Introduction

Postmastectomy radiotherapy (PMRT) has been shown to improve locoregional tumor control and overall survival in patients with node-positive breast cancer [1]. In randomized trials, comprehensive loco-regional radiotherapy (RT) is delivered to the chest wall (CW), the axilla, the supraclavicular fossa (SCF), and the internal mammary nodes (IMC) [2–4]. However, results from several large studies evaluating patterns of locoregional failure in patients received adjuvant systemic therapy without RT indicated that the CW followed by the SCF are the most common sites of locoregional recurrence. Recurrences were less frequent in the axilla and rare in the IMC [5–8]. The results from Eastern Cooperative Oncology Group (ECOG) trials demonstrated that patients with positive axillary lymph nodes commonly developed recurrence in the CW (12 %), the supra/infraclavicular nodes (8 %), the axilla (4 %), and the IMC (0.2 %) [5]. Therefore, the key target for RT is the CW and the supra/infraclavicular nodes.

In mainland China, total mastectomy and axillary dissection has been the main surgical approach for most patients with non-metastatic breast cancer regardless of the stage. The appropriate application of PMRT is important to ensure the quality of patient care. However, in a country such as mainland China with a large and populous geography and limited resources, there is a wide variation in the practice of locoregional radiotherapy for breast cancer. In order to provide evidence that could improve management, we conducted a retrospective epidemiological study to investigate the status of and changes in PMRT targets in the management of breast cancer in seven representative hospitals in China between 1999 and 2008. This study was approved by the institutional review board (IRB) of the Cancer Foundation of China.

Methods

Patient selection

Mainland China is divided into seven regions (north, northeast, central, south, east, northwest, and southwest), and one tertiary academic hospital from each region was selected. Each hospital has its own RT facilities. Further details on these hospitals can be seen in Table 1. Patients were randomly selected and the relevant information was collected. One month per year (except for January or February) was randomly selected to represent each year from 1999 to 2008 in every hospital. All inpatient cases within the selected month were reviewed and the information was collected. For each selected month, if patient numbers were fewer than 50, then more cases from the neighboring months were reviewed until the total number reached 50. If patient number in the selected month exceeded 50, all cases in that month were reviewed. All patients met the following inclusion criteria: (1) pathology confirmed primary breast cancer; (2) the inpatient admission date was within the selected month in the study hospital; and (3) treatment (surgery, chemotherapy, or radiotherapy) for breast cancer was recorded. The method used has been previously described, among 45,200 breast cancer patients treated in seven hospitals during 10 years, 4,211 (9.3 %) patients were randomly selected [9]. Patients who met the following criteria were enrolled in this study: (1) a mastectomy and axillary dissection had been performed; (2) adjuvant postmastectomy radiotherapy had been delivered; and (3) radiotherapy sites were known. A total of 661 patients were included in this study, which accounts for 1.5 % of the total number of breast cancer patients treated in these seven hospitals during 10 years. Table 1 indicated that the number of patients included in this study are not evenly distributed between all the hospitals mainly because of the variations in the use of PMR between hospitals. As the majority of patients in hospital #3 were treated on out-patient basis, only seven in-patients were included.

Table 1 Information on all seven hospitals (1, north; 2, northeast; 3, central; 4, south; 5, east; 6, northwest; and 7, southwest)
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Patients were classified into three groups according to disease stage: high-risk group, defined as T3–4, or with four or more positive axillary lymph nodes or positive surgical margins; intermediate-risk group, defined as tumor size 5 cm or less, with one to three positive axillary nodes; and low-risk group, defined as tumor size 5 cm or less, with negative axillary nodes.

Statistical analyses

The Cochran-Armitage trend test was used to evaluate trends in the use of different RT targets and in variations in patient groups from 1999 to 2008. The chi-square test was used to compare differences in the use of RT targets between different hospitals and between different patient groups. Statistical significance was assessed using two-tailed tests with an alpha level of 0.05. The SAS statistical software was used for data analysis.

Results

Of 661 patients included, 532 (80.5 %) had undergone a modified radical mastectomy, 126 (19.1 %) had undergone a radical mastectomy and three patients (0.4 %) had had an extended radical mastectomy. The median number of axillary nodes dissected was 16 (range, 1–66). Other than the 18 patients (1.8 %) for whom complete pathology results were not available, the axillary nodes were negative in 127 patients (19.2 %), one to three nodes were positive in 168 patients (25.4 %), and four or more were positive in 354 patients (53.6 %).

