Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Efficacy and safety of re-irradiation for locoregional esophageal squamous cell carcinoma recurrence after radiotherapy: a systematic review and meta-analysis

Efficacy and safety of re-irradiation for locoregional esophageal squamous cell carcinoma... Background: There is currently no standard treatment for locoregional recurrence of esophageal squamous cell car- cinoma (ESCC) previously treated with radiotherapy. This study aimed to assess the efficacy and safety of re-irradiation for ESCC patients with locoregional recurrence. Methods: The PubMed, EmBase, and Cochrane library databases were systematically searched for eligible stud- ies published before January 2021. The pooled effect estimates were calculated using the random effects model. Subgroup analyses were conducted to assess the treatment effectiveness of re-irradiation based on specific characteristics. Results: Nine retrospective studies including 573 ESCC patients with locoregional recurrence were selected. The pooled incidences of the 1-year, 2-year, 3-year, and 5-year survival for patients after re-irradiation were 59% (95% confidence interval [CI]: 35–83; P < 0.001), 25% (95% CI: 16–33; P < 0.001), 25% (95% CI: 4–45; P = 0.017), and 15% (95% CI: 2–27; P = 0.024), respectively. The rates of complete response and local re-recurrence after re-irradiation were 54% (95% CI: 21–88; P = 0.001) and 62% (95% CI: 55–70; P < 0.001), respectively. The median overall survival and local failure-free survival for patients after re-irradiation were 13.94 months (95% CI: 4.18–46.51; P < 0.001) and 11.01 months (95% CI: 5.99–20.22; P < 0.001), respectively. Grade ≥ 3 adverse events of esophageal perforation, tracheoesophageal fistula, and radiation pneumonitis were significantly more common after re-irradiation. Conclusions: This study found that re-irradiation for ESCC patients with locoregional recurrence after previous radiotherapy was feasible. However, patients should be carefully observed in order to treat associated adverse events, including esophageal perforation, tracheoesophageal fistula, and radiation pneumonitis. Keywords: Re-irradiation, Esophageal squamous cell carcinoma, Recurrence, Radiotherapy, Systematic review, Meta- analysis Introduction Esophageal cancer is the eighth most common cancer worldwide, with more than 450,000 new cases annu- ally, and the sixth leading cause of cancer-related deaths [1]. Esophageal squamous cell carcinoma (ESCC) is the predominant histological type of esophageal can- *Correspondence: smxyycjh@163.com Department of Radiotherapy, Cancer Branch of Sanmenxia Central cer [2]. Although patients with early ESCC undergo Hospital, Sanmenxia 472000, China © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom- mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lan and Chen Radiation Oncology (2022) 17:61 Page 2 of 11 esophagectomy, most ESCC patients are diagnosed with country, study design, sample size, mean age, male pro- locally advanced disease. Therefore, surgery alone is usu - portion, tumor stage, interval from prior therapy to irra- ally insufficient, and radiotherapy or chemotherapy are diation, total radiation dose, and reported outcomes. administered [3, 4]. However, the prognosis of ESCC The quality of each individual study was assessed using remains poor, and local recurrence or metastasis play a the Newcastle–Ottawa Scale, and the starring system for critical role in treatment failure and mortality [5]. each study ranged from 0 to 9 [10]. Studies with 6 stars Previous studies have shown that local recurrence were considered to be of moderate quality, and studies is the major cause of ESCC recurrence after definitive with 4 or 5 stars were regarded as low quality. Incon- chemoradiotherapy, which accounts for nearly 40–60% sistent results between reviewers for extracted data and of ESCC cases [6, 7]. Re-irradiation is a common sal- quality assessment were settled by an additional reviewer vage treatment strategy and is widely administered for after referring to the original article. recurrent ESCC after radical radiotherapy or chemora- diotherapy. Chen et al. found that re-irradiation was able Statistical analysis to relieve symptoms and prolong survival [8]. However, The pooled incidence of survival at 1, 2, 3, and 5  years, the efficacy of re-irradiation for locoregional recurrent complete response, local re-recurrence, and grade ≥ 3 ESCC previously treated with radiotherapy is variable, adverse events were calculated based on the number of and whether the efficacy of re-irradiation is affected by events and total patients, whereas pooled overall survival patient characteristics remains controversial. We there- and local failure-free survival were calculated based on fore performed a systematic review and meta-analysis to mean survival and 95% confidence intervals (CIs). The assess the efficacy and safety of re-irradiation for ESCC pooled effect estimates were calculated using the random patients with locoregional recurrence who were previ- effects model, and underlying variations across included ously treated with radiotherapy. studies were considered [11, 12]. Heterogeneity among the included studies for each outcome was assessed using Methods I2 and the Q statistic, and significant heterogeneity was Search strategy and selection criteria defined as I > 50.0% or P < 0.10 [13, 14]. The robustness The Preferred Reporting Items for Systematic Reviews of the pooled conclusion was assessed using sensitiv- and Meta-Analysis guideline was used to guide this sys- ity analysis by sequentially removing a single study [15]. tematic review and meta-analysis [9]. Studies investigat- Subgroup analyses for survival at 1, 2, 3, and 5 years were ing the treatment effects of re-irradiation for patients also performed according to sample size, mean age, male with locoregional recurrent ESCC previously treated proportion, tumor stage, interval from prior therapy with radiotherapy were eligible. Only studies published to radiotherapy, and study quality, and the differences in English were included. The PubMed, EmBase, and between subgroups were assessed using the interaction Cochrane library databases were searched for eligible P test [16]. Funnel plot, Egger test, and Begg’s tests were studies published through January 2021, and the follow- used to assess potential publication bias [17, 18]. The P ing search terms were used: esophageal squamous cell values for pooled conclusions are two-sided, and the carcinoma, recurrence or recurrent, and radiotherapy or inspection level was 0.05. All statistical analyses in this irradiation. We also manually reviewed the reference lists study were performed using STATA software (version of retrieved studies to identify any additional studies that 10.0; Stata Corporation, College Station, TX, USA). met the inclusion criteria. The inclusion criteria were as follows: (1) Study design: retrospective, prospective, or randomized controlled tri- Results als; (2) Patients: patients with recurrent ESCC previously Literature search treated with definitive radiotherapy; (3) Intervention: re- A total of 781 articles were identified from initial irradiation; and (4) Outcomes: survival rate at 1, 2, 3, or searches of the PubMed, EmBase, and Cochrane 5  years, complete response, local re-recurrence, overall library databases, and 422 studies were retained after survival, local failure-free survival, and