of non-sentinel lymph node metastasis, regional irradiation including undissected axilla should be considered. For patients with a low risk of non-sentinel lymph node metastasis, tangential RT alone is recommended (Grade B). A systematic review by Pepels et al. [19] reported low axillary recurrence rates in patients with positive sentinel lymph nodes who did not undergo axillary dissection. Based on this, the omission of axillary lymph node dissection for patients with positive sentinel nodes has been explored. For patients with breast cancer and micrometastasis in sentinel nodes, the effect of axillary lymph node dissection was evaluated in a phase III trial (International Breast Cancer Study Group (IBCSG) 23-01 trial) [20]. At a median follow-up of 5 years, there was no difference between axillary dissection and no axillary dissection groups regarding the primary endpoint of disease-free survival. The rate of complications in the axillary surgery group was higher. Two randomized phase III trials (also refer to Surgery CQ13) were performed to investigate the effect of axillary lymph node dissection for patients with T1-2, clinically node-negative and positive sentinel nodes. In a trial of EORTC 10981-22023 ‘After Mapping of the Axilla: Radiotherapy Or Surgery’(AMAROS) [21], axillary lymph node dissection was compared with axillary RT, and it was compared with no further treatment in the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial [22]. As a result, there were no significant differences in regional control between groups with and without axillary lymph node dissection at a median follow-up duration of 6 years in either trial. The surgical morbidity rate was significantly lower in patients with undissected axilla. In the ACOSOG Z0011 trial [22], postoperative adjuvant irradiation was not delivered to the axilla but the breast only; nevertheless, the axillary recurrence rate remained low. Therefore, it was indicated that axillary control may possibly be attributed to adjuvant systemic therapy or partial axillary irradiation by tangents. However, a marked protocol violation was identified after reviewing case report forms regarding RT. In the AMAROS trial [23], axillary irradiation yielded at least an equivalent axillary control benefit in comparison with axillary dissection.

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Based on the above, for patients with micrometastasis in axillary nodes, routine adjuvant axillary RT to undissected axilla is not recommended when appropriate systemic therapy is available. In contrast, it is recommended to consider high axillary tangents encompassing the whole breast and axilla, or regional irradiation including the axilla, for those who have macrometastasis in sentinel lymph nodes and an increased risk of non-sentinel lymph node metastasis. For patients with a low risk of non-sentinel lymph node metastasis, tangential RT alone is recommended. CQ4. What are the optimal radiation fields for regional lymph nodes in high-risk patients after BCS? CQ4-a. Is supraclavicular nodal irradiation recommended for high-risk patients after BCS? Recommendation Supraclavicular nodal irradiation is recommended for highrisk patients after BCS (Grade B).

CQ4-b. Is parasternal nodal irradiation recommended for high-risk patients after BCS? Recommendation Parasternal nodal irradiation is recommended for patients with clinically or pathologically positive parasternal lymph nodes (Grade B). Parasternal nodal irradiation is not necessary, but may be considered in patients without clinically or pathologically positive parasternal lymph nodes (Grade C1). In patients who have undergone breast-conserving surgery, the rates of supraclavicular lymph node and internal mammary node metastases have been reported to be 0–8.7 and 0.1–2.8 %, respectively [13–15, 24]. The MA.20 study is one of the few randomized controlled trials investigating regional nodal irradiation for patients after BCS. There is no difference in the 10-year overall survival after BCS with or without elective nodal irradiation including the internal mammary nodes [25]. In some retrospective studies, supraclavicular nodal irradiation has been reported to improve local control [13], and so elective supraclavicular nodal irradiation is recommended in high-risk groups. However, parasternal nodal irradiation is not necessary when internal mammary lymph node metastasis is not present clinically or confirmed pathologically.