The distribution of RT targets for the 661 patients is shown in Table 2. Overall, the CW was irradiated in 596 patients (90.2 %), the SCF in 606 patients (91.5 %), the axilla in 196 patients (29.6 %), and the IMC in 297 patients (44.9 %). The RT techniques and the doses used for the CW and the nodal regions are shown in Table 3. The majority of patients received a total dose of 50 Gy, using conventional fractionation of 2 Gy per day. Low-energy electrons are used in about 60 % of patients for CW RT and bolus was used in 27.2 % of patients. Combined photon and electron, or photon alone were used frequently for SCF RT.

Table 2 Distribution of radiation targets in 661 patients with breast cancer
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Table 3 Radiation techniques and doses to chest wall and nodal regions
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From 1999 to 2008, there was an increase in the use of CW RT, and a decrease in the use of axillary and IMC RT (Fig. 1). The use of CW RT increased from 67.3 % in 1999 to 98.4 % in 2003, then remained relatively stable between 2004 and 2008 (p < 0.001). The use of axillary RT fluctuated between 25.5 and 44.9 % from 1999 to 2005, then steadily decreased from 36.8 % in 2006 to 22.8 % in 2008 (p = 0.027). The use of IMC RT decreased significantly from 81.8 % in 1999 to 25.3 % in 2008 (p < 0.001). However, there was no significant change in the use of SCF RT from 1999 to 2008, varying between 83.7 and 96.5 % (p = 0.597; Fig. 1).

Fig. 1
figure 1

Use of locoregional postmastectomy radiotherapy in patients with breast cancer, from 1999 to 2008

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There were significant differences between different regions in the use of CW, axillary, and IMC RT (Fig. 2). The use of CW RT varied between 71.4 and 97.9 % (p = 0.008). The use of axillary RT varied between 3.1 and 85.4 % (p < 0.001). The use of IMC RT varied between 14.3 and 85.6 % (p < 0.001). However, there was no significant difference between different regions in the use of SCF RT, which varied between 84.1 and 97.9 % (p = 0.371; Fig. 2).

Fig. 2
figure 2

Use of locoregional postmastectomy radiotherapy in patients with breast cancer in seven regions

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Among the 661 patients, 568 patients had available staging information and were divided into low-, intermediate-, and high-risk groups. There were no significant changes in the distribution of low-, intermediate-, and high-risk groups from 1999 to 2008 (p = 0.768; Fig. 3). The association between RT targets and risk groups were analyzed for these 568 patients (Table 4). Patients in high-risk groups received CW RT more frequently than low- and intermediate-risk groups. Patients in high- and intermediate-risk groups received SCF RT more frequently than low-risk groups. There was no association between risk group and axillary RT, or between risk group and IMC RT.

Fig. 3
figure 3

Distribution of low-, intermediate-, and high-risk patients with breast cancer, from 1999 to 2008

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Table 4 Use of chest wall and regional node radiation in low-, intermediate-, and high-risk patient groups
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The correlation between the use of regional node RT and axillary node status was shown in Table 5. Except for that, the use of axillary RT was associated with positive axillary nodal ratio of 20 % or more. Overall, 23.4 % of patients with a nodal ratio less than 20 and 33.3 % of patients with a nodal ratio 20 % or more received axillary RT (p = 0.007). The use of IMC RT was associated with primary tumor location, with 53.8 % of patients with tumor located at the inner quadrant and 42.6 % of patients with tumor at the outer quadrant receiving IMC RT (p = 0.015).

Table 5 The correlation between regional node RT field and the axillary nodal status
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Discussion

In this retrospective epidemiological study, we found that the CW and the SCF were the two principal targets most often irradiated in PMRT, and more than 90 % of patients had received CW and SCF RT. The use of CW RT increased, and axillary and IMC RT decreased from 1999 to 2008. This finding is consistent with the evidence, which suggests that the CW and the SCF are the two most common sites of locoregional recurrence, reflecting the American Society of Clinical Oncology recommendation that PMRT includes treatment to the chest wall and the draining lymphatics in the undissected axillary apex and supraclavicular fossa [10]. This finding also demonstrates that the treatment standard in China has improved, mainly because the continuing medical education makes more and more radiation oncologists aware of the evidence abroad and of our own [11].

