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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 84-89

Concurrent adjuvant radiochemotherapy versus standard chemotherapy followed by radiotherapy in operable breast cancer after breast conserving therapy: A meta-analysis


1 Department of Surgery, Ruijin Hospital, Medical School of Shanghai Jiaotong University, Shanghai, China
2 International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University, Shanghai, China

Date of Web Publication13-Apr-2016

Correspondence Address:
Kunwei Shen
Department of Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University No.197 Ruijin Er, Huangpu District, Shanghai 200025
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.148702

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 > Abstract 

Background: To compare the efficacy of concurrent and sequential administration of radiotherapy and chemotherapy on patients with operable breast cancer after breast.conserving surgery. (BCS). Materials and Methods: We searched MEDLINE (National Library of Medicine, Bethesda, Maryland) and EMBASE (Elsevier, Amsterdam, Netherlands) databases for eligible studies. Clinical outcomes (such as overall and locoregional recurrence-free survival, toxicity related complications) used as evaluation indexes of efficacy. Odds ratios (ORs) with 95% confidence intervals (CI) of each index was calculated and analyzed with the RevMan Version 5.2 software. Results: Three articles (two trials), which compared the clinical efficacy of concurrent and sequential administration of radiotherapy and chemotherapy for operable breast cancer patients, were eligible in this meta-analysis. There were significant differences between concurrent and sequential treatments in 5-year loco-regional recurrence free survival (OR: 0.39, 95% CI: 0.20–0.75, P = 0.005) and late skin toxicity of telangiectasia (OR: 2.00, 95% CI: 1.39–2.87, P = 0.0002). However, no significant difference was discovered in five-year overall survival (OR: 0.62, 95% CI: 0.35–1.11, P > 0.05), acute skin toxicity (OR: 1.73, 95% CI: 0.98–3.04, P > 0.05) and late skin toxicity of lymphedema (OR: 1.27, 95% CI: 0.88–1.83, P > 0.05). Conclusion: Our study demonstrated that the concurrent administration of chemotherapy (anthracycline-based) and radiotherapy was superior to the sequential administration in locoregional recurrence-free survival for the operable node positive breast cancer patients. However, choose of treatment for operable breast cancer patients must be cautious due to high risk of lymphedema.

Keywords: Breast neoplasm, concurrent treatment, meta-analysis, sequential treatment


How to cite this article:
Huang O, Wu D, Zhu L, Li Y, Chen W, Shen K. Concurrent adjuvant radiochemotherapy versus standard chemotherapy followed by radiotherapy in operable breast cancer after breast conserving therapy: A meta-analysis. J Can Res Ther 2016;12:84-9

How to cite this URL:
Huang O, Wu D, Zhu L, Li Y, Chen W, Shen K. Concurrent adjuvant radiochemotherapy versus standard chemotherapy followed by radiotherapy in operable breast cancer after breast conserving therapy: A meta-analysis. J Can Res Ther [serial online] 2016 [cited 2021 Apr 15];12:84-9. Available from: https://www.cancerjournal.net/text.asp?2016/12/1/84/148702




 > Introduction Top


Operable breast cancer is defined as presenting with International Union Against Cancer (UICC) stage 1-3a assessed on the basis of diagnostic procedures undertaken before therapeutic surgery.[1] Postoperative radiotherapy is the current standard therapy for early operable breast cancer after breast-conserving surgery (BCS).[2],[3] Adjuvant chemotherapy is recommended for patients at risk of distant metastases, especially for patients with positive axillary nodes.[4],[5] Typically, radiotherapy is administrated after completion of adjuvant chemotherapy in these patients to reduce the risk of metastatic disease,[3] while concurrent administration of chemotherapy and radiotherapy have been suggested recently.[6],[7]

