Qiao Ke1, Nanping Lin1, Manjun Deng1, Lei Wang1,2, Yongyi Zeng1, Jingfeng Liu1,3. 1. Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, PR, China. 2. Department of Radiation Oncology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, PR, China. 3. Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, PR, China.
Abstract
BACKGROUD: Resection is still the only potentially curative treatment for patients with intrahepatic cholangiocarcinoma (ICC), but the prognosis remains far from satisfactory. However, the benefit of adjuvant therapy (AT) remains controversial, although it has been conducted prevalently. Hence, a meta-analysis was warranted to evaluate the effect of AT for patients with ICC after resection. PATIENTS AND METHODS: PubMed, MedLine, Embase, the Cochrane Library, Web of Science were used to identify potentially eligible studies from Jan.1st 1990 to Aug. 31st 2019, investigating the effect of AT for patients with ICC after resection. Primary endpoint was overall survival (OS), and secondary endpoints was recurrence-free survival (RFS). Hazard ratio (HR) with 95% confidence interval (CI) was used to determine the effect size. RESULTS: 22 studies with 10181 patients were enrolled in this meta-analysis, including 832 patients in the chemotherapy group, 309 patients in the transarterial chemoembolization (TACE) group, 1192 patients in the radiotherapy group, 235 patients in the chemoradiotherapy group, and 6424 patients in the non-AT group. The pooled HR for the OS rate and RFS rate in the AT group were 0.63 (95%CI 0.52~0.74), 0.74 (95%CI 0.58~0.90), compared with the non-AT group. Subgroup analysis showed that the pooled HR for the OS rate in the AT group compared with non-AT group were as follows: chemotherapy group was 0.57 (95%CI = 0.44~0.70), TACE group was 0.56 (95%CI = 0.31~0.82), radiotherapy group was 0.71 (95%CI = 0.39~1.03), chemoradiotherapy group was 0.73 (95%CI = 0.57~0.89), positive resection margin group was 0.60 (95%CI = 0.51~0.69), and lymph node metastasis (LNM) group was 0.67 (95%CI = 0.57~0.76). CONCLUSION: With the current data, we concluded that AT such as chemotherapy, TACE and chemoradiotherapy could benefit patients with ICC after resection, especially those with positive resection margin and LNM, but the conclusion needed to be furtherly confirmed.
BACKGROUD: Resection is still the only potentially curative treatment for patients with intrahepatic cholangiocarcinoma (ICC), but the prognosis remains far from satisfactory. However, the benefit of adjuvant therapy (AT) remains controversial, although it has been conducted prevalently. Hence, a meta-analysis was warranted to evaluate the effect of AT for patients with ICC after resection. PATIENTS AND METHODS: PubMed, MedLine, Embase, the Cochrane Library, Web of Science were used to identify potentially eligible studies from Jan.1st 1990 to Aug. 31st 2019, investigating the effect of AT for patients with ICC after resection. Primary endpoint was overall survival (OS), and secondary endpoints was recurrence-free survival (RFS). Hazard ratio (HR) with 95% confidence interval (CI) was used to determine the effect size. RESULTS: 22 studies with 10181 patients were enrolled in this meta-analysis, including 832 patients in the chemotherapy group, 309 patients in the transarterial chemoembolization (TACE) group, 1192 patients in the radiotherapy group, 235 patients in the chemoradiotherapy group, and 6424 patients in the non-AT group. The pooled HR for the OS rate and RFS rate in the AT group were 0.63 (95%CI 0.52~0.74), 0.74 (95%CI 0.58~0.90), compared with the non-AT group. Subgroup analysis showed that the pooled HR for the OS rate in the AT group compared with non-AT group were as follows: chemotherapy group was 0.57 (95%CI = 0.44~0.70), TACE group was 0.56 (95%CI = 0.31~0.82), radiotherapy group was 0.71 (95%CI = 0.39~1.03), chemoradiotherapy group was 0.73 (95%CI = 0.57~0.89), positive resection margin group was 0.60 (95%CI = 0.51~0.69), and lymph node metastasis (LNM) group was 0.67 (95%CI = 0.57~0.76). CONCLUSION: With the current data, we concluded that AT such as chemotherapy, TACE and chemoradiotherapy could benefit patients with ICC after resection, especially those with positive resection margin and LNM, but the conclusion needed to be furtherly confirmed.