grade ≥ 3 adverse duplicate titles were removed. A further 390 stud- events. Study selection was performed by two reviewers, ies were excluded because they covered irrelevant and conflicts between reviewers was settled by group dis - topics. The remaining 32 studies were retrieved for cussion until a consensus was reached. full-text evaluation, and 23 studies were excluded for the following reasons: not recurrent ESCC (n = 15), Data collection and quality assessment patients were previously without radiotherapy (n = 5), Two reviewers independently extracted the follow- and other interventions (n = 3). Reviewing the refer- ing information: first author’s name, publication year, ence lists yielded one additional potential study, but Lan and Chen Radiation Oncology (2022) 17:61 Page 3 of 11 this study was also retrieved by our electronic search. Survival rate at 1, 2, 3, and 5 years Finally, nine studies were selected for the final meta- Six, five, four, and five studies reported the effects of analysis (Fig. 1) [19–27]. re-irradiation on survival at 1, 2, 3, and 5  years, respec- tively (Fig.  2). The pooled incidences of 1-year, 2-year, 3-year, and 5-year survival for patients after re-irradi- ation were 59% (95% confidence interval [CI]: 35–83; Study characteristics P < 0.001), 25% (95% CI: 16–33; P < 0.001), 25% (95% CI: The characteristics of the included studies and patients 4–45; P = 0.017), and 15% (95% CI: 2–27; P = 0.024), are summarized in Table  1. All of the studies were respectively. There was significant heterogeneity for the retrospective, and a total of 573 ESCC patients with survival rates at 1  year (I = 97.4%; P < 0.001), 2  years locoregional recurrence were included. Four studies 2 2 (I = 58.5%; P = 0.034), 3 years (I = 95.6%; P < 0.001), and were conducted in Japan, four studies were conducted 5 years (I = 95.0%; P < 0.001). Sensitivity analyses found in China, and one study was conducted in Korea. the ranges for survival at 1, 2, 3, and 5  years were 52.3– The mean age for patients ranged from 60.8  years to 67.7%, 20.2–27.4%, 15.0–28.2%, and 6.7–18.1%, respec- 72.5  years, and the male proportion ranged from 49.1 tively (Additional file  1). There was potential significant to 100.0%. Four studies were of moderate quality, and publication bias for the 1-year survival rate (Egger test P: the remaining five studies were of low quality. Fig. 1 The PRISMA flowchart for study selection process Lan and Chen Radiation Oncology (2022) 17:61 Page 4 of 11 Table 1 The baseline characteristics of the eligible studies and included patients Study Country Study design Sample size Age (years) Male (%) Stage (I–II/III–IV) Interval from Total Study prior therapy to radiation quality irradiation dose Shioyama 2007 [19] Japan Retrospective 82 61.0 85.4 57/24 10.0 months 50.4 Gy 6 Nonoshita 2007 [20] Japan Retrospective 6 70.5 100.0 6/0 4.3 months 22.8 Gy 4 Maruyama 2011 Japan Retrospective 28 64.2 92.9 12/16 NA 60 Gy 4 [21] Kim 2012 [22] Korea Retrospective 10 72.5 90.0 6/4 15.6 months 46.5 Gy 5 Zhou 2015 [23] China Retrospective 55 66.8 49.1 54/1 NA 51.9 Gy 6 Katano 2017 [24] Japan Retrospective 6 60.8 100.0 NA 25.2 months 50.4 Gy 4 Hong 2018 [25] China Retrospective 87 62.0 74.7 23/47 16.0 months 60 Gy 5 Xu 2019 [26] China Retrospective 47 72.0 74.5 24/23 26.0 months 58 Gy 6 Zhao 2020 [27] China Retrospective 252 69.0 81.7 79/173 30.0 months 72 Gy 6 0.017; Begg’s test P: 0.548), but there was no significant were significantly more common after re-irradiation publication bias for the 2-year (Egger test P: 0.625; Begg’s (Fig.  5). However, re-irradiation was not associated with test P: 0.452), 3-year (Egger test P: 0.595; Begg’s test P: increased incidences of thrombocytopenia, anemia, or 0.806), or 5-year (Egger test P: 0.477; Begg’s test P: 0.221) neutropenia. There was no significant heterogeneity for survival rates (Additional file 1). grade ≥ 3 adverse events. Complete response and local re‑recurrence Subgroup analysis Three and four studies reported the effects of re-irra - The results of subgroup analyses for survival at 1, 2, diation on complete response and local re-recurrence, 3, and 5  years are shown in Table  2. The 1-year sur - respectively (Fig.  3). The pooled incidences of complete vival rate after re-irradiation was higher in studies with response and local re-recurrence after re-irradiation were a sample size ≥ 50, mean age ≥ 65  years, male propor- 54% (95% CI: 21–88; P = 0.001) and 62% (95% CI: 55–70; tion < 90%, ≥ 50% patients with tumor stage III and P < 0.001), respectively. There was significant heteroge - IV, mean interval from prior therapy to radiother- neity for complete response (I = 60.7%; P = 0.079), but apy ≥ 24  months, and moderate quality. The 2-year sur - no evidence of heterogeneity was observed for local re- vival rate after re-irradiation was higher in studies with a recurrence (I = 0.0%; P = 0.496). mean age ≥ 65  years and mean interval from prior ther- apy to radiotherapy ≥ 24 months. The 3-year survival rate Overall survival and local failure‑free survival after re-irradiation was higher in studies with a sample Three and three studies reported the effects of re- size ≥ 50, mean age ≥ 65 years, ≥ 50% patients with tumor irradiation on overall survival and local failure-free stage III and IV, mean interval from prior therapy to radi- survival, respectively (Fig.  4). The pooled overall sur - otherapy ≥ 24  months, and moderate quality. The 5-year vival and local failure-free survival after re-irradiation survival rate after re-irradiation was higher in stud- were 13.94  months (95% CI: 4.18–46.51; P < 0.001) and ies with a sample size ≥ 50, mean age ≥ 65  years, ≥ 50% 11.01  months (95% CI: 5.99–20.22; P < 0.001), respec- patients with tumor stage III and IV, mean interval from tively. There was significant heterogeneity for overall sur - prior therapy to radiotherapy ≥ 24 months, and moderate vival (I = 79.4%; P = 0.008) but not for local failure-free quality. survival (I = 25.4%; P = 0.262). Discussion Grade ≥ 3 adverse events In this meta-analysis, we included nine studies assess- Esophageal perforation (pooled incidence: 21%; 95% CI: ing the effectiveness of re-irradiation in 573 ESCC 11–31; P < 0.001), tracheoesophageal fistula (pooled inci - patients with locoregional recurrence, and the effect dence: 30%; 95% CI: 2–58; P = 0.038), and radiation pneu- estimates varied across the included studies. Although monitis (pooled incidence: 4%; 95% CI: 2–6; P < 0.001) patients should be monitored for grade ≥ 3 esophageal Lan and Chen Radiation Oncology (2022) 17:61 Page 5 of 11 Fig. 2 The pooled incidences of survival at 1, 2, 3, and 5 years after re-irradiation Lan and Chen Radiation Oncology (2022) 17:61 Page 6 of 11 Fig. 3 The pooled incidences of complete response and re-recurrence after re-irradiation perforation, tracheoesophageal fistula, and radiation prognostic factors should be explored in further pneumonitis in clinical practice, re-irradiation was effec - studies. tive for locoregional recurrent ESCC previously treated Our results on the pooled incidences of survival and with radiotherapy. Moreover, the treatment effects of re- recurrence after re-irradiation showed that re-irradia- irradiation on survival rate were affected by sample size, tion is feasible. Although most studies suggested that mean age, male proportion, tumor stage, interval from re-irradiation could improve the survival rate at various