A systematic reviews by Chen et al.,[8] and Huang et al.,[9] concluded that delay in the initiation of radiotherapy increased the local recurrence rate of breast cancer. The concurrent administration of chemotherapy and radiotherapy would avoid unnecessary delays in the initiation of the second treatment and it is possible that concurrent treatment acts synergistically.[10],[11] Several retrospective observational studies have assessed the feasibility and effectiveness of concomitant adjuvant radio-chemotherapy.[12],[13],[14],[15],[16],[17] Among them, some studies supported the concurrent treatment of chemotherapy and radiotherapy for breast cancer with better clinical efficacy and safety compared with the sequential treatment of chemotherapy and radiotherapy.[12],[13],[14],[15] However, one previous study found that the concurrent administration of adjuvant chemotherapy and radiotherapy leads to an unacceptably high level of acute toxicity.[16] Moreover, a previous meta-analysis found that the loco-regional recurrence and survival were similar among concurrent radiochemotherapy, radiotherapy followed by chemotherapy, and chemotherapy followed by radiotherapy when radiotherapy was initiated within 7 months after BSC.[18] Thus, based on these inconsistent foundations, we could not draw a firm conclusion for the efficacy of concurrent vs. sequential administration of radiotherapy and chemotherapy for breast cancer, especially for operable breast cancer. Thus, we performed a meta-analysis with recent studies to compare the effect of concurrent and sequential administration of radiotherapy and chemotherapy on the survival outcomes and toxicity related complications in patients with operable breast cancer after BCS.


 > Materials and Methods Top


Search strategy

The MEDLINE (National Library of Medical, Bethesda, Maryland) and EMBASE (Elsevier, Amsterdam, the Nethrlands) databases were searched for eligible articles with the publication year from January 1950 to May 2013. The search strategy was based on keywords or Medical Subject Heading (MeSH) terms Breast Neoplasm) and the following combination of terms: (1) Radiation OR irradiation OR radiotherapy, (2) concurrent OR concomitant OR simultaneous combined, and (3) chemotherapy OR chemo- OR systemic. The reference lists of the included articles were also searched for additional articles. Moreover, the publications citing one of the included studies were also examined using the social sciences citation index through the Web of Science.

Study selection

Two authors independently reviewed all the potentially eligible studies to identify whether they met the inclusion criteria. Any discrepancies were resolved by discussion. Studies were included if they met the following criteria: (1) They were randomized controlled trials (RCTs); (2) they were peer-reviewed original studies in English; (3) the sample size was at least 10; (4) participants were operable breast cancer patients; (6) efficacy of concurrent vs. sequential administration of chemotherapy and radiotherapy (concurrent group vs. sequential group) was investigated; (8) at least one of the clinical outcomes including overall and loco-regional recurrence-free survival, and toxicity related complications were reported. In addition, the studies were excluded if (1) Studies were reviews, comments, letters or editorials; (2) the participants included metastatic or recurrent patients; (3) studies did not reported the comparison or only one method was investigated; (4) there was no available data. Furthermore, only the studies with most complete data were included for the duplicated publications.

Data extraction and quality assessment

Two investigators independently extracted and recorded data using pre-specified data collection forms: Authors, publication year, sample size, region of investigation, follow-up duration, patient characteristics (tumor stage, chemotherapy and radiotherapy regimen, endocrine therapy regimen), and clinical outcomes. Disagreements were resolved by discussion with each other or by an additional investigator with over 20 years of experience in breast diagnosis and treatment.

Two reviewers independently evaluate the methodological quality of each eligible trial by using the validated scale developed by Jadad et al.[19] Given the treatments studied in these trials, blinding of participants and assessors was not possible; we did not use blinding as a criterion to assess the quality of the study. The items for quality assessment included randomization and reporting of withdrawals and dropouts. The quality of study was considered high (recorded as “A”) if two items were all reported, medium (recorded as “B”) if only one item were reported, and low (recorded as “C”) if there was no any detailed information of these two items. Disagreements were solved through discussion.

Statistical methods

Data were analyzed using RevMan Version 5.2 software which provided by the Cochrane Collaboration (http://ims.cocrane.org/revman). Clinical outcomes (such as overall and loco-regional recurrence-free survival, toxicity related complications) used as the evaluation indexes of efficacy. Dichotomous data were presented as odds ratios (ORs) with 95% confidence intervals (CI). Significant heterogeneity was evaluated using a Chi-square test with P < 0.05 and the I2 statistic with I2> 50%. Furthermore, A fixed-effect model weighted using Mantel-Haenszel methods was applied to calculate the pooled data when no significant heterogeneity was observed among the included studies (P ≥ 0.05 and I2 < 50%), otherwise, random-effect model using DerSimonian-Laird methods was used when significantly heterogeneity was found (P < 0.05, I2> 50%). In addition, publication bias was examined with funnel plots. An asymmetrical appearance of dots in the funnel plots would indicate the presence of publication bias.