Intrahepatic cholangiocarcinoma (ICC) is the second most common primaryliver cancer following hepatocellular carcinoma with a stably growing incidence and mortality[1, 2]. Surgical resection is still the most preferred treatment for patients with ICC, but only 15% of patients have the chance of surgery at initial diagnosis[3-5]. However, the prognosis of patients with ICC after resection remains far from satisfactory with the 5-year survival rate around 30%[6, 7]. Hence, concerns have always been focused on any strategies intended to improve the prognosis.Various kinds of adjuvant therapies (AT), such as chemotherapy[8-10], radiotherapy[11, 12], transarterial chemoembolization (TACE)[13, 14], and chemoradiotherapy[15] have been conducted prevalently to improve the prognosis of patients after resection, and 21.4%-57.7% of patients were reported to receive AT after resection[14, 16]. However, the benefit of AT remains controversial[8, 9, 12]. Considering that randomized controlled trials or prospective studies evaluating the clinical vale of AT are hard to conduct, a comprehensive systematic review and meta-analysis is needed to confirm it.
Material and method
This study was based on published studies and the informed consent of the patients and the ethical approval were not required. This meta-analysis was conducted according to the preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
Literature search
A comprehensive search on the existing published medical literature was conducted by Qiao Ke and Nanping Lin to investigate the value of the AT for patients with ICC after surgical resection. English electronic databases such as PubMed, MedLine, Embase, the Cochrane Library, Web of Science were used to search the literature from Jan.1st 1990 to Aug. 31st 2019. Key words were as follows: (“intrahepatic cholangiocarcinoma” or “ICC” or “iCCA”) AND (“adjuvant therapy” or “transarterial chemoembolization” or “chemotherapy or “radiotherapy” or “chemoradiotherapy”). Any potentially eligible studies were then identified manually through the references of the included studies, reviews, letters and comments.
Selection criteria
Inclusion criteria
i) patients with ICC confirmed by pathology; ii) patients receiving surgical resection; iii) groups must include AT group and non-AT group; iv) outcomes must include the long-term outcomes.
Exclusion criteria
i) patients including gallbladder carcinoma or extrahepatic cholangiocarcinoma; ii) patients receiving neoadjuvant therapy; iii) patients receiving palliative resection; ⅳ) data on the long-term outcomes was not available; ⅴ) studies based on overlapping cohorts deriving from the same center; ⅵ) reviews, comments, letters, case report, and conference abstract.Of note, considering that the data of most of the American studies came from the national cancer data base (NCDB), we only incorporated the study with longest research span if overlapping cohorts existed among studies.
Intervention
Hepatectomy was conducted with or without lymph node dissection[17, 18], regardless of margin status.AT was defined as any strategies administrated before recurrence, regardless of TACE, chemotherapy, radiotherapy, and chemoradiotherapy.
Data extraction
Data such as the author’s first name, year of publication, study methods, patient’s characteristic, interventions, and outcomes were extracted and assessed by Qiao Ke and Nanping Lin with predefined forms. The hazard ratios (HRs) of OS or RFS were extracted directedly from the original data or extracted from the Kaplan-Meier curves according to the methods described in detail by Tierney et al[19]. and Parmar et al[20]. In case of disagreement, a third investigator, Manjun Deng, was intervened to reach a conclusion.
Quality assessment
The quality of non-randomized studies was assessed by the modified Newcastle-Ottawa Scale (NOS)[21], and more than 7 stars were defined as high quality, 4~6 star as medium quality, and <4 stars as low quality.
Statistical analysis
The meta-analysis was registered at http://www.crd.york.ac.uk/PROSPERO/ (Review registry 145810) and was performed using Stata 14. Considering all of the included studies were retrospective cohort studies, endpoints in this meta-analysis were evaluated by HRs and 95%CIs using the random-effects model[22, 23]. Subgroup analyses were conducted in the group of different AT strategies, R1 resection, and lymph node metastasis. Sensitivity analysis was conducted to observe whether the present result would be affected by any one study. Publication bias was determined using Begg’s and Egger’s tests, and “trim and fill” method was introduced to check the effect of potentially unpublished studies on the present result.
Results
Base characteristic of the included studies
Totally, 1267 records were excluded from the initially identified 1289 records. 22 studies including 23 cohorts and 10181 patients were enrolled in this meta-analysis[9, 11–14, 16, 24–39]. Groups were classified as follows: 832 patients in the chemotherapy group, 309 patients in the TACE group, 1192 patients in the radiotherapy group, 235 patients in the chemoradiotherapy group, and 6424 patients in the non-AT group. Of note, both adjuvant chemotherapy and adjuvant chemoradiotherapy were evaluated in Sur’s study[33], so the former was defined as Sur 2014a and the latter was defined as Sur 2014b. The search strategies and results were shown in Fig 1.