prior therapy to radiotherapy, and study quality. timepoints, several studies reported a lower survival rate To our knowledge, this is the first meta-analysis than expected [22, 24]. Kim et  al. found an overall sur- focused on the treatment effects of re-irradiation for vival longer than 12 months in only one patient, and the locoregional recurrent ESCC previously treated with mean overall survival was 6.73  months [22]. However, radiotherapy. Several features of this study should be three patients experienced grade 5 tracheoesophageal mentioned. First, it mainly included studies with lower fistula. Moreover, in the study by Katano et al., only one quality, which restricted the representativeness of the patient survived longer than 2  years [24]. Furthermore, cohort, and lower comparability, which could affect two included studies found that the incidence of com- the reliability of the pooled results. Second, the heter- plete response, which was lower than expected and the ogeneity in the survival rate at various timepoints was pooled conclusion was variable [21, 24]. substantial, which could be explained by differences in With regard to the safety of re-irradiation, our results tumor stage at initial diagnosis, initial treatment strat- showed that grade ≥ 3 esophageal perforation, tracheoe- egy, and radiation dose. Therefore, the results of this sophageal fistula, and radiation pneumonitis were more study should be generalized cautiously, and potential common after re-irradiation. However, whether these Lan and Chen Radiation Oncology (2022) 17:61 Page 7 of 11 Fig. 4 The pooled overall survival and local failure-free survival after re-irradiation adverse events were related to re-irradiation is unclear. needs to be further explored. (4) The baseline tumor The dose of irradiation for ESCC patients with locore - stage before chemoradiotherapy or radiotherapy is a sig- gional recurrence after initial radiotherapy is important nificant prognostic factor for ESCC [32]. (5) The interval and needs further investigation [28]. from prior therapy to radiotherapy is significantly related Subgroup analyses showed that the survival rate after to the response and progression of disease at initial treat- re-irradiation was affected by sample size, mean age, ment. (6) The quality of studies is significantly related male proportion, tumor stage, interval from prior therapy to the reliability of the conclusions, and the representa- to radiotherapy, and study quality. Interestingly, re-irradi- tiveness of the result is stronger in studies with higher ation provided better survival outcomes for patients with quality. high risk. There could be several reasons for these results. Several shortcomings of this study should be acknowl- (1) The sample size was related to the power and weight edged. First, all of the included studies were retrospec- from the overall analysis, which affected the robustness tive, and the results could be affected by uncontrolled of the pooled conclusion. (2) Patient age is significantly selection and confounder biases. Second, the analysis related to disease severity and treatment tolerability. (3) was based on a small number of studies, and the pooled The effect of radiosensitivity for ESCC patients might dif - conclusions were variable. Third, this study was based on fer in men and women. Moreover, androgen could facili- published articles, and unpublished data were not avail- tate the growth of human ESCC cells, and the activation able. Therefore, publication bias is inevitable. Finally, the of androgen receptors could induce the progression of analysis was based on pooled data, and whether the treat- ESCC [29–31]. Therefore, the association of androgen ment effects of re-irradiation differ based on patients’ levels with the prognosis of ESCC after radiotherapy characteristics needs to be further evaluated. Lan and Chen Radiation Oncology (2022) 17:61 Page 8 of 11 Fig. 5 The pooled grade ≥ 3 adverse events after re-irradiation greater effect on survival outcomes in high-risk patients Conclusions than in low-risk patients. Further prospective controlled In summary, this study found that re-irradiation was clinical trials should be conducted to compare the effi - effective for locoregional recurrent ESCC. However, cacy and safety of re-irradiation versus non-re-irradiation patients should be carefully monitored for grade ≥ 3 for locoregional recurrent ESCC previously treated with esophageal perforation, tracheoesophageal fistula, and radiotherapy. radiation pneumonitis. Further, re-irradiation had a Lan and Chen Radiation Oncology (2022) 17:61 Page 9 of 11 Table 2 Subgroup analyses for survival at 1, 2, 3, and 5 years Outcomes Factors Groups Number Incidence and 95% CI P value I (%) P value for P value of Q statistic between studies subgroups 1-year survival rate Sample size ≥ 50 3 0.74 (0.42–1.00) < 0.001 98.3 < 0.001 < 0.001 < 50 4 0.46 (0.15–0.78) 0.004 89.8 < 0.001 Mean age (years) ≥ 65 4 0.67 (0.41–0.94) < 0.001 97.1 < 0.001 < 0.001 < 65 3 0.44 (0.35–0.53) < 0.001 0.0 0.622 Male (%) ≥ 90 3 0.36 (0.04–0.67) 0.026 79.8 0.007 < 0.001 < 90 4 0.74 (0.48–1.00) < 0.001 97.7 < 0.001 Stage III–IV (%) ≥ 50 3 0.64 (0.21–1.00) 0.004 98.4 < 0.001 < 0.001 < 50 3 0.56 (0.19–0.93) 0.003 95.8 < 0.001 Interval from prior therapy to RT ≥ 24 3 0.79 (0.55–1.00) < 0.001 90.0 < 0.001 < 0.001 < 24 2 0.27 (− 0.04 to 0.57) 0.088 88.0 0.004 Study quality Moderate 3 0.86 (0.70–1.00) < 0.001 90.8 < 0.001 < 0.001 Low 4 0.37 (0.18–0.56) < 0.001 73.5 0.010 2-year survival rate Sample size ≥ 50 3 0.25 (0.10–0.39) 0.001 82.1 0.004 0.576 < 50 3 0.26 (0.16–0.36) < 0.001 0.0 0.743 Mean age (years) ≥ 65 2 0.34 (0.18–0.50) < 0.001 68.1 0.077 0.010 < 65 4 0.19 (0.13–0.25) < 0.001 0.0 0.523 Male (%) ≥ 90 2 0.27 (0.11–0.42) 0.001 0.0 0.444 0.696 < 90 4 0.25 (0.14–0.35) < 0.001 73.5 0.010 Stage III–IV (%) ≥ 50 2 0.22 (0.13–0.30) < 0.001 7.2 0.299 0.635 < 50 3 0.27 (0.11–0.43) 0.001 80.1 0.006 Interval from prior therapy to RT ≥ 24 2 0.24 (0.13–0.36) < 0.001 0.0 0.591 0.006 < 24 2 0.18 (0.11–0.24) < 0.001 0.0 0.430 Study quality Moderate 3 0.27 (0.11–0.43) 0.001 80.1 0.006 0.365 Low 3 0.21 (0.14–0.28) < 0.001 0.0 0.558 3-year survival rate Sample size ≥ 50 3 0.29 (0.01–0.57) 0.045 97.6 < 0.001 0.007 < 50 2 0.17 (0.07–0.27) 0.001 0.0 0.983 Mean age (years) ≥ 65 3 0.31 (0.06–0.56) 0.015 95.5 < 0.001 < 0.001 < 65 2 0.12 (0.05–0.18) < 0.001 0.0 0.740 Male (%) ≥ 90 1 0.17 (− 0.13 to 0.46) 0.273 – – 0.381 < 90 4 0.26 (0.04–0.48) 0.023 96.6 < 0.001 Stage III–IV (%) ≥ 50 2 0.32 (− 0.08 to 0.73) 0.119 98.7 < 0.001 0.004 < 50 2 0.19 (0.12–0.27) < 0.001 0.0 0.539 Interval from prior therapy to RT ≥ 24 3 0.30 (0.01–0.59) 0.042 94.3 < 0.001 < 0.001 < 24 2 0.16 (0.06–0.26) 0.002 59.9 0.114 Study quality Moderate 3 0.31 (0.06–0.56) 0.015 95.5 < 0.001 < 0.001 Low 2 0.12 (0.05–0.18) < 0.001 0.0 0.740 5-year survival rate Sample size ≥ 50 3 0.16 (− 0.03 to 0.35) 0.102 96.4 < 0.001 < 0.001 < 50 2 0.12 (− 0.11 to 0.36) 0.294 84.6 0.011 Mean age (years) ≥ 65 2 0.17 (− 0.12 to 0.46) 0.255 98.5 < 0.001 0.031 < 65 3 0.11 (0.01–0.21) 0.032 67.0 0.048 Male (%) ≥ 90 1 0.26 (0.08–0.44) 0.004 – – 0.074 < 90 4 0.12 (− 0.01 to 0.26) 0.077 96.1 < 0.001 Stage III–IV (%) ≥ 50 3 0.21 (− 0.01 to 0.42) 0.062 96.5 < 0.001 < 0.001 < 50 2 0.05 (− 0.03 to 0.14) 0.215 60.5 0.112 Interval from prior therapy to RT ≥ 24 2 0.17 (− 0.12 to 0.46) 0.255 98.5 < 0.001 0.009 < 24 2 0.06 (0.01–0.12) 0.027 23.4 0.253 Study quality Moderate 3 0.15 (− 0.06 to 0.36) 0.156 97.1 < 0.001 0.019 Low 2 0.14 (− 0.07 to 0.34) 0.202 80.8 0.023 Lan and Chen Radiation Oncology (2022) 17:61 Page 10 of 11 Abbreviations 6. Welsh J, Settle SH, Amini A, et al. Failure patterns in patients with CIs: Confidence intervals; ESCC: Esophageal squamous cell carcinoma. esophageal cancer treated with definitive chemoradiation. Cancer. 