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Cardiorespiratory dose comparison among six radiotherapy regimens for patients with left-sided breast cancer – Scientific Reports


Study selection

After removing duplicates, preliminary searches in PubMed, Embase, the Cochrane Library, and Web of Science yielded 220 original studies. According to the initial screening of titles and abstracts, 29 papers were deemed eligible. Following an examination of the entire texts of these reports, 17 articles were removed for the following reasons: (1) publication of duplicate data; (2) lack of valid data; (3) publication as conference abstracts. Following the inclusion and exclusion criteria, twelve studies8,19,20,21,22,23,24,25,26,27,28,29 were ultimately included in this network meta-analysis. Figure 1 depicts the flowchart of the selection process.

Figure 1

Flow chart of the search process for the meta-analysis.

Study characteristics

The twelve studies in the meta-analysis8,19,20,21,22,23,24,25,26,27,28,29 involved 714 left-sided breast cancer patients. All included articles were retrospective studies determined to be of high quality, according to the Newcastle–Ottawa Scale15. Table 1 provides a summary of the baseline data for the twelve included studies. When multiple groups of data were included in the same study, each data group had to be counted separately.

Table 1 Characteristics of the studies included in the meta-analysis.

Direct meta-analysis

Figures 2, 3, 4, 5 present the direct meta-analysis results of heart mean dose, left anterior descending (LAD)mean dose, ipsilateral lung mean dose, and ipsilateral lung V20, respectively. Heart mean dose data were extracted from all twelve articles8,19,20,21,22,23,24,25,26,27,28,29, comprising 664 patients. Since between-study heterogeneity was negligible (I2 < 50%, P ≥ 0.10), we applied a fixed-effects model. The pooled results indicated that there was a substantial difference between the DIBH-3D-CRT and FB-3D-CRT groups, as well as between the DIBH-IMRT and FB-IMRT groups. Eight studies19,20,21,22,23,24,27,28 involving 372 patients were eligible for LAD mean dose analysis. No significant heterogeneity was identified (I2 < 50%, P ≥ 0.10), so a fixed-effects model was employed to calculate the pooled data. Results revealed that the average dose of LAD in the DIBH-3D-CRT group was significantly lower than in the FB-3D-CRT group. An identical situation also appeared in the comparison between the DIBH-IMRT group and the FB-IMRT group. Ipsilateral lung mean dose data were extracted from eight studies8,20,22,24,25,26,27,28 comprising 446 patients. The heterogeneity test revealed statistically significant differences among the studies (I2 ≥ 50%, P ≤ 0.10), therefore, a random-effects model was applied. The mean dose to the ipsilateral lung in the DIBH-3D-CRT group was lower than that of the FB-3D-CRT group, and the dose in the DIBH-IMRT group was also lower than the FB-IMRT group. Ten studies8,19,20,22,23,24,25,26,27,28 were appropriate for analyzing ipsilateral lung V20. We employed a random-effects model because a significant difference was observed in the heterogeneity test (I2 ≥ 50%, P ≤ 0.10). The results showed that the V20 value of the DIBH-3D-CRT group was lower than that of the FB-3D-CRT group, and the performance of the DIBH-IMRT group was also better than that of the FB-IMRT group.

Figure 2
figure 2

Direct meta-analyses of heart mean dose.

Figure 3
figure 3

Direct meta-analyses of LAD mean dose.

Figure 4
figure 4

Direct meta-analyses of lung mean dose.

Figure 5
figure 5

Direct meta-analyses of lung V20.

In summary, by combining the results with the clinical information from the included studies, we realized that in the two methods of 3D-CRT and IMRT, the DIBH approach was more effective than FB in reducing heart mean dose, LAD mean dose, ipsilateral lung mean dose, and ipsilateral lung V20. It should be noted that there were only two studies that explored VMAT, so data merging and direct meta-analysis were not possible. Table 2 shows the summary results of the direct meta-analysis.

Table 2 Summary results of direct meta-analysis

Networks for multiple treatment comparisons

A network map of the six interventions was generated using Stata 15.0, as Fig. 6 shows. The size of the points in the graph represents the weight of the sample number of interventions, and the thickness of the lines in the figure is proportional to the correlation between the two interventions. The figure indicates that DIBH-3D-CRT and FB-3D-CRT were the two most effective strategies in this study. DIBH-IMRT and FB-IMRT were the next most effective, DIBH-VMAT and FB-VMAT were the least. It is important to note that Fig. 6 denotes a measure based on mean cardiac dose, which signifies that there are direct pairwise comparisons between all protocols. However, the network graph is not closed for the other three metrics involved in this study. As a result, a network meta-analysis was performed to combine direct comparisons with indirect comparisons.

