Evaluating the efficacy of post-surgery adjuvant therapies used for ductal carcinoma in situ patients: a network meta-analysis

Objective Post-surgery adjuvant therapies are very important for patients suffering from ductal carcinoma in situ (DCIS). In this study we conducted a network meta-analysis (NMA) to evaluate the efficacy of different post-surgery adjuvant therapies including tamoxifen, anastrozole and radiation therapy (RT) and their combinations (RT+ tamoxifen and RT+ anastrozole). Methods We searched several databases, including Embase, MEDLINE / PUBMED, Cochrane Library, and Science Citation Index, for relevant studies. We then extracted the data from eligible studies in order to perform our NMA. We measured the comparative efficacy of each treatment option based on the calculated odds ratios (ORs) and the corresponding 95% credibility interval (95%CrI) for each treatment option. We calculated the surfaces under the cumulative ranking curves (SUCRA) in order to rank the therapies according to their different outcomes. Results In this study, local recurrence (LC) was chosen as the primary outcome. Metastasis, contralateral-breast cancer (CBC), ipsilateral-breast cancer (IBC) and death were secondary outcomes. Patients treated with RT and RT + tamoxifen exhibited a lower risk of LC compared with control group (OR=0.54, 95%CrI: 0.40-0.73; OR=0.41, 95%CrI: 0.19-0.90). Patients treated by RT and RT + tamoxifen also exhibited a significantly lower risk of IBC compared with control group (OR=0.55, 95%CrI: 0.37-0.82; OR=0.42, 95%CrI: 0.18-0.99). Results from the SUCRA indicated that RT + anastrozole and RT + tamoxifen were potentially the best adjuvant treatments for patients with DCIS. Conclusions In conclusion, the RT + anastrozole and RT + tamoxifen are recommended for their performance and effectiveness.


INTRODUCTION
Ductal carcinoma in situ (DCIS) of the breast is the result of the clonal proliferation of malignant-appearing cells contained in the mammary duct lumens. It is a precursor to invasive breast carcinoma [1]. It is estimated that 45-78% of invasive breast carcinomas are associated with DCIS [2]. Although DCIS itself has a relatively low risk of metastasis [3], about 25% to 50% of DCIS patients eventually develop invasive cancers [4]. In cases of invasive relapse, the patient survival rate is about 15% Clinical Research Paper www.impactjournals.com/oncotarget [5]. The discovery of similar chromosomal changes in DCIS and invasive cancers patients suggests a potential relationship between DCIS and invasive cancers [6,7].
Although DCIS is usually not detectable in its early stages, mammographic screening techniques can be used to detect it before clinical symptoms are generally observable [3,8]. The number of diagnosed DCIS cases in the US has increased notably after mammographic screening techniques were introduced [9].
Traditional mastectomy is frequently used to prevent local recurrence (LC) in patients with DCIS, however it may cause severe side effects [3,10,11]. As a result, the conventional mastectomy has been replaced by breast-conserving surgery (BCS) with or without the use of adjuvant endocrine or radiation therapy (RT) [12]. Randomized controlled trials (RCTs) in previous studies have indicated a remarkable decrease in the risk of LC among DCIS patients who were managed by postlumpectomy RT [13,14]. Another (National Surgical Adjutant Breast/Bowel Project) NSABP B-17 trial suggested that the LC rate during an eight-year period decreased to 12% in DCIS patients with postoperative RT [13]. Some consistent results were reported The European Cooperative Study Group Trial (EORTC), reported consistent results in their study of 1,010 females who were diagnosed with DCIS [14]. These trials demonstrated that RT could reduce the risk of LC in DCIS patients.
On the other hand, tamoxifen is often used as an adjuvant endocrine therapy for invasive breast carcinoma and it is able to reduce the risk of LC and death [4]. Moreover, tamoxifen has gradually gained use as an adjuvant therapy for DCIS patients in order to prevent ipsilateral and contralateral failure. In the NSABP B-24 trial, females with tamoxifen therapy following BCS and post-lumpectomy irradiation had significantly fewer breast cancer events than those with placebo during an 83-month follow-up period [15]. The effectiveness of tamoxifen in patients treated by BCS and postoperative RT has been verified and hence tamoxifen is often recommended to DCIS patients in order to prevent invasion [4].
Anastrozole is a non-steroidal aromatase-inhibiting medication. It is also an approved treatment option for breast cancer patients and it has been suggested that it is even more effective than tamoxifen with respect to disease progression and overall response rates [16]. Although anastrozole and tamoxifen have similar side effects and toxicity, patients treated by anastrozole exhibited fewer thromboembolic events compared to those treated by tamoxifen [15]. The ATAC6 trial, which was conducted in females with early-stage invasive breast carcinoma, revealed similar results [17]. In addition, patients treated with anastrozole were associated with fewer cases of deepvein thrombosis, hot flush, endometrial cancer and stroke compared with those treated by tamoxifen [15].
However, there is no NMA comparing different adjuvant therapies for patients with DCIS. This NMA was conducted to compare the efficacy of various postoperative adjuvant therapies for patients suffering from DCIS in order to evaluate the performance of different post-surgery treatments and provide grounded information for clinical practice. The therapies considered include: tamoxifen, anastrozole, RT, RT + tamoxifen and RT + anastrozole. The control group, set up for the purpose of comparison, consisted of patients treated with placebo. This study used endpoints, including LC, metastasis (M), contralateral breast cancer (CBC), ipsilateral-breast cancer (IBC) and death (D) to assess the efficacy of the above treatments.