2012;118:2632–40. 7. Ghaly G, Kamel M, Nasar A, et al. Locally advanced esophageal Supplementary Information cancer: what becomes of 5-year survivors? J Thorac Cardiovasc Surg. The online version contains supplementary material available at https:// doi. 2016;151:726–31. org/ 10. 1186/ s13014- 022- 02019-0. 8. Chen Y, Lu Y, Wang Y, et al. Comparison of salvage chemoradiation versus salvage surgery for recurrent esophageal squamous cell carcinoma after definitive radiochemotherapy or radiotherapy alone. Dis Esophagus. Additional file 1: Fig. S1. Sensitivity analysis for the 1-year survival rate 2014;27:134–40. (52.3–67.7%). CI: confidence interval; Fig. S2. Funnel plot for the 1-year 9. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for sys- survival rate; Fig. S3. Sensitivity analysis for the 2-year survival rate (20.2– tematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 27.4%); Fig. S4. Funnel plot for the 2-year survival rate; Fig. S5. Sensitivity 2009;6:e1000097. analysis for the 3-year survival rate (15.0–28.2%); Fig. S6. Funnel plot for 10. Stang A. Critical evaluation of the Newcastle–Ottawa scale for the assess- the 3-year survival rate; Fig. S7. Sensitivity analysis for the 5-year survival ment of the quality of nonrandomized studies in meta-analyses. Eur J rate (6.7–18.1%); Fig. S8. Funnel plot for the 5-year survival rate. Epidemiol. 2010;25:603–5. 11. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88. Acknowledgements 12. Ades AE, Lu G, Higgins JP. The interpretation of random-effects metaanal- Not applicable. ysis in decision models. Med Decis Mak. 2005;25:646–54. 13. Deeks JJ, Higgins JPT, Altman DG. Analyzing data and undertaking Authors’ contributions meta-analyses. In: Higgins J, Green S, editors. Cochrane handbook for LK acquisition of data, analysis and interpretation of data, drafting the article, systematic reviews of interventions 5.0.1; chapter 9. Oxford: The Cochrane final approval; LT acquisition of data, analysis and interpretation of data, draft - Collaboration; 2008. ing the article, final approval; CH interpretation of data, revising the article, 14. Higgins JPT, Thompson SG, Deeks JJ, et al. Measuring inconsistency in final approval; CH interpretation of data, revising the article, final approval; CH meta-analyses. BMJ. 2003;327:557–60. conception and design of the study, critical revision, final approval. All authors 15. Tobias A. Assessing the influence of a single study in meta-analysis. Stata read and approved the final manuscript. Tech Bull. 1999;47:15–7. 16. Altman DG, Bland JM. Interaction revisited: the difference between two Funding estimates. BMJ. 2003;326:219. Not applicable. 17. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34. Availability of data and materials 18. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test The datasets used and/or analysed during the current study are available from for publication bias. Biometrics. 1994;50:1088–101. the corresponding author on reasonable request. 19. Shioyama Y, Nakamura K, Ohga S, et al. Radiation therapy for recurrent esophageal cancer after surgery: clinical results and prognostic factors. Jpn J Clin Oncol. 2007;37:918–23. Declarations 20. Nonoshita T, Sasaki T, Hirata H, et al. High-dose-rate brachytherapy for previously irradiated patients with recurrent esophageal cancer. Radiat Ethics approval and consent to participate Med. 2007;25:373–7. Not applicable. 21. Maruyama K, Motoyama S, Anbai A, et al. Therapeutic strategy for the treatment of postoperative recurrence of esophageal squamous cell car- Consent for publication cinoma: clinical efficacy of radiotherapy. Dis Esophagus. 2011;24:166–71. Not applicable. 22. Kim YS, Lee CG, Kim KH, et al. Re-irradiation of recurrent esophageal can- cer after primary definitive radiotherapy. Radiat Oncol J. 2012;30:182–8. Competing interests 23. Zhou ZG, Zhen CJ, Bai WW, et al. Salvage radiotherapy in patients with The authors declare that they have no competing interests. local recurrent esophageal cancer after radical radiochemotherapy. Radiat Oncol. 2015;10:54. Received: 18 October 2021 Accepted: 24 February 2022 24. Katano A, Yamashita H, Nakagawa K. Re-irradiation of locoregional esophageal cancer recurrence following definitive chemoradiotherapy: a report of 6 cases. Mol Clin Oncol. 2017;7:681–6. 25. Hong L, Huang YX, Zhuang QY, et al. Survival benefit of re-irradiation in esophageal cancer patients with locoregional recurrence: a propensity References score-matched analysis. Radiat Oncol. 2018;13:171. 1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality 26. Xu X, Wang Z, Jiang S, et al. Evaluating the optimal re-irradiation dose for worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int locally recurrent esophageal squamous cell carcinoma after definitive J Cancer. 2015;136:E359–86. radiotherapy. Radiat Oncol. 2019;14:191. 2. Pennathur A, Gibson MK, Jobe BA, et al. Oesophageal carcinoma. Lancet. 27. Zhao K, Si Y, Sun L, et al. Efficacy and toxicity of re-irradiation for 2013;381:400–12. esophageal cancer patients with locoregional recurrence: a retrospective 3. Wu YF, Chu SC, Chang BS, et al. Hematologic markers as prognostic analysis. Radiat Oncol. 2020;15:243. factors in nonmetastatic esophageal cancer patients under concurrent 28. Zhang J, Peng F, Li N, et al. Salvage concurrent radio-chemotherapy for chemoradiotherapy. Biomed Res Int. 2019;2019:1263050. post-operative local recurrence of squamous-cell esophageal cancer. 4. Hong ZN, Weng K, Peng K, et al. Neoadjuvant immunotherapy combined Radiat Oncol. 2012;7:93–100. chemotherapy followed by surgery versus surgery alone for locally 29. Matsuoka H, Sugimachi K, Ueo H, et al. Sex hormone response of a newly advanced esophageal squamous cell carcinoma: a propensity score- established squamous cell line derived from clinical esophageal carci- matched study. Front Oncol. 2021;11:797426. noma. Cancer Res. 1987;47:4134–40. 5. Ye Y, Xu Y, Fu Q, et al. Enteral nutrition support does not improve PNI in 30. Dong H, Xu J, Li W, et al. Reciprocal androgen receptor/interleukin-6 radiotherapy patients with locally advanced esophageal cancer. Nutr crosstalk drives oesophageal carcinoma progression and contributes to Cancer. 2019;71:223–9. patient prognosis. J Pathol. 2017;241:448–62. 31. Luo HS, Xu HY, Du ZS, et al. Impact of sex on the prognosis of patients with esophageal squamous cell cancer underwent definitive Lan and Chen Radiation Oncology (2022) 17:61 Page 11 of 11 radiotherapy: a propensity score-matched analysis. Radiat Oncol. 2019;14:74. 32. Kondo S, Tajika M, Tanaka T, et al. Prognostic factors for salvage endo- scopic resection for esophageal squamous cell carcinoma after chemora- diotherapy or radiotherapy alone. Endosc Int Open. 2016;4:E841–8. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Efficacy and safety of re-irradiation for locoregional esophageal squamous cell carcinoma recurrence after radiotherapy: a systematic review and meta-analysis

Lan, Kuntian; Chen, Jiaohong
Radiation Oncology , Volume 17 (1) – Mar 28, 2022
Download PDF
11 pages

Loading next page...