It is clear that for patients who did not receive PMRT, the chest wall is the most common site of locoregional recurrence, accounting for 55–70 % of all locoregional recurrences [5–8]. In this study, the use of the CW target varied significantly between different regions. Fortunately, from 1999 to 2008, the use of CW RT increased significantly from 67.3 % in 1999 to 96.2 % in 2008, and has remained on a high level since 2003. In CW RT, low-energy electrons are more frequently used, probably due to the thin and less curved chest wall postmastectomy in most Chinese women. Wang et al. has reported a 5-year chest wall recurrence rate of 2.9 % using single low-energy electron beam for postmastectomy chest wall radiation in 328 Chinese women with breast cancer. Figure 4 illustrates typical electron field for chest wall marked on a patient’s skin surface [12]. About 20 % more patients in current study received CW RT with photon or cobalt tangential fields. The difference in use of electrons or photon/cobalt tangential fields reflects the availability of different types of machines in different hospitals. The variation in the treatment technique would not be expected to influence the treatment outcome, because Hehr et al. has reported that the 5-year locoregional tumor control rates with electron or photon techniques were comparable, being 92 vs. 89 % [13]. When the chest wall is treated, a tissue equivalent material known as bolus is commonly placed on the skin to reduce the skin-sparing effects of beams and to increase dose to the skin, subcutaneous tissue, and dermal lymphatics. Chest wall bolus was used in about one-fourth of patients in this study, though there is little outcome evidence for this bolus technique. Graham et al. reported that parascar bolus and no bolus performed no worse than did whole chest wall bolus with regard to chest wall recurrence. However, daily 1-cm whole chest wall bolus may have an impact on early cessation of radiotherapy caused by skin toxicity, which then may influence chest wall recurrence [14]. An international survey of radiation oncologists found that the use of bolus is frequently determined by the personal preference of the treating radiation oncologist. It was found that 68 % of radiation oncologists use chest wall bolus all the time, 6 % never used bolus, and 26 % used bolus only for specific indications including skin involvement, inflammatory disease, close or positive margins, or lymph-vascular invasion-positive tumors [15]. The guidelines of the American Society of Clinical Oncologists highlighted the lack of evidence to guide clinicians in bolus practice: “Whether it is necessary to apply bolus every day, less frequently, or at all is uncertain” [10]. In regard to this, we typically use bolus during half course of CW RT to increase dose to the dermal lymphatics, meanwhile not to increase the skin toxicity.

Fig. 4
figure 4

A typical electron field for chest wall marked on a patient’s skin surface

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The results of a survey conducted in 2004 indicated that the supraclavicular region was the most commonly irrradiated target in mainland China (96.2), followed by IMC (85.2 %), CW (79.0 %), and axilla (74.8 %) [16]. A subsequent survey in 2010 showed that both chest wall and supraclavicular regions were the most common RT target in China (97.0 %), radiation of IMC and the axilla decreased (39.1 and 50.0 %) [17]. This change clearly suggested that the CW should be a principal PMRT target for breast cancer, a proposal that achieved a consensus in China.

In the current study, SCF RT was used in more than 80 % of patients, irrespective of year and geographical region. The use of SCF was observed more frequently in patients with positive axillary nodes. Evidence suggests that SCF RT is effective in reducing the rate of SCF failures [2, 4, 18, 19]. The magnitude of benefit is related to the risk of involvement/failure. No surgical resection data exists that has evaluated the risk of SCF involvement at presentation, but it has been found that the risk of SCF failure is closely related to the degree of axillary involvement. A recent study of 1,031 patients who did not receive RT following mastectomy and chemotherapy, found that the 10-year risk of recurrence in the axillary apex/supraclavicular fossa was 14 to 19 % for those with four or more positive lymph nodes, 20 % or greater positive lymph nodes, or extracapsular extension of disease that measured more than 2 mm [20]. The use of SCF RT increased the risk of brachial plexus neuropathy, radiation pneumonitis, and arm edema. Considering the balance of efficacy and toxicity, SCF RT is recommended for patients with four or more positive axillary nodes. There is controversy about SCF RT in patients with one to three positive nodes [10]. Some physicians believe that SCF RT is not worthwhile as the reported rate of clinical SCF failure is low in this group, whereas others believe that improvements in SCF control may be more readily translated into survival benefit due to the lower risk of distant metastases in patients with one to three positive nodes. In a survey of radiation oncologists in North America and Europe, respondents were divided on whether to treat the SCF in this setting [21]. Patients with one to three positive nodes have a heterogeneous risk of SCF recurrence and high-risk patients should be identified to deliver SCF radiation. Yates et al. analyzed 1,065 breast cancer patients with one to three positive nodes who did not receive adjuvant SCF radiation, the 10-year SCF recurrence rate was only 9.2 %. But higher grade and number of positive lymph nodes were the most significant predictors of SCF recurrence. The 10-year SCF recurrence rate was 30 % in those having grade 3 cancers with three positive nodes [22].