Fig 1
PRISMA flow diagram showing selection of articles for meta-analysis.
The characteristics and baseline demographic data of the patients in each research were listed in Table 1. Of note, two studies were international multi-centers ones[16, 33]. Details of AT in the included studies were depicted in Table 2. NOS score of each included study was exhibited in Table 3, among of which 20 studies were scored 7–9[9, 11–14, 16, 25–37, 39] and two were scored 5–6[24, 38].
The OS and RFS comparing between AT group and non-AT group were evaluated in 22[9, 11–14, 16, 24–34, 36–39] and 6 included cohorts [14, 24, 27, 32, 35, 36], respectively. Using a random-effect model, the pooled HR for the OS and RFS in the AT group were 0.63 (95%CI 0.52~0.74, Fig 2A), and 0.74 (95%CI 0.58~0.90, Fig 2B), respectively, compared with the non-AT group.
Fig 2
Forest plot of the overall survival and recurrence-free survival rates between adjuvant therapy and operation only.
A, overall survival; B, recurrence-free survival.
Forest plot of the overall survival and recurrence-free survival rates between adjuvant therapy and operation only.
A, overall survival; B, recurrence-free survival.
Subgroup analysis stratified by different AT strategies
The OS and RFS comparing between adjuvant chemotherapy group and non-AT group were evaluated in 9[9, 25, 29–31, 33, 36–38] and 2[35, 36] included cohorts, respectively. Using a random-effect model, the pooled HR for the OS and RFS in the AT group were 0.57 (95%CI 0.44~0.70, Fig 3A), and 0.75 (95%CI 0.45~1.05, Fig 3B), respectively, compared with the non-AT group.
Fig 3
Forest plot of the overall survival and recurrence-free survival rates between adjuvant chemotherapy and operation only.
A, overall survival; B, recurrence-free survival.
Forest plot of the overall survival and recurrence-free survival rates between adjuvant chemotherapy and operation only.
A, overall survival; B, recurrence-free survival.The OS and RFS comparing between adjuvant TACE group and non-AT group were evaluated in 5[13, 14, 27, 28, 32] and 3[14, 27, 32] included cohorts, respectively. Using a random-effect model, the pooled HR for the OS and RFS in the adjuvant TACE group were 0.56 (95%CI 0.31~0.82, Fig 4A), and 0.74 (95%CI 0.55~0.93, Fig 4B), respectively, compared with the non-AT group.
Fig 4
Forest plot of the overall survival and recurrence-free survival rates between adjuvant TACE and operation only.
A, overall survival; B, recurrence-free survival.
Forest plot of the overall survival and recurrence-free survival rates between adjuvant TACE and operation only.
A, overall survival; B, recurrence-free survival.The OS comparing between adjuvant radiotherapy group or adjuvant chemoradiotherapy group and non-AT group were evaluated in 4[11, 12, 26, 34] and 3[24, 33, 39] included cohorts, respectively. Using a random-effect model, the pooled HR for the OS in the adjuvant radiotherapy group and adjuvant chemoradiotherapy group were 0.71 (95%CI 0.39~1.03, Fig 5A), and 0.73 (95%CI 0.57~0.89, Fig 5B), respectively, compared with the non-AT group.
Fig 5
Subgroup analysis of OS stratified by adjuvant radiotherapy and chemoradiotherapy.
A, adjuvant radiotherapy; B, adjuvant chemoradiotherapy.
Subgroup analysis of OS stratified by adjuvant radiotherapy and chemoradiotherapy.
A, adjuvant radiotherapy; B, adjuvant chemoradiotherapy.
Subgroup analysis stratified by high risk factors
The effect of AT on the patients with positive resection margin was evaluated in 4 included cohorts [16, 24, 25, 29]. Using a random-effect model, the pooled HR for the OS in the AT group was 0.60 (95%CI 0.51~0.69, Fig 6A), compared with the non-AT group. The effect of AT on the patients with LNM was evaluated in 4 included cohorts [9, 16, 24, 26]. Using a random-effect model, the pooled HR for the OS in the AT group was 0.67 (95%CI 0.57~0.76, Fig 6B), compared with the non-AT group.