 > Results Top


Eligible studies and studies characteristics

After initial search in the databases, we identified 236 potentially relevant reports. After excluding the obviously irrelevant studies based on their titles and abstracts, 97 articles were remained for full-text review. Then 88 studies were eliminated for the following reasons: (1) They were review or editorial articles (N = 27), (2) the studies included patients treated with neoadjuvant therapy (N = 14), (3) the participants included metastatic or recurrent patients (N = 20), (4) the investigations were not about comparison of concurrent and sequential administration of radiotherapy and chemotherapy (N = 16), (4) the studies was not RCTs (N = 11), and (5) there was no available data (N = 6). Among the reaming three studies, the study of Rouesse J et al.,[20] were included for meeting the selection criteria. For the other two studies, same population was reported in them. Thus, we included the data from node-positive subgroup of the Toledano A et al., 2007[21] and supplemented data of toxicity related complications from the previous publication by Toledano A et al., in 2006.[22] Ultimately, the studies of Rouesse J et al., published in 2006 and Toledano A et al., published in 2007[21] and 2006[22] were included in this meta-analysis [Figure 1].
Figure 1: Flowchart of the search strategy and the selection of studies

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Characteristics of the included studies

Three articles (two trials) including 761 patients with operable node-positive breast cancers were included in this meta-analysis. The quality assessment and main characteristics of the included studies were summarized in [Table 1] and [Table 2], respectively. No low quality studies were found in this study. Both trials were multi-center RCTs from French. The durations of follow-up were all over 60 months. The chemotherapy regimen was different between concurrent group (FNC: 5-fluorouracil, 500 mg/m 2; mitoxantrone, 12 mg/m 2; cyclophosphamide 500 mg/m 2 q3w; 4 circles.) and sequential group (FEC: 5-fluorouracil 500 mg/m 2; epirubicin, 60 mg/m 2; cyclophosphamide 500 mg/m 2; 4 circles) for study of Rouesse J et al.,[20] while 6 circles FNC was used in both group for the study of Toledano A et al.[21],[22].
Table 1: Methodological quality of studies included in the meta-analysis

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Table 2: Characteristics of included studies

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Main analysis

For survival outcomes, we pooled the data from the operable node positive patients in the study of Rouesse et al., and Toledano A et al., 2007. There was no heterogeneity between the two studies in the analysis of loco-regional recurrence free survival (P = 0.49, I2 = 0%) and overall survival (P = 0.46, I2 = 0%) so that a fixed-effect model was applied to estimate the overall outcomes. The OR of concurrent therapy vs. sequential therapy was 0.39 (95% CI: 0.20–0.75, P = 0.005) for 5-year locoregional recurrence free survival and was 0.62 (95% CI: 0.35–1.11, P = 0.11) for 5-year overall survival, indicating that there was significant lower rate of loco-regional recurrence in concurrent group compared to sequential group for operable node positive patients [Figure 2].
Figure 2: Forest plots for the comparison of outcomes between operable node positive patients received concurrent and sequential therapy (a) 5-year loco-regional recurrence free survival (b) 5-year overall survival

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Rouesse et al.,[20] reported that the incidence of alopecia (Grade 2–3), and febrile neutropenia and leucopenia (Grade 3–4) were significantly increased in concurrent group compared with the sequential group. No significant difference was found in the incidence of anemia (Grade 3), nausea and/or vomiting (Grade 3–4), and cardiotoxicity (Grade 3). The study of Toledano A et al.,[21],[22] reported acute and late toxicity but did not report specific details for the node-positive subgroup. Thus, we pooled data from all population in the studies of Rouesse et al., and Toledano A et al., 2006 to examine the overall incidence of acute and late skin toxicity. A fixed-effect model was applied since no heterogeneity was observed between the two trials in acute skin toxicity (P = 0.76, I2 = 0%), late skin toxicity of lymphedema (P = 0.75, I2 = 0%), and late skin toxicity of telangiectasia (P = 0.17, I2 = 48%). The overall estimate revealed that no significant difference was found between concurrent and sequential group for acute skin toxicity (OR: 1.73, 95% CI: 0.98–3.04, P = 0.06, [Figure 3]a and late skin toxicity of lymphedema (OR: 1.27, 95% CI: 0.88–1.83, P = 0.21, [Figure 3]b. However, the incidence of telangiectasia, another sign of late skin toxicity, was significantly increased in concurrent group than in sequential group (OR: 2.00, 95% CI: 1.39–2.87, P = 0.0002), as shown in [Figure 3]c.
Figure 3: Forest plots for the comparison of toxicity related complications between operable patients received concurrent and sequential therapy (a) acute skin toxicity (b) late skin toxicity of lymphedema (c) late skin toxicity of telangiectasia