 
/lp/springer-journals/efficacy-and-safety-of-re-irradiation-for-locoregional-esophageal-m2oCSDOO9h

References (34)

Publisher
Springer Journals
Copyright
Copyright © The Author(s) 2022
eISSN
1748-717X
DOI
10.1186/s13014-022-02019-0
Publisher site
See Article on Publisher Site

Abstract

Background: There is currently no standard treatment for locoregional recurrence of esophageal squamous cell car- cinoma (ESCC) previously treated with radiotherapy. This study aimed to assess the efficacy and safety of re-irradiation for ESCC patients with locoregional recurrence. Methods: The PubMed, EmBase, and Cochrane library databases were systematically searched for eligible stud- ies published before January 2021. The pooled effect estimates were calculated using the random effects model. Subgroup analyses were conducted to assess the treatment effectiveness of re-irradiation based on specific characteristics. Results: Nine retrospective studies including 573 ESCC patients with locoregional recurrence were selected. The pooled incidences of the 1-year, 2-year, 3-year, and 5-year survival for patients after re-irradiation were 59% (95% confidence interval [CI]: 35–83; P < 0.001), 25% (95% CI: 16–33; P < 0.001), 25% (95% CI: 4–45; P = 0.017), and 15% (95% CI: 2–27; P = 0.024), respectively. The rates of complete response and local re-recurrence after re-irradiation were 54% (95% CI: 21–88; P = 0.001) and 62% (95% CI: 55–70; P < 0.001), respectively. The median overall survival and local failure-free survival for patients after re-irradiation were 13.94 months (95% CI: 4.18–46.51; P < 0.001) and 11.01 months (95% CI: 5.99–20.22; P < 0.001), respectively. Grade ≥ 3 adverse events of esophageal perforation, tracheoesophageal fistula, and radiation pneumonitis were significantly more common after re-irradiation. Conclusions: This study found that re-irradiation for ESCC patients with locoregional recurrence after previous radiotherapy was feasible. However, patients should be carefully observed in order to treat associated adverse events, including esophageal perforation, tracheoesophageal fistula, and radiation pneumonitis. Keywords: Re-irradiation, Esophageal squamous cell carcinoma, Recurrence, Radiotherapy, Systematic review, Meta- analysis Introduction Esophageal cancer is the eighth most common cancer worldwide, with more than 450,000 new cases annu- ally, and the sixth leading cause of cancer-related deaths [1]. Esophageal squamous cell carcinoma (ESCC) is the predominant histological type of esophageal can- *Correspondence: smxyycjh@163.com Department of Radiotherapy, Cancer Branch of Sanmenxia Central cer [2]. Although patients with early ESCC undergo Hospital, Sanmenxia 472000, China © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom- mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lan and Chen Radiation Oncology (2022) 17:61 Page 2 of 11 esophagectomy, most ESCC patients are diagnosed with country, study design, sample size, mean age, male pro- locally advanced disease. Therefore, surgery alone is usu - portion, tumor stage, interval from prior therapy to irra- ally insufficient, and radiotherapy or chemotherapy are diation, total radiation dose, and reported outcomes. administered [3, 4]. However, the prognosis of ESCC The quality of each individual study was assessed using remains poor, and local recurrence or metastasis play a the Newcastle–Ottawa Scale, and the starring system for critical role in treatment failure and mortality [5]. each study ranged from 0 to 9 [10]. Studies with 6 stars Previous studies have shown that local recurrence were considered to be of moderate quality, and studies is the major cause of ESCC recurrence after definitive with 4 or 5 stars were regarded as low quality. Incon- chemoradiotherapy, which accounts for nearly 40–60% sistent results between reviewers for extracted data and of ESCC cases [6, 7]. Re-irradiation is a common sal- quality assessment were settled by an additional reviewer vage treatment strategy and is widely administered for after referring to the original article. recurrent ESCC after radical radiotherapy or chemora- diotherapy. Chen et al. found that re-irradiation was able Statistical analysis to relieve symptoms and prolong survival [8]. However, The pooled incidence of survival at 1, 2, 3, and 5  years, the efficacy of re-irradiation for locoregional recurrent complete response, local re-recurrence, and grade ≥ 3 ESCC previously treated with radiotherapy is variable, adverse events were calculated based on the number of and whether the efficacy of re-irradiation is affected by events and total patients, whereas pooled overall survival patient characteristics remains controversial. We there- and local failure-free survival were calculated based on fore performed a systematic review and meta-analysis to mean survival and 95% confidence intervals (CIs). The assess the efficacy and safety of re-irradiation for ESCC pooled effect estimates were calculated using the random patients with locoregional recurrence who were previ- effects model, and underlying variations across included ously treated with radiotherapy. studies were considered [11, 12]. Heterogeneity among the included studies for each outcome was assessed using Methods I2 and the Q statistic, and significant heterogeneity was Search strategy and selection criteria defined as I > 50.0% or P < 0.10 [13, 14]. The robustness The Preferred Reporting Items for Systematic Reviews of the pooled conclusion was assessed using sensitiv- and Meta-Analysis guideline was used to guide this sys- ity analysis by sequentially removing a single study [15]. tematic review and meta-analysis [9]. Studies investigat- Subgroup analyses for survival at 1, 2, 3, and 5 years were ing the treatment effects of re-irradiation for patients also performed according to sample size, mean age, male with locoregional recurrent ESCC previously treated proportion, tumor stage, interval from prior therapy with radiotherapy were eligible. Only studies published to radiotherapy, and study quality, and the differences in English were included. The PubMed, EmBase, and between subgroups were assessed using the interaction Cochrane library databases were searched for eligible P test [16]. Funnel plot, Egger test, and Begg’s tests were studies published through January 2021, and the follow- used to assess potential publication bias [17, 18]. The P ing search terms were used: esophageal squamous cell values for pooled conclusions are two-sided, and the carcinoma, recurrence or recurrent, and radiotherapy or inspection level was 0.05. All statistical analyses in this irradiation. We also manually reviewed the reference lists study were performed using STATA software (version of retrieved studies to identify any additional studies that 10.0; Stata Corporation, College Station, TX, USA). met the inclusion criteria. The inclusion criteria were as follows: (1) Study design: retrospective, prospective, or randomized controlled tri- Results als; (2) Patients: patients with recurrent ESCC previously Literature search treated with definitive radiotherapy; (3) Intervention: re- A total of 781 articles were identified from initial irradiation; and (4) Outcomes: survival rate at 1, 2, 3, or searches of the PubMed, EmBase, and Cochrane 5  years, complete response, local re-recurrence, overall library databases, and 422 studies were retained after survival, local failure-free survival, and