Literature selection
As shown in Figure 1, study selection was carried out in three steps: study identification, screening and inclusion. We identified a total of 2,369 studies, 2,346 of which were identified using the literature search strategy outlines above, and 23 of which were identified by additional reviews. However, only 84 full-length articles were retrieved and the remaining articles were rejected due to duplication, insufficient information or irrelevant outcomes. Another 36 articles were excluded because of insufficient data, insufficient network connections or irrelevant outcomes. Therefore, 48 eligible publications were eventually subject to data extraction [13,15,. The detailed characteristics of eligible studies are displayed in Table 1. Of the 48 eligible studies, 29 were observational studies and the other 19 were RCTs. A total of 41,922 patients were included in our NMA and the corresponding following-up duration of each study ranged from 3 to 20 years. Up to 40 studies covered the comparison of the RT group and control group. The network plot for each outcome is illustrated in Figure 2, in which each node corresponds to a post-surgery adjuvant therapy and each solid line corresponds to a direct comparison between two therapies. The thickness of solid lines is proportional to the number of direct comparisons between two therapies whereas the size of nodes is proportional to the sample size involved in each therapy.

Analysis based on both observational studies and RCTs
All eligible studies, including observational studies and RCTs, were included in the analysis procedure. The results are shown in the lower diagonal of Table 2 and in Figure 3. Patients treated by RT, and RT + tamoxifen were associated with a significantly decreased risk of LC compared to the control group (RT: OR = 0.54, 95% CrI = 0.40-0.73; RT + Tamoxifen: OR = 0.41, 95% CrI = 0.19-0.90). Similarly, RT and RT + tamoxifen were associated with a lower risk of IBC compared to the control group (OR = 0.55, 95%CrI = 0.37-0.82; OR = 0.42, 95%CrI = 0.18-0.99, respectively). No statistically significance differences were observed with regard to the outcomes CBC, D and M.