All patients in this study received axillary dissection with a median of 16 lymph nodes recovered, and 29.6 % of patients received axillary RT. The use of axillary RT decreased significantly from 1999 to 2008, and its use varied greatly between different regions. Axillary RT was used more frequently in patients with positive axillary nodes, or with a nodal ratio of 20 % or greater (p = 0.007). There is a lack of high-level evidence to support the benefit of post-dissection axillary RT. Controversy exists among American and European radiation oncologists regarding the use of axillary radiotherapy [21]. The 10-year risk of level I or II axillary recurrence was merely 3 % and was not predicted by the extent of axillary disease or extracapsular extension according to a study published by Strom et al., in which all patients had a standard axillary lymph node dissection (median number of lymph nodes recovered was 17) and did not receive RT after treatment with mastectomy and chemotherapy [20]. By contrast, in patients treated in the no RT arms of the Danish PMRT trials and who developed a local–regional recurrence, 43 % experienced the axilla as a component of the recurrence [8]. The higher axillary recurrence rate in these Danish studies was probably due to the less extensive levels I or II dissection (the median number of lymph nodes recovered was seven). This suggests that the decision to include levels I or II as a target for PMRT is largely determined by the completeness of the axillary dissection.

Combined photon and electron, or photon alone were used frequently for SCF RT in this study, electron alone was used in a small number of patients (6.8 %). Wang et al. has reported that there was no difference in 5-year SCF recurrence rates for patients irradiated with photon, electrons, or combined photon and electron (2.1, 3.6, and 3.2 %, respectively) [12]. However, Huang et al. found that patients irradiated with electrons had significantly higher SCF relapse rate than those with photons, which was possibly because the coverage of deep nodes and those located underneath bone would be often insufficient due to inadequate electron depth dose and selective bone absorption [23]. Therefore, we recommend combined photon and electron or photon alone for SCF RT.

The treatment of the IMC in patients undergoing PMRT is controversial and the subject of ongoing phase III studies. In our study, 44.9 % of patients received IMC RT. The use of IMC RT decreased significantly from 1999 to 2008 and it varied greatly between different regions. It was used more frequently in patients with tumors located at the inner quadrant, but was not associated with axillary node status. The justification for including this region is based on previous experience of dissecting the internal mammary chain, which revealed that 35 to 50 % of patients with clinically advanced disease have microscopic involvement of lymph nodes in this area [24, 25]. Randomized trials that have shown a survival advantage for PMRT included the IMC within their treatment target volume [2, 4]. However, there is a large difference between reported rates of microscopic involvement of the IMC and the subsequent rates of clinically overt failure in the IMC if left untreated. The reported rates of recurrence in the IMC are as low as 0–1.5 % [5–7, 26]. Randomized trial shows similar results with or without IMC dissection [27]. There is also a possible risk of long-term cardiac toxicity following IMC RT. A potential compromise approach would be to irradiate the superiorly placed IMC nodal regions, and not the inferiorly placed nodal regions, in order to spare the heart from RT exposure, while at the same time covering the nodal areas more often involved in tumor deposits. In the survey mentioned above, respondents were more likely to use IMC RT in the presence of greater axillary involvement [21]. European respondents were more likely to treat the IMC than their North American counterparts. Academic physicians were more likely to treat the IMC than those in nonacademic positions. Thus, there appears to be significant variations in attitude regarding treatment of the IMC [28]. More evidences are needed to select high-risk patients to deliver IMC RT and patients with positive IMC appear to benefit from IMC radiation. Veronesi et al. reported 663 patients with breast carcinoma mainly in the inner quadrants who underwent a biopsy of IMC. Positive IMC were found in 68 out of 663 cases (10.3 %). Patients with IMC metastases treated with IMC radiation and appropriate systemic treatment achieved an excellent survival (95 % at 5 years) [29].

Conclusion

Chest wall and supraclavicular fields are the most frequently irradiated targets for PMRT in mainland China. The use of axillary and IMC RT had significantly decreased during the 10-year period studied. There was a large variation in the use of CW, axillary, and IMC RT between different hospitals, indicating the need for consensus and for evidence.