grade ≥ 3 adverse duplicate titles were removed. A further 390 stud- events. Study selection was performed by two reviewers, ies were excluded because they covered irrelevant and conflicts between reviewers was settled by group dis - topics. The remaining 32 studies were retrieved for cussion until a consensus was reached. full-text evaluation, and 23 studies were excluded for the following reasons: not recurrent ESCC (n = 15), Data collection and quality assessment patients were previously without radiotherapy (n = 5), Two reviewers independently extracted the follow- and other interventions (n = 3). Reviewing the refer- ing information: first author’s name, publication year, ence lists yielded one additional potential study, but Lan and Chen Radiation Oncology (2022) 17:61 Page 3 of 11 this study was also retrieved by our electronic search. Survival rate at 1, 2, 3, and 5 years Finally, nine studies were selected for the final meta- Six, five, four, and five studies reported the effects of analysis (Fig. 1) [19–27]. re-irradiation on survival at 1, 2, 3, and 5  years, respec- tively (Fig.  2). The pooled incidences of 1-year, 2-year, 3-year, and 5-year survival for patients after re-irradi- ation were 59% (95% confidence interval [CI]: 35–83; Study characteristics P < 0.001), 25% (95% CI: 16–33; P < 0.001), 25% (95% CI: The characteristics of the included studies and patients 4–45; P = 0.017), and 15% (95% CI: 2–27; P = 0.024), are summarized in Table  1. All of the studies were respectively. There was significant heterogeneity for the retrospective, and a total of 573 ESCC patients with survival rates at 1  year (I = 97.4%; P < 0.001), 2  years locoregional recurrence were included. Four studies 2 2 (I = 58.5%; P = 0.034), 3 years (I = 95.6%; P < 0.001), and were conducted in Japan, four studies were conducted 5 years (I = 95.0%; P < 0.001). Sensitivity analyses found in China, and one study was conducted in Korea. the ranges for survival at 1, 2, 3, and 5  years were 52.3– The mean age for patients ranged from 60.8  years to 67.7%, 20.2–27.4%, 15.0–28.2%, and 6.7–18.1%, respec- 72.5  years, and the male proportion ranged from 49.1 tively (Additional file  1). There was potential significant to 100.0%. Four studies were of moderate quality, and publication bias for the 1-year survival rate (Egger test P: the remaining five studies were of low quality. Fig. 1 The PRISMA flowchart for study selection process Lan and Chen Radiation Oncology (2022) 17:61 Page 4 of 11 Table 1 The baseline characteristics of the eligible studies and included patients Study Country Study design Sample size Age (years) Male (%) Stage (I–II/III–IV) Interval from Total Study prior therapy to radiation quality irradiation dose Shioyama 2007 [19] Japan Retrospective 82 61.0 85.4 57/24 10.0 months 50.4 Gy 6 Nonoshita 2007 [20] Japan Retrospective 6 70.5 100.0 6/0 4.3 months 22.8 Gy 4 Maruyama 2011 Japan Retrospective 28 64.2 92.9 12/16 NA 60 Gy 4 [21] Kim 2012 [22] Korea Retrospective 10 72.5 90.0 6/4 15.6 months 46.5 Gy 5 Zhou 2015 [23] China Retrospective 55 66.8 49.1 54/1 NA 51.9 Gy 6 Katano 2017 [24] Japan Retrospective 6 60.8 100.0 NA 25.2 months 50.4 Gy 4 Hong 2018 [25] China Retrospective 87 62.0 74.7 23/47 16.0 months 60 Gy 5 Xu 2019 [26] China Retrospective 47 72.0 74.5 24/23 26.0 months 58 Gy 6 Zhao 2020 [27] China Retrospective 252 69.0 81.7 79/173 30.0 months 72 Gy 6 0.017; Begg’s test P: 0.548), but there was no significant were significantly more common after re-irradiation publication bias for the 2-year (Egger test P: 0.625; Begg’s (Fig.  5). However, re-irradiation was not associated with test P: 0.452), 3-year (Egger test P: 0.595; Begg’s test P: increased incidences of thrombocytopenia, anemia, or 0.806), or 5-year (Egger test P: 0.477; Begg’s test P: 0.221) neutropenia. There was no significant heterogeneity for survival rates (Additional file 1). grade ≥ 3 adverse events. Complete response and local re‑recurrence Subgroup analysis Three and four studies reported the effects of re-irra - The results of subgroup analyses for survival at 1, 2, diation on complete response and local re-recurrence, 3, and 5  years are shown in Table  2. The 1-year sur - respectively (Fig.  3). The pooled incidences of complete vival rate after re-irradiation was higher in studies with response and local re-recurrence after re-irradiation were a sample size ≥ 50, mean age ≥ 65  years, male propor- 54% (95% CI: 21–88; P = 0.001) and 62% (95% CI: 55–70; tion < 90%, ≥ 50% patients with tumor stage III and P < 0.001), respectively. There was significant heteroge - IV, mean interval from prior therapy to radiother- neity for complete response (I = 60.7%; P = 0.079), but apy ≥ 24  months, and moderate quality. The 2-year sur - no evidence of heterogeneity was observed for local re- vival rate after re-irradiation was higher in studies with a recurrence (I = 0.0%; P = 0.496). mean age ≥ 65  years and mean interval from prior ther- apy to radiotherapy ≥ 24 months. The 3-year survival rate Overall survival and local failure‑free survival after re-irradiation was higher in studies with a sample Three and three studies reported the effects of re- size ≥ 50, mean age ≥ 65 years, ≥ 50% patients with tumor irradiation on overall survival and local failure-free stage III and IV, mean interval from prior therapy to radi- survival, respectively (Fig.  4). The pooled overall sur - otherapy ≥ 24  months, and moderate quality. The 5-year vival and local failure-free survival after re-irradiation survival rate after re-irradiation was higher in stud- were 13.94  months (95% CI: 4.18–46.51; P < 0.001) and ies with a sample size ≥ 50, mean age ≥ 65  years, ≥ 50% 11.01  months (95% CI: 5.99–20.22; P < 0.001), respec- patients with tumor stage III and IV, mean interval from tively. There was significant heterogeneity for overall sur - prior therapy to radiotherapy ≥ 24 months, and moderate vival (I = 79.4%; P = 0.008) but not for local failure-free quality. survival (I = 25.4%; P = 0.262). Discussion Grade ≥ 3 adverse events In this meta-analysis, we included nine studies assess- Esophageal perforation (pooled incidence: 21%; 95% CI: ing the effectiveness of re-irradiation in 573 ESCC 11–31; P < 0.001), tracheoesophageal fistula (pooled inci - patients with locoregional recurrence, and the effect dence: 30%; 95% CI: 2–58; P = 0.038), and radiation pneu- estimates varied across the included studies. Although monitis (pooled incidence: 4%; 95% CI: 2–6; P < 0.001) patients should be monitored for grade ≥ 3 esophageal Lan and Chen Radiation Oncology (2022) 17:61 Page 5 of 11 Fig. 2 The pooled incidences of survival at 1, 2, 3, and 5 years after re-irradiation Lan and Chen Radiation Oncology (2022) 17:61 Page 6 of 11 Fig. 3 The pooled incidences of complete response and re-recurrence after re-irradiation perforation, tracheoesophageal fistula, and radiation prognostic factors should be explored in further pneumonitis in clinical practice, re-irradiation was effec - studies. tive for locoregional recurrent ESCC previously treated Our results on the pooled incidences of survival and with radiotherapy. Moreover, the treatment effects of re- recurrence after re-irradiation showed that re-irradia- irradiation on survival rate were affected by sample size, tion is feasible. Although most studies suggested that mean age, male proportion, tumor stage, interval from re-irradiation could improve the survival rate