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CQ5. Is postoperative RT recommended for patients with a pathologic complete response (pCR) after neoadjuvant chemotherapy? Recommendation Postoperative RT is recommended for patients with pCR after neoadjuvant chemotherapy (Grade B). Recently, treatment strategies of neoadjuvant chemotherapy followed by surgery have been increasingly used in the management of breast cancer patients after consideration of the tumor subtypes. The aim of neoadjuvant chemotherapy is to reduce the size of the primary tumor to increase the likelihood of breast conservation, to assess the response to chemotherapy, and to predict the disease-free survival period. We assessed whether or not postoperative RT is necessary for patients who achieved pCR by BCS after neoadjuvant chemotherapy. The MD Anderson Cancer Center retrospectively reported that the 5-year locoregional recurrence rate remained high when RT was not used in patients with stage III disease who achieved pCR [26]. This finding suggests that the stage before the initiation of chemotherapy also correlates with the locoregional recurrence rate, although the effect of neoadjuvant chemotherapy is an important prognostic factor. Another report from the MD Anderson Cancer Center [27] in addition to principal reviews and randomized trials [28, 29] showed that RT is necessary for all patients who underwent BCS after neoadjuvant chemotherapy, regardless of the response to chemotherapy. Although there are no references with high-level evidence, postoperative RT is recommended for patients who underwent BCS after neoadjuvant chemotherapy even if pCR is achieved. CQ6. Is RT recommended for ductal carcinoma in situ (DCIS) after BCS? Recommendation RT should be recommended for patients with DCIS after BCS (Grade A). Four randomized trials (National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 [30], EORTC 10853 [31], UK/ANZ DCIS trial [32], and SweDCIS [33]) and the Cochrane Database Systematic Review [34] investigating the efficiency of postoperative RT for patients with DCIS who underwent BCS showed that postoperative RT reduced the rate of ipsilateral breast tumor recurrence. Furthermore, the meta-analysis conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) on these trials [35] showed that postoperative RT reduced the absolute 10-year risk of any ipsilateral tumor

recurrence from 28 to 13 %. However, after a 10-year follow-up, there was no significant effect on breast cancerrelated mortality, mortality from causes other than breast cancer, or all-cause mortality. Additionally, several studies attempted to identify whether DCIS patients with a favorable prognosis could be treated with local excision alone without RT to yield acceptably low local recurrence rates [36]. A randomized trial by The Radiation Therapy Oncology Group (RTOG9804) in women with low- or intermediategrade DCIS, measuring less than 2.5 cm with margins ]3 mm, compared RT with observation after surgery. At 7 years, the local failure rate was 0.9 % in the RT arm versus 6.7 % in the observation arm [37]. Taken together, there is no sufficient evidence to identify those patients to be treated without postoperative RT. At present, therefore, postoperative RT is recommended for DCIS patients after breast-conserving surgery. CQ7. Is postmastectomy RT (PMRT) recommended for patients with advanced breast cancer? CQ7-a. Is PMRT recommended for patients with 4 or more positive axillary lymph nodes? Recommendation PMRT should be recommended for patients with 4 or more positive axillary lymph nodes (Grade A). As a result of the integrated analysis of the Danish Breast Cancer Cooperative Group. (DBCG) 82c randomized trial including postmenopausal patients and DBCG 82b randomized trial including premenopausal patients, PMRT was found to improve the survival rate in patients with 4 or more positive axillary lymph nodes [38]. In addition, an EBCTCG meta-analysis including 1772 patients with four or more positive axillary lymph nodes concluded that PMRT reduced 10-year locoregional recurrence and 20-year breast cancer mortality [18]. CQ7-b. Is PMRT recommended for patients with 1–3 positive axillary lymph nodes? Recommendation PMRT is recommended for patients with 1–3 positive axillary lymph nodes (Grade B). As a result of the integrated analysis of Danish 82c and Danish 82b, PMRT was found to improve the overall survival in patients with 1–3 positive axillary lymph nodes [38]. On the other hand, as a subset analysis of a Canadian randomized trial at the 20-year follow-up, breast cancerspecific survival was significantly improved by PMRT,

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although overall survival showed no significant difference [39]. An EBCTCG meta-analysis including 1314 patients with 1–3 positive axillary lymph nodes concluded that PMRT reduced 10-year locoregional recurrence and 20-year breast cancer-related mortality. Therefore, PMRT is also recommended for patients with 1–3 positive axillary lymph nodes.