Figure 6
figure 6

Network established for multiple treatment comparisons (the graph’s points are proportional to the sample number of interventions, and the lines’ thickness is proportional to their association).

Network meta-analyses

Table 3 summarized the results of the multiple-treatments meta-analyses regarding heart mean dose, LAD mean dose, ipsilateral lung mean dose and ipsilateral lung V20 according to network. Statistically significant results are shown in bold in Table 3. According to the network results, the choice of deep inspiratory breath-holding for respiratory management with a fixed radiotherapy technique (3D-CRT, IMRT, or VMAT) had better results. Coherence between direct and indirect comparisons based on networks was confirmed. In terms of heart mean dose, the network analysis results do not support the comparison of the advantages and disadvantages of the three regimens of FB-3D-CRT, FB-IMRT and FB-VMAT, but the results show that the average cardiac dose of DIBH-3D-CRT is lower than that of FB-IMRT and FB-VMAT. In addition, the results also showed that the mean cardiac dose of DIBH-IMRT was lower than that of FB-3D-CRT, FB-IMRT and FB-VMAT, but the mean heart dose of DIBH-3D-CRT compared with DIBH-IMRT did not show an advantage. Finally, Bayesian analysis showed that DIBH-VAMT was only superior to the FB-VAMT regimen in terms of mean cardiac dose, with insignificant differences with the other four regimens; For the LAD mean dose, the results showed that the FB-3D-CRT group had higher values than all the other five groups, while the DIBH-VMAT had lower values than the other five groups. We might conclude that for the average dose of LAD, the DIBH-VMAT scheme is the best choice and the FB-3D-CRT is the worst choice. In addition, the results also showed that the FB-VMAT regimen was the best choice in the free breathing group, because the average dose of LAD in this regimen was both smaller than that of the FB-IMRT squid FB-3D-CRT; Regarding the mean dose in the ipsilateral lung, the results showed no statistically significant difference between FB-3D-CRT and FB-IMRT, but FB-3D-CRT had a disadvantage compared with the other four groups; Regarding the ipsilateral lung V20 indicator, the Bayesian analysis results show that DIBH-3D-CRT scheme is not only inferior to DIBH-VMAT, but also worse than FB-IMRT, which has never been reported in previous studies. In addition, the analysis results of V20 indicators showed FB-3D-CRT may still be the least optional of the six solutions.

Table 3 Multiple treatment comparison for dosimetry indicators based on network (bolded bold indicates that the pair of comparisons is statistically significant).

Rank probabilities

Figure 7 presents a ranking that indicates the probability of being the best treatment, second best, third best, and so on, among all the therapy regimens. Agents with higher values in the histogram were associated with greater probabilities for worse outcomes. Based on the network, the cumulative probability of being the most intrusive treatment in the dosimetric index were (heart mean dose, LAD mean dose, lung mean dose, lung V20): DIBH-3D-CRT (0, 0, 1%, NA), FB-3D-CRT (13%, 98%, 95%, 79%), DIBH-IMRT (0, 0, 0, 0) FB-IMRT (23%, 2%, 4%, 20%), DIBH-VMAT (0, 0, 0, 0), FB-VMAT (63%, 0, 0, 0). The numbers in brackets represent the heart mean dose, LAD mean dose, ipsilateral lung mean dose, and ipsilateral lung V20, respectively (Table 4). As the histogram in Fig. 7 illustrates, FB-3D-CRT ranked highest among all the regimens in terms of LAD mean dose, ipsilateral lung mean dose, and ipsilateral lung V20, suggesting that the FB-3D-CRT regimen is the least desirable. Moreover, FB-IMRT ranks second among all regimens in terms of LAD mean dose, ipsilateral mean dose, and ipsilateral lung V20, indicating that it is superior only to the FB-3D-CRT regimen and is inferior to even the DIBH-3D-CRT scheme. For average cardiac dose, the graph shows that FB-VMAT is the least preferred approach. Additionally, it is impossible to compare the three schemes DIBH-3D-CRT, DIBH-IMRT, and DIBH-VMAT. The detailed rank probabilities of each treatment for different outcomes are summarized in Table 4.

Figure 7
figure 7

Distribution of probabilities of each agent being ranked the first place based on network (A represents the intercomparison of four indicators within different treatment techniques. B represents the comparison between different treatment techniques for the same indicator).

Table 4 Rank probabilities of each plan for different outcomes based on network.



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