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Publication bias

The funnel plots formed a very distinctly symmetrical funnel shape with the log ORs of overall survival and late skin toxicity of telangiectasia. Therefore, no publication bias was detected in the present study [Figure 4].
Figure 4: Funnel plots for publication bias of included studies in the analyses of (a) overall survival and (b) late skin toxicity of telangiectasia

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 > Discussion Top


Combination of chemotherapy and radiotherapy is the current standard adjuvant treatment for BCS breast cancer with high risk of systemic spread. In this meta-analysis, we compared the effect of concurrent and sequential administration of radiotherapy and chemotherapy on survival outcomes and toxicity related complications in operable breast cancer after BCS. Our results suggested that operable node positive breast cancer patients received concurrent administration of radiotherapy and chemotherapy had a lower loco-regional recurrence-free survival rate than that received sequential administration of radiotherapy and chemotherapy, while the overall survival rate was similar between them. Moreover, the results also indicated that concurrent administration increased the incidence of lymphedema compared with sequential administration for operable breast cancer patients.

The results supported the concurrent administration of radiotherapy and chemotherapy with lower loco-regional recurrence-free survival rate. It was consistent with the results of previous studies,[15] which indicated concurrent administration of chemotherapy and radiotherapy might be reserved for patients at high risk of local recurrence. However, there was no significant difference in overall survival. It suggested that concurrent administration of radiotherapy and chemotherapy might be benefit for the local recurrence survival but not for reducing risk of death. More studies were required for confirming this speculation.

In addition, we also found concurrent administration of chemotherapy and radiotherapy could increase the incidence of lymphedema compared with sequential administration. This result was inconsistent with the previous studies,[13],[14],[15] in which no evidence of an increased risk of toxicity was observed between the concurrent and sequential administration. However, these studies did not investigate the specific toxicity symptoms such as lymphedema and telangiectasia. More specific toxicity symptoms must be investigated in the further studies with more sample size and verify the results of this study.

There was some difference between the results of this study and a previous systematic review,[18] which found there was no significant difference in local recurrence and survival among concurrent chemotherapy and radiotherapy, radiotherapy followed by chemotherapy, and chemotherapy followed by radiotherapy in early operable breast cancer. Compared with this review, there were some advantages in this study. First, the included studies of this study were more recent so that the results of this study could represent current clinical technology and the conclusion was more reliable. Second, toxicity related complications were investigated in this study. We obtained additional conclusions related with safety of treatment compared with the previous review. In addition, no publication bias and significant heterogeneity among studies were found in this study.

However, there were also several limitations in our study. First, both trials included were designed two decades ago (1994 for Rouesse J et al., 1996 for Toledano A et al.) and the adjuvant chemotherapy regimens (FNC regimen) used was not considered optimal currently. The original standard anthracycline-based chemotherapy regimens have been replaced by taxanes-based regimens, particularly in high-risk younger patients. However, there is no available data regarding the optimum sequencing of radiotherapy and chemotherapy based taxanes. Second, for analysis of toxicity related complications. We failed to perform a sub-analysis for node-positive patients with BCS, since no detailed data could be used. Third, there was some difference in the study design between the included studies, such as the chemotherapy regimens and surgery type, which may influence the results of meta-analysis. Furthermore, the sample size and number of included studies were too small to strengthen the reliable and stable of this results study.

Our study demonstrated that the concurrent administration of chemotherapy (anthracycline-based) and radiotherapy was superior to the sequential administration in loco-regional recurrence-free survival for the operable node positive breast cancer patients. However, choose of treatment for operable breast cancer patients must be cautious due to high risk of lymphedema. More studies are needed to further compare the concurrent vs sequential administration of chemotherapy and radiotherapy using new chemotherapy regimens and radiotherapy techniques.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]



 

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