CQ8. What are the optimal irradiation fields for PMRT? CQ8-a. Is chest wall irradiation recommended for patients given PMRT? Recommendation Chest wall irradiation should be recommended for patients given PMRT (Grade A). CQ8-b. Is supraclavicular nodal irradiation recommended in patients given PMRT? Recommendation Supraclavicular nodal irradiation is recommended in patients given PMRT (Grade B). CQ8-c. Is parasternal nodal irradiation recommended for patients given PMRT? Recommendation Parasternal nodal irradiation is recommended for patients with clinically or pathologically positive parasternal lymph nodes (Grade B). Parasternal nodal irradiation is not necessary, but may be considered for patients lacking clinically or pathologically positive parasternal lymph nodes (Grade C1). Whether or not the parasternal nodes should be included in the radiation field is controversial. One randomized clinical trial has been conducted in France to evaluate the significance of the parasternal node irradiation. The study included 1334 women treated with mastectomy and PMRT including the chest wall plus supraclavicular nodes. They were randomly assigned to treatment with or without parasternal RT. After a median follow-up of 11.3 years, no benefit of parasternal node irradiation on the overall survival at 10 years was demonstrated [40]. The survival benefit of parasternal nodal irradiation remains unclear. Therefore, irradiation to the parasternal region is recommended for patients with clinically or pathologically positive parasternal lymph nodes, and is not

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necessary, but may be considered for patients lacking clinically or pathologically positive parasternal lymph nodes. CQ9. Is PMRT recommended for patients showing a response following neoadjuvant chemotherapy? Recommendation PMRT is recommended for patients showing a response following neoadjuvant chemotherapy, based on the pretreatment stage indication (Grade B). Although there is no high-level evidence, PMRT is recommended based on the pretreatment tumor characteristics for patients with advanced breast cancer even if a favorable response is achieved with chemotherapy [41]. CQ10. What is the optimal timing of RT after breast surgery? An extension of the overall treatment time may result in an unfavorable outcome owing to tumor regrowth. Therefore, although the early start of postoperative RT is preferable, there is a tendency toward a delay due to postoperative complications and/or the manpower of a therapy facility, and also to the patient’s schedule. In addition, if chemotherapy is carried out first, the start of RT will inevitably be postponed. There is little evidence regarding safety, when endocrine therapy and/or a molecular-targeted therapy are combined with RT. CQ10-a. From when should RT be initiated for patients without postoperative chemotherapy? Recommendation RT initiation is recommended as early as possible after the operation, preferably not exceeding 20 weeks postoperation (Grade B). There has been no randomized controlled trial investigating whether outcomes are affected by the timing of RT initiation after BCS; only cohort studies and reviews were identified. Although there is no consistency in the conclusion of each report, the meta-analysis by Huang et al. concluded that local recurrence is increased when RT is delayed by more than 8 weeks after surgery [42]. The review by Tsoutsou et al. concluded that a delay in starting RT reduced the rates of local control and survival, although there was a wide threshold of variation, from 6 to 20 weeks [43]. In a report from Sweden, an RT delay of\20 weeks was significantly correlated with baseline factors such as the age, menopausal status, and estrogen-receptor status. After adjustment for these factors, the timing of RT was not significantly correlated with the interval to local

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recurrence, disease-free survival, or overall survival. When appropriate endocrine therapy is carried out after an operation, a delay in RT is permitted. In general, however, it is preferable to start it within 20 weeks [44]. Based on the findings described above, it is difficult to establish an optimal time to commence RT after BCS. However, there is no medical merit in delaying the start of RT, at least after an operative wound heals, so it would appear to be desirable to start it as soon as possible. CQ10-b. For patients who are recommended to receive adjuvant chemotherapy after breast surgery, should chemotherapy be administered prior to RT?

CQ11. Is RT recommended for patients after breast reconstruction? CQ11-a. Is RT recommended for patients after breast reconstruction with autologous tissue transplantation? Recommendation RT may be carefully considered for patients after breast reconstruction with autologous tissue transplantation (Grade C1).