at various prior therapy to radiotherapy, and study quality. timepoints, several studies reported a lower survival rate To our knowledge, this is the first meta-analysis than expected [22, 24]. Kim et  al. found an overall sur- focused on the treatment effects of re-irradiation for vival longer than 12 months in only one patient, and the locoregional recurrent ESCC previously treated with mean overall survival was 6.73  months [22]. However, radiotherapy. Several features of this study should be three patients experienced grade 5 tracheoesophageal mentioned. First, it mainly included studies with lower fistula. Moreover, in the study by Katano et al., only one quality, which restricted the representativeness of the patient survived longer than 2  years [24]. Furthermore, cohort, and lower comparability, which could affect two included studies found that the incidence of com- the reliability of the pooled results. Second, the heter- plete response, which was lower than expected and the ogeneity in the survival rate at various timepoints was pooled conclusion was variable [21, 24]. substantial, which could be explained by differences in With regard to the safety of re-irradiation, our results tumor stage at initial diagnosis, initial treatment strat- showed that grade ≥ 3 esophageal perforation, tracheoe- egy, and radiation dose. Therefore, the results of this sophageal fistula, and radiation pneumonitis were more study should be generalized cautiously, and potential common after re-irradiation. However, whether these Lan and Chen Radiation Oncology (2022) 17:61 Page 7 of 11 Fig. 4 The pooled overall survival and local failure-free survival after re-irradiation adverse events were related to re-irradiation is unclear. needs to be further explored. (4) The baseline tumor The dose of irradiation for ESCC patients with locore - stage before chemoradiotherapy or radiotherapy is a sig- gional recurrence after initial radiotherapy is important nificant prognostic factor for ESCC [32]. (5) The interval and needs further investigation [28]. from prior therapy to radiotherapy is significantly related Subgroup analyses showed that the survival rate after to the response and progression of disease at initial treat- re-irradiation was affected by sample size, mean age, ment. (6) The quality of studies is significantly related male proportion, tumor stage, interval from prior therapy to the reliability of the conclusions, and the representa- to radiotherapy, and study quality. Interestingly, re-irradi- tiveness of the result is stronger in studies with higher ation provided better survival outcomes for patients with quality. high risk. There could be several reasons for these results. Several shortcomings of this study should be acknowl- (1) The sample size was related to the power and weight edged. First, all of the included studies were retrospec- from the overall analysis, which affected the robustness tive, and the results could be affected by uncontrolled of the pooled conclusion. (2) Patient age is significantly selection and confounder biases. Second, the analysis related to disease severity and treatment tolerability. (3) was based on a small number of studies, and the pooled The effect of radiosensitivity for ESCC patients might dif - conclusions were variable. Third, this study was based on fer in men and women. Moreover, androgen could facili- published articles, and unpublished data were not avail- tate the growth of human ESCC cells, and the activation able. Therefore, publication bias is inevitable. Finally, the of androgen receptors could induce the progression of analysis was based on pooled data, and whether the treat- ESCC [29–31]. Therefore, the association of androgen ment effects of re-irradiation differ based on patients’ levels with the prognosis of ESCC after radiotherapy characteristics needs to be further evaluated. Lan and Chen Radiation Oncology (2022) 17:61 Page 8 of 11 Fig. 5 The pooled grade ≥ 3 adverse events after re-irradiation greater effect on survival outcomes in high-risk patients Conclusions than in low-risk patients. Further prospective controlled In summary, this study found that re-irradiation was clinical trials should be conducted to compare the effi - effective for locoregional recurrent ESCC. However, cacy and safety of re-irradiation versus non-re-irradiation patients should be carefully monitored for grade ≥ 3 for locoregional recurrent ESCC previously treated with esophageal perforation, tracheoesophageal fistula, and radiotherapy. radiation pneumonitis. Further, re-irradiation had a Lan and Chen Radiation Oncology (2022) 17:61 Page 9 of 11 Table 2 Subgroup analyses for survival at 1, 2, 3, and 5 years Outcomes Factors Groups Number Incidence and 95% CI P value I (%) P value for P value of Q statistic between studies subgroups 1-year survival rate Sample size ≥ 50 3 0.74 (0.42–1.00) < 0.001 98.3 < 0.001 < 0.001 < 50 4 0.46 (0.15–0.78) 0.004 89.8 < 0.001 Mean age (years) ≥ 65 4 0.67 (0.41–0.94) < 0.001 97.1 < 0.001 < 0.001 < 65 3 0.44 (0.35–0.53) < 0.001 0.0 0.622 Male (%) ≥ 90 3 0.36 (0.04–0.67) 0.026 79.8 0.007 < 0.001 < 90 4 0.74 (0.48–1.00) < 0.001 97.7 < 0.001 Stage III–IV (%) ≥ 50 3 0.64 (0.21–1.00) 0.004 98.4 < 0.001 < 0.001 < 50 3 0.56 (0.19–0.93) 0.003 95.8 < 0.001 Interval from prior therapy to RT ≥ 24 3 0.79 (0.55–1.00) < 0.001 90.0 < 0.001 < 0.001 < 24 2 0.27 (− 0.04 to 0.57) 0.088 88.0 0.004 Study quality Moderate 3 0.86 (0.70–1.00) < 0.001 90.8 < 0.001 < 0.001 Low 4 0.37 (0.18–0.56) < 0.001 73.5 0.010 2-year survival rate Sample size ≥ 50 3 0.25 (0.10–0.39) 0.001 82.1 0.004 0.576 < 50 3 0.26 (0.16–0.36) < 0.001 0.0 0.743 Mean age (years) ≥ 65 2 0.34 (0.18–0.50) < 0.001 68.1 0.077 0.010 < 65 4 0.19 (0.13–0.25) < 0.001 0.0 0.523 Male (%) ≥ 90 2 0.27 (0.11–0.42) 0.001 0.0 0.444 0.696 < 90 4 0.25 (0.14–0.35) < 0.001 73.5 0.010 Stage III–IV (%) ≥ 50 2 0.22 (0.13–0.30) < 0.001 7.2 0.299 0.635 < 50 3 0.27 (0.11–0.43) 0.001 80.1 0.006 Interval from prior therapy to RT ≥ 24 2 0.24 (0.13–0.36) < 0.001 0.0 0.591 0.006 < 24 2 0.18 (0.11–0.24) < 0.001 0.0 0.430 Study quality Moderate 3 0.27 (0.11–0.43) 0.001 80.1 0.006 0.365 Low 3 0.21 (0.14–0.28) < 0.001 0.0 0.558 3-year survival rate Sample size ≥ 50 3 0.29 (0.01–0.57) 0.045 97.6 < 0.001 0.007 < 50 2 0.17 (0.07–0.27) 0.001 0.0 0.983 Mean age (years) ≥ 65 3 0.31 (0.06–0.56) 0.015 95.5 < 0.001 < 0.001 < 65 2 0.12 (0.05–0.18) < 0.001 0.0 0.740 Male (%) ≥ 90 1 0.17 (− 0.13 to 0.46) 0.273 – – 0.381 < 90 4 0.26 (0.04–0.48) 0.023 96.6 < 0.001 Stage III–IV (%) ≥ 50 2 0.32 (− 0.08 to 0.73) 0.119 98.7 < 0.001 0.004 < 50 2 0.19 (0.12–0.27) < 0.001 0.0 0.539 Interval from prior therapy to RT ≥ 24 3 0.30 (0.01–0.59) 0.042 94.3 < 0.001 < 0.001 < 24 2 0.16 (0.06–0.26) 0.002 59.9 0.114 Study quality Moderate 3 0.31 (0.06–0.56) 0.015 95.5 < 0.001 < 0.001 Low 2 0.12 (0.05–0.18) < 0.001 0.0 0.740 5-year survival rate Sample size ≥ 50 3 0.16 (− 0.03 to 0.35) 0.102 96.4 < 0.001 < 0.001 < 50 2 0.12 (− 0.11 to 0.36) 0.294 84.6 0.011 Mean age (years) ≥ 65 2 0.17 (− 0.12 to 0.46) 0.255 98.5 < 0.001 0.031 < 65 3 0.11 (0.01–0.21) 0.032 67.0 0.048 Male (%) ≥ 90 1 0.26 (0.08–0.44) 0.004 – – 0.074 < 90 4 0.12 (− 0.01 to 0.26) 0.077 96.1 < 0.001 Stage III–IV (%) ≥ 50 3 0.21 (− 0.01 to 0.42) 0.062 96.5 < 0.001 < 0.001 < 50 2 0.05 (− 0.03 to 0.14) 0.215 60.5 0.112 Interval from prior therapy to RT ≥ 24 2 0.17 (− 0.12 to 0.46) 0.255 98.5 < 0.001 0.009 < 24 2 0.06 (0.01–0.12) 0.027 23.4 0.253 Study quality Moderate 3 0.15 (− 0.06 to 0.36) 0.156 97.1 < 0.001 0.019 Low 2 0.14 (− 0.07 to 0.34) 0.202 80.8 0.023 Lan and Chen Radiation Oncology (2022) 17:61 Page 10 of 11 Abbreviations 6. Welsh J, Settle SH, Amini A, et al. Failure patterns in patients with CIs: Confidence intervals; ESCC: Esophageal squamous cell carcinoma. esophageal cancer treated with definitive chemoradiation. Cancer. 