Analysis based on RCTs
In order to ensure that included observational studies did not introduce bias into this NMA, RCTs were selected from eligible studies and then analyzed using the same method. The corresponding results of our NMA are displayed in the upper diagonal of Table  2 and Figure 4. The results of the RCTs were similar to those of the observational studies, which indicated that the inclusion of observational studies introduced little heterogeneity to this NMA. Patients treated with RT and RT + tamoxifen exhibited a lower risk of LC compared to the control group (OR=0.53, 95% CrI = 0.32-0.92; OR = 0.31, 95% CrI = 0.12-0.79, respectively). Moreover, patients with RT+ tamoxifen also exhibited a lower risk of LC compared with tamoxifen alone (OR = 0.28, 95% CrI = 0.10-0.68). Additionally, RT was associated with a lower risk of IBC compared to the control group (OR = 0.47, 95% CrI = 0.27-0.84) and there was no statistically significant difference among different treatments in terms of M and D. However, RT was associated with a higher risk of CBC compared with the control group (OR = 1.48,

Ranking results
According to the SUCRA presented in Table 3, the results between comparisons based on observational studies and RCTs and those based on RCTs alone were similar. RT + anastrozole ranked first in IBC, LC, M and CBC, and RT + tamoxifen also exhibited good performance in terms of IBC, LC, and M. In addition, tamoxifen was associated with a lower risk of CBC compared to all treatments except for RT + anastrozole, and besides RT + anastrozole and RT + tamoxifen, RT alone also effectively reduced the events of LC and IBC. However, no treatments exhibited outstanding performance with respect to D.

DISCUSSION
The number of diagnosed cases of DCIS has increased due to the advent of new mammography techniques, and this increase has resulted in the challenge of tailoring post-surgery adjuvant therapies to individual patients. Some DCIS patients with low-risk lesions have been over-treated, while others with high-risk lesions have been under-treated. This may be associated with the recurrence or development of invasive breast cancer (IBC) [64]. Accordingly, differentiating post-surgery adjuvant therapies based on their efficacy may provide clinicians with assistance in order to overcome these issues.  This NMA evaluated five post-surgery treatments based on observational studies and RCTs. According to our results, treatments containing RT were effective in reducing the rate of LC and IBC. Moreover, RT + anastrozole and RT + tamoxifen were also associated with lower risk of M and CBC, which was confirmed by  previous studies. As suggested by a long-term follow-up study, which focused on four randomized trials comparing lumpectomy with or without RT, radiation significantly reduced the local failure rate in DCIS patients [65]. Besides, two phase III trials indicated that tamoxifen with a dose of 20 mg/day reduced the risk of ipsilateral and contralateral events by approximately 30% [57,58]. However, due to the lack of evidence, this NMA did not cover an analysis of safety, and it was reported that about 11%-31% patients treated with RT + tamoxifen did not complete the five-year tamoxifen treatment [66]. This poor rate of compliance may have been the result of long-term toxic effects associated with endometrial cancer or vascular thrombotic events. It was also reported that both RT and tamoxifen may trigger severe adverse events such as endometrial cancers, venous thromboembolism and secondary malignancies [67][68][69]. Therefore, longterm follow-up studies that consider the efficacy of RT or tamoxifen should be carried out in order to provide a more comprehensive suggestion for clinical practice.
Moreover, according to this NMA, RT + anastrozole seemed to be slightly more effective than RT + tamoxifen. Actually, aromatase inhibitors are potentially more effective than tamoxifen for preventing recurrence in postmenopausal females with invasive breast cancer and positive ER [57]. Various aromatase inhibitors have offered effective alternatives to tamoxifen, but the relative effectiveness of aromatase inhibitors compared to tamoxifen remains controversial. For instance, a randomized double-blinded trial (NSABP B-35) suggested that anastrozole significantly improved the breast cancerfree interval in DCIS patients under the age of 60 compared to the tamoxifen group, while another study reported no significant difference in the risk of overall recurrence between the anastrozole and tamoxifen group [70]. Therefore, although RT + anastrozole seemed to be more highly recommended than RT + tamoxifen, clinical decisions should be made based on several factors, including the patients' physical characteristics, age, excision method and tolerance level.
Our study provides guidance for discriminating between the available post-surgery adjuvant therapies, however our NMA does contain some inherent limitations. First of all, although a large number of studies were included, their differences in follow-up times may increase the heterogeneity of this study. For example, adverse events such as LC, metastasis, progression to invasive breast cancers or death are rare events; therefore, the likelihood of the occurrence of such events in each study may be proportional to the duration. Studies with longer follow-up durations may contain more of these events. Having acknowledged this, our study did not adjust for duration when adverse events were taken into account. Apart from that, other variables, including age, Figure 4: Forest plots of all outcomes based on RCTs. ORs with corresponding 95% CrIs were calculated to measure the relative efficacy of different treatments. www.impactjournals.com/oncotarget margin and hormone-receptor status, may also increase the heterogeneity of patients and thus weaken the reliability of the results. Therefore, more detailed analyses should be conducted before certain conclusions are drawn. Most of the included studies cover the comparison of RT and placebo (control group). However, few trials include the analysis of anastrozole. Also, due to a lack of evidence, outcome information under certain treatments, including anastrozole and tamoxifen, was missing, and more comprehensive studies should be carried out in the future.
Overall, our study is an excellent start, as it demonstrates that patients treated with post-surgery adjuvant therapies had significant reduction in the risk of LC and IBC. Of all the treatments, RT + tamoxifen and RT + anastrozole were the two most recommended therapies. However, due to the lack of evidence demonstrating their safety, they should be applied with extra care.