Recommendation

CQ11-b. Is RT recommended for patients with temporary tissue expanders?

Chemotherapy should be administered prior to RT (Grade B).

Recommendation

CQ10-c. Is concurrent RT and chemotherapy recommended after breast surgery? Recommendation Concurrent RT and chemotherapy is not recommended fundamentally, because there have been some reports of increasing adverse event rates (Grade C2). CQ10-d. Is concurrent RT and endocrine therapy recommended after breast surgery? Recommendation There is neither a poor outcome clinically nor increase in the adverse event rate; when it is judged to be required, concurrent RT and endocrine therapy after breast surgery may be considered (Grade C1). CQ10-e. Is concurrent RT and molecular-targeted therapy recommended after breast surgery?

RT is not recommended for patients with temporary tissue expanders, because the complication rate in patients with such expanders is higher than in those with permanent implants (Grade C2).

CQ11-c. Is RT recommended for patients after breast reconstruction with permanent implants? Recommendation RT may be carefully considered for patients after breast reconstruction with implants, as there is insufficient information about safety (Grade C1).

CQ12. For which patients is postoperative RT not recommended? Recommendation

Recommendation Concurrent RT and trastuzumab for patients with HER2positive breast cancer may be considered, because clinical adverse events have not been reported in the short term (Grade C1). The concurrent administration of RT with trastuzumab does not appear to result in an increased complication rate according to previous reports. However, assessment of the cardiac toxicity of RT requires long-term follow-up, and late adverse effects are unclear at this time. Therefore, we should pay special attention to the exposure dose to the heart in patients with left-sided breast cancer.

Postoperative RT is contraindicated for patients during pregnancy or in those who have received prior RT to the ipsilateral breast or chest wall (Grade D). Recommendation Postoperative RT is relatively contraindicated for patients with active connective tissue disease (especially scleroderma and systemic lupus erythematosus), with genetic disorder at very high risk of radiation-induced second malignancy, such as Li Fraumeni syndrome except BRCA

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1/2 mutation, or who cannot raise their ipsilateral arms in a supine position (Grade C2). Li Fraumeni syndrome is a hereditary disorder predominantly caused by mutations of the TP53 gene and features the occurrence of breast cancer in young women. Since TP53 mutation has been reported to be relevant to second malignancy after radiation exposure, RT should be avoided if possible. CQ13 Is postoperative RT recommended for patients with positive or strongly suspected BRCA 1/2 mutations? Recommendation RT after BCS for such patients is employed according to the clinical indications irrespective of the BRCA 1/2 mutation status. (Grade B). Breast-conserving therapy may be carefully considered for patients with positive BRCA 1/2 mutations. (Grade C1). There have been no randomized clinical trials evaluating the safety or efficacy of postoperative RT for patients with BRCA 1/2 mutations. First, the prognosis of patients after breast-conserving therapy (BCT) was investigated according to the BRCA 1/2 mutation status. There have been several reports referring to this issue [45–47]. According to the meta-analysis by Valachis et al. [48], there was no significant difference in ipsilateral breast recurrence (IBR) between carriers and controls. However, a significantly higher risk of ipsilateral breast recurrence in BRCA-mutation carriers was observed in 5 studies with at least a 7-year follow-up. The contralateral breast cancer incidence was also significantly higher in carriers versus controls. Uses of adjuvant chemotherapy and oophorectomy were associated with a significantly lower risk of IBR in BRCA-mutation carriers. Second, the risk after receiving RT among BRCA1/2 mutation carriers with breast cancer was explored. A multiinstitutional study [49] assessed the prognosis after BCT or mastectomy among 655 women with BRCA1/2 mutations diagnosed with breast cancer. All treated with BCS and 29 % treated with mastectomy received adjuvant RT. Local failure as the first failure was significantly more likely in those treated with BCT compared to mastectomy, with a cumulative estimated risk of 24 vs. 6 %, respectively, at 15 years (p \ 0.0001). However, when BCT was combined with chemotherapy, 15-year estimates of local failure decreased to 12 % (p = 0.08 when compared to mastectomy). The risk of contralateral breast cancer was high in both groups, exceeding 40 %, but was not significantly different between with and without the use of adjuvant RT (p = 0.44). There were no differences in regional or systemic recurrences between the groups, and BRCA1/2 mutation carriers with breast cancer exhibited similar survival data.