2012;118:2632–40. 7. Ghaly G, Kamel M, Nasar A, et al. Locally advanced esophageal Supplementary Information cancer: what becomes of 5-year survivors? J Thorac Cardiovasc Surg. The online version contains supplementary material available at https:// doi. 2016;151:726–31. org/ 10. 1186/ s13014- 022- 02019-0. 8. Chen Y, Lu Y, Wang Y, et al. Comparison of salvage chemoradiation versus salvage surgery for recurrent esophageal squamous cell carcinoma after definitive radiochemotherapy or radiotherapy alone. Dis Esophagus. Additional file 1: Fig. S1. Sensitivity analysis for the 1-year survival rate 2014;27:134–40. (52.3–67.7%). CI: confidence interval; Fig. S2. Funnel plot for the 1-year 9. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for sys- survival rate; Fig. S3. Sensitivity analysis for the 2-year survival rate (20.2– tematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 27.4%); Fig. S4. Funnel plot for the 2-year survival rate; Fig. S5. Sensitivity 2009;6:e1000097. analysis for the 3-year survival rate (15.0–28.2%); Fig. S6. Funnel plot for 10. Stang A. Critical evaluation of the Newcastle–Ottawa scale for the assess- the 3-year survival rate; Fig. S7. Sensitivity analysis for the 5-year survival ment of the quality of nonrandomized studies in meta-analyses. Eur J rate (6.7–18.1%); Fig. S8. Funnel plot for the 5-year survival rate. Epidemiol. 2010;25:603–5. 11. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88. Acknowledgements 12. Ades AE, Lu G, Higgins JP. The interpretation of random-effects metaanal- Not applicable. ysis in decision models. Med Decis Mak. 2005;25:646–54. 13. Deeks JJ, Higgins JPT, Altman DG. Analyzing data and undertaking Authors’ contributions meta-analyses. In: Higgins J, Green S, editors. Cochrane handbook for LK acquisition of data, analysis and interpretation of data, drafting the article, systematic reviews of interventions 5.0.1; chapter 9. Oxford: The Cochrane final approval; LT acquisition of data, analysis and interpretation of data, draft - Collaboration; 2008. ing the article, final approval; CH interpretation of data, revising the article, 14. Higgins JPT, Thompson SG, Deeks JJ, et al. Measuring inconsistency in final approval; CH interpretation of data, revising the article, final approval; CH meta-analyses. BMJ. 2003;327:557–60. conception and design of the study, critical revision, final approval. All authors 15. Tobias A. Assessing the influence of a single study in meta-analysis. Stata read and approved the final manuscript. Tech Bull. 1999;47:15–7. 16. Altman DG, Bland JM. Interaction revisited: the difference between two Funding estimates. BMJ. 2003;326:219. Not applicable. 17. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34. Availability of data and materials 18. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test The datasets used and/or analysed during the current study are available from for publication bias. Biometrics. 1994;50:1088–101. the corresponding author on reasonable request. 19. Shioyama Y, Nakamura K, Ohga S, et al. Radiation therapy for recurrent esophageal cancer after surgery: clinical results and prognostic factors. Jpn J Clin Oncol. 2007;37:918–23. Declarations 20. Nonoshita T, Sasaki T, Hirata H, et al. High-dose-rate brachytherapy for previously irradiated patients with recurrent esophageal cancer. Radiat Ethics approval and consent to participate Med. 2007;25:373–7. Not applicable. 21. Maruyama K, Motoyama S, Anbai A, et al. Therapeutic strategy for the treatment of postoperative recurrence of esophageal squamous cell car- Consent for publication cinoma: clinical efficacy of radiotherapy. Dis Esophagus. 2011;24:166–71. Not applicable. 22. Kim YS, Lee CG, Kim KH, et al. Re-irradiation of recurrent esophageal can- cer after primary definitive radiotherapy. Radiat Oncol J. 2012;30:182–8. Competing interests 23. Zhou ZG, Zhen CJ, Bai WW, et al. Salvage radiotherapy in patients with The authors declare that they have no competing interests. local recurrent esophageal cancer after radical radiochemotherapy. Radiat Oncol. 2015;10:54. Received: 18 October 2021 Accepted: 24 February 2022 24. Katano A, Yamashita H, Nakagawa K. Re-irradiation of locoregional esophageal cancer recurrence following definitive chemoradiotherapy: a report of 6 cases. Mol Clin Oncol. 2017;7:681–6. 25. Hong L, Huang YX, Zhuang QY, et al. Survival benefit of re-irradiation in esophageal cancer patients with locoregional recurrence: a propensity References score-matched analysis. Radiat Oncol. 2018;13:171. 1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality 26. Xu X, Wang Z, Jiang S, et al. Evaluating the optimal re-irradiation dose for worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int locally recurrent esophageal squamous cell carcinoma after definitive J Cancer. 2015;136:E359–86. radiotherapy. Radiat Oncol. 2019;14:191. 2. Pennathur A, Gibson MK, Jobe BA, et al. Oesophageal carcinoma. Lancet. 27. Zhao K, Si Y, Sun L, et al. Efficacy and toxicity of re-irradiation for 2013;381:400–12. esophageal cancer patients with locoregional recurrence: a retrospective 3. Wu YF, Chu SC, Chang BS, et al. Hematologic markers as prognostic analysis. Radiat Oncol. 2020;15:243. factors in nonmetastatic esophageal cancer patients under concurrent 28. Zhang J, Peng F, Li N, et al. Salvage concurrent radio-chemotherapy for chemoradiotherapy. Biomed Res Int. 2019;2019:1263050. post-operative local recurrence of squamous-cell esophageal cancer. 4. Hong ZN, Weng K, Peng K, et al. Neoadjuvant immunotherapy combined Radiat Oncol. 2012;7:93–100. chemotherapy followed by surgery versus surgery alone for locally 29. Matsuoka H, Sugimachi K, Ueo H, et al. Sex hormone response of a newly advanced esophageal squamous cell carcinoma: a propensity score- established squamous cell line derived from clinical esophageal carci- matched study. Front Oncol. 2021;11:797426. noma. Cancer Res. 1987;47:4134–40. 5. Ye Y, Xu Y, Fu Q, et al. Enteral nutrition support does not improve PNI in 30. Dong H, Xu J, Li W, et al. Reciprocal androgen receptor/interleukin-6 radiotherapy patients with locally advanced esophageal cancer. Nutr crosstalk drives oesophageal carcinoma progression and contributes to Cancer. 2019;71:223–9. patient prognosis. J Pathol. 2017;241:448–62. 31. Luo HS, Xu HY, Du ZS, et al. Impact of sex on the prognosis of patients with esophageal squamous cell cancer underwent definitive Lan and Chen Radiation Oncology (2022) 17:61 Page 11 of 11 radiotherapy: a propensity score-matched analysis. Radiat Oncol. 2019;14:74. 32. Kondo S, Tajika M, Tanaka T, et al. Prognostic factors for salvage endo- scopic resection for esophageal squamous cell carcinoma after chemora- diotherapy or radiotherapy alone. Endosc Int Open. 2016;4:E841–8. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions

Journal

Radiation Oncology – Springer Journals

Published: Mar 28, 2022

Keywords: Re-irradiation; Esophageal squamous cell carcinoma; Recurrence; Radiotherapy; Systematic review; Meta-analysis

There are no references for this article.