Systematic review and search for relevant studies
This study is based on a systematic and thorough review, which was conducted at an early stage in order to ensure the quality of our network meta-analysis. The review team included an experienced statistician, a clinician with expert knowledge and reviewers with competent search and information retrieval skills. Our review team also examined the corresponding research question in order to ensure that our study could produce meaningful results. The following aspects were considered in the systematic literature review: study population, comparators of our interest, clinical outcome definitions, study inclusion criteria, data extraction procedures, study quality assessment and the selection of an appropriate data analysis approach.
We performed an extensive literature search based on our systematic review, using the following medical subject headings (MeSH), in conjunction with their corresponding synonyms, to formulate a search strategy: DCIS of the breast, mastectomy (M), local excision (LE), BCS, breast sector resection (BSR), wide local excision (WLE), lumpectomy (L), localized surgery (LS), postsurgery adjuvant endocrine therapy, post-surgery radiation therapy (RT), efficacy. We included both observational trials and RCTs in this NMA. We searched a variety of databases, including Embase, MEDLINE/PUBMED, Cochrane Library, and Science Citation Index (SCI), according to the criteria mentioned above. Two reviewers carried out the entire search process independently of one another, and any disagreements were subject to third-party discussion.

Studies selection
Retrieved articles were subject to the following eligibility criteria: 1) patients were at least 18 years old; 2) The diagnosis of DCIS must have been obtained by mammographic screening or histological examination; 3) Patients must have been treated by surgical procedures including mastectomy, M, L, LE, BCS, BSR, WLE, LS; 4) treatments must have contained at least two of the following treatments: tamoxifen, anastrozole, RT + tamoxifen, RT + anastrozole and placebo (control group); 5) outcomes must have included one of the following items, including LC, M, CBC, IBC and D; 6) Sufficient data for conducting a network meta-analysis could be obtained from studies. Studies which fell into one of the following categories were excluded: 1) duplicated studies; 2) meta-analysis or NMA; 3) reviews, abstracts, and case reports.

Data extraction
Raw data were extracted from eligible studies using a data extraction spreadsheet, including study characteristics, baseline demographics and raw/summary statistics of the corresponding outcomes. The baseline characteristics of all trials were collected, including first author, publication year, country, study design, subgroup, sample size, follow-up time, surgery type, treatment, group size and outcomes.

Statistical analysis
Software R 3.3.2 was used to conduct this Bayesian NMA and the random-effects assumption was adopted throughout our analysis due to the heterogeneous nature of included studies with respect to study design, population selection and following-up duration [71]. We used odds ratios (ORs) with 95% credible intervals to measure the relative efficacy of each treatment under different outcomes. Furthermore, the SUCRA was computed to obtain the relative ranking of different treatments. Moreover, in order to guarantee the reliability of this NMA, RCTs were selected from all eligible studies and then analyzed following the steps above.