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In a case–control study [50], the risk of developing contralateral breast cancer was elevated among BRCA1/2 mutation carriers (RR = 4.5), and also among those treated with RT (RR = 1.2). The prevalence of carriers was similar in controls who did versus did not receive RT. However, among mutation carriers, an incremental increase in the risk associated with the radiation dose was not significant. Accordingly, there was no clear indication that carriers were more susceptible to the carcinogenic effects of radiation than non-carriers. Referring to adverse events of RT, multi-institutional collaborative studies [51, 52] demonstrated no evidence of increased acute or chronic radiation-associated morbidity in breast tissue with BRCA1/2 mutation compared with controls. Based on current evidence, RT after BCS can be employed from a clinical point of view, irrespective of the BRCA 1/2 status. BCT in BRCA-mutation carriers can be considered a reasonable option. However, several risk-related aspects should be discussed with patients before the final decisionmaking. CQ14. Is RT for the primary site recommended for stage IV breast cancer? Recommendation For patients with an unresectable primary tumor, RT may be considered to preserve their quality of life (QOL) (Grade C1). For patients after resecting the primary tumor, RT is not recommended because the evidence is insufficient (Grade C2). Although RT of the primary tumor has been recognized as a useful treatment option in breast cancer patients with distant metastases, the data are limited. A report from Surveillance, Epidemiology, and End Results (SEER, 1988–2003) showed that the survival of stage IV breast cancer patients treated with RT is improved in comparison with patients without RT [53], but another report showed no improvement [54]. A study from France investigated whether local therapy contributes to survival improvement in stage IV breast cancer patients. It was shown that the overall survival (OS) of patients treated with local therapy is superior to that of patients without local treatment [55]. A report from Canada showed that 5-year OS of a local treatment group (surgery alone, RT alone, surgery plus postoperative RT) was better than that of a no-local treatment group in stage IV breast cancer patients (21 vs. 14 %, respectively; p \ 0.001) [56].

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It was reported that 239 stage IV breast cancer patients received loco-regional treatment (loco-regional RT (LRRT) alone (n = 147) or breast and axillary surgery ± LRRT (n = 92) at Institut Gustave Roussy [57]. A long-term loco-regional clinical response was observed in 85 % of patients following loco-regional RT, and no significant differences in 3-year OS were observed between the two groups [57]. Taken together, there are no studies offering high-level evidence because of the character of the stage IV disease. Furthermore, since local RT could be delivered selectively to patients with a favorable performance status, it is difficult to evaluate the effectiveness of RT. However, local RT delivered to the primary tumor of stage IV breast cancer patients may be considered if the control of the primary site could contribute to the improvement of patients’ QOL. On the other hand, RT is not recommended for stage IV patients after resecting the primary tumor, because evidence regarding the effectiveness of postoperative RT is insufficient. After the resection of the primary tumor, close observations are needed, and when local recurrence is observed, the next treatment, such as reresection or RT for the primary site, should be discussed at that point according to the performance status of the patient.

CQ15. Is RT recommended for painful bone metastasis?

Based upon a systematic review, a single 8-Gy administration of RT facilitates the same high palliation rate for pain relief from bone metastases as those of higher doses of fractionated RT regimens [58].

CQ15-b. Is fractionated RT recommended for impending pathologic fracture or epidural spinal cord compression caused by bone metastasis? Recommendation Fractionated RT is recommended for impending pathologic fracture or epidural spinal cord compression caused by bone metastasis (Grade B). Complete and impending pathologic fractures of bone metastasis are treated with durable fixation or reconstruction followed by postoperative RT [59]. The management of patients with neoplastic epidural spinal cord compression includes aggressive tumor resection and stabilization followed by external fractionated RT, or stereotactic body RT, resulting in an increased likelihood of regaining the ability to walk [59]. The protracted fractionated RT promotes remineralization, the alleviation of pain, and an improved functional status by treating metastatic bone disease [60].

CQ15-c. Is a second-time RT recommended for refractory or relapsed pain due to bone metastasis?

Recommendation Recommendation RT is recommended for patients with painful bone metastasis (Grade A). The goals of palliative treatment for bone metastases are pain relief, the preservation of function, and maintenance of skeletal integrity. When bone pain is confined to a limited number of sites, local field external beam RT to the painful sites can provide pain relief in 80–90 % of cases [58]. Early or appropriate timing of RT may be useful for maintaining the quality of life of patients with bone metastases.

CQ15-a. Is a single 8-Gy administration of RT recommended for painful bone metastasis? Recommendation A single 8-Gy administration of RT is recommended for patients with painful bone metastasis (Grade B).

A second-time RT is recommended for refractory or relapsed pain due to bone metastasis (Grade B). A meta-analysis of 7 trials revealed that re-irradiation is a useful option for patients with refractory or relapsed painful bone metastases with acceptable toxicities [61].

CQ15-d. Is a radiopharmaceutical recommended for refractory pain due to widespread bone metastases? Recommendation A radiopharmaceutical is an optional treatment for refractory pain due to widespread bone metastases (Grade C1). For patients with widespread symptomatic lesions, radiopharmaceuticals (bone-targeting radioisotopes; strontium-89) provide useful palliative alternatives [62].

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CQ16. Is RT recommended for brain metastasis? Recommendation RT is recommended for patients with brain metastasis (Grade B). Prognostic classification systems, such as RTOG recursive partitioning analysis (RPA) [63] and the diseasespecific graded prognostic assessment (GPA) [64], can aid in defining favorable versus poor prognosis patients to help guide decision-making for each treatment.

CQ16-a. Is RT recommended for patients with a single or limited number of brain metastases? Recommendation For patients with a single or limited number (generally two to four lesions) of brain metastases, with a favorable performance status, stereotactic radiosurgery (SRS) is recommended (Grade B). For patients with a single or limited number (generally two to four lesions, up to ten) of metastases, treatment is individualized, based on such factors as the tumor size and location, tumor biology, and anticipated treatment toxicity [65–67]. Additional whole-brain RT (WBRT) after SRS is optional [65, 68]. However, careful follow-up within a short interval using MRI provides an opportunity to postpone WBRT until the recurrence of brain metastases without decreasing the patient’s daily activities or quality of life [65, 68].

CQ17. Is RT recommended for patients who develop isolated locoregional recurrence after mastectomy? Recommendation RT is recommended for patients who develop isolated locoregional recurrence after mastectomy in combination with systemic pharmaceutical therapy (Grade B). For patients who develop isolated locoregional recurrence after mastectomy, management is complex and usually requires multidisciplinary assessment and planning. There is little consensus on how best to manage these patients. It is preferable to administer systemic therapy first, not only to facilitate successful locoregional treatment, but also to be certain that early evidence of distant metastases does not emerge. For women who did not undergo immediate PMRT, external beam RT is a standard treatment for isolated chest wall recurrence. Optimal RT management generally involves treatment to the entire chest wall and draining lymph node areas, even if the recurrence is localized to a small area of the chest wall. External beam RT has the potential to provide long-term disease control [70]. Compliance with ethical standards Conflict of interest Yoshinori Ito received lecture fees from Chugai, Esai, Novartis and research grants from Novartis, Chugai, Parexel, Esai, Sanofi, Taiho, EPS, Dai-ichi-sankyo, Boehringeringelheim. The other authors declared no potential conflicts of interest.

References CQ16-b. Is RT recommended for patients with multiple brain metastases? Recommendation For patients with multiple metastases, WBRT is recommended (Grade B). For patients with multiple metastases, we recommend whole-brain RT (WBRT) [63]. SRS may be added after WBRT for patients with a favorable prognosis and limited number of residual lesions [69].

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The Japanese Breast Cancer Society Clinical Practice Guideline for radiation treatment of breast cancer, 2015 edition.

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