Fig 6
Subgroup analysis stratified by high risk factors.
A, positive resection margin; B. lymph node metastasis.
Subgroup analysis stratified by high risk factors.
A, positive resection margin; B. lymph node metastasis.
Sensitivity analysis
Sensitivity analysis was conducted in the primary endpoint comparing between AT group and non-AT group, and result showed that the pooled HR for the OS in the AT group did not change substantially after any study was removed compared with the non-AT group (Fig 7), which indicated that the present results in this study were robust.
Fig 7
Sensitivity analysis for overall survival in the included studies.
Publication bias analysis
Publication bias analysis was conducted in the primary endpoint comparing between AT group and non-AT group. Asymmetry was observed in the funnel plot (Fig 8) with significant publication bias in the egger’s test (p = 0.004) but not in the Begg’s test (p = 0.09). “Trim and fill” analysis was then conducted, and 5 more studies were found to be potentially unpublished. The adjusted HR for the OS in the AT group was 0.73 (95%CI 0.63–0.85), compared with the non-AT group, indicating that the present result could not be affected by the unpublished studies.
Fig 8
Funnel plot of overall survival in the included studies.
Discussion
The prognosis of patients with ICC after resection is still poor[5, 6], but the benefit of AT has always been questioned in clinical partly because the natural life span is too short and most of the patients have lost the chance of resection at diagnosis[3, 4]. Currently, with the advocation of LND and development of extended resection[40-42], the clinical value of AT should be re-evaluated. This is the first systematic review evaluating the clinical value of AT in the treatment of ICC comprehensively, which included 22 studies with 10181 patients, and results showed that patients could be benefited from AT in a whole. However, in our opinion, identifying the selected patients and choosing the appropriate AT strategy are the keys.Chemotherapy is first to be administrated in the postoperative adjuvant treatments of ICC, and adjuvant chemotherapy is still the most preferred strategy in clinical up to now with the reported incidence as high as 46.6%[15]. However, the benefit of chemotherapy has been always been questioned mainly because cholangiocarcinoma is not sensitive to chemotherapeutics[43]. In this meta-analysis, adjuvant chemotherapy was confirmed to be associated with improved OS, which was coincident with the previous meta-analysis[10, 44]. In addition, Gemcitabine-based chemotherapy was confirmed to be superior to 5-Fu based chemotherapy in the improvement of prognosis[10, 44].TACE is conducted widely in the management of ICC, such as adjuvant therapy for patients receiving resection[13, 14], and palliative treatment for unresectable ICC[45, 46]. However, someone argued the benefit of adjuvant TACE for ICC[27], mainly because ICC could metastasize specifically through lymph node. To the best of our knowledge, this is the first meta-analysis confirming the benefit of adjuvant TACE. Reasons are mainly due to that most of the recurrences are still intrahepatic ones[47], but it deserves further validation.Radiotherapy is playing an increasing important role in the management of ICC with the development of stereotactic body radiotherapy[11]. From the other hand, metastatic lymph node is much more sensitive to radiotherapy[12]. However, the benefit of radiotherapy was not confirmed in this meta-analysis, which deserved our deep rethink. In addition, chemoradiotherapy is being more and more preferred in clinical, because synergistic effect is believed to between radiotherapy and chemotherapy[15]. This is the first meta-analysis identifying the benefit of adjuvant chemoradiotherapy, but either sequential or concurrent chemoradiotherapy deserves further study.As is known to all, one size does not fit all, so identifying the selected patients who could be benefited from AT is also a big deal. Adjuvant chemotherapy and TACE are found to only benefit patients with “high risk”, such as positive margins[24, 29], LNM[48], and advanced stages[16], but as for radiotherapy it is hard to say. Zheng et al[11] found that adjuvant radiotherapy could benefit patients with narrow surgical margin, but Hammad et al[12] reported that adjuvant radiotherapy could only improve the prognosis of patients with R0 resection rather than those with R1 resection and LNM. Hence, who would be benefited from AT, either with high risk or with low risk, is still a puzzle.In the recent decades, pathway-targeted therapies made a rapid progress in solid tumors[49, 50]. Previous studies found that approximately 30%~40% of ICCpatients exhibited actionable mutations, such as epidermal growth factor receptor (EGFR), and fibroblast growth factor receptor (FGFR) which shed light on the molecular targeted therapies on ICC[51, 52]. From the other hand, next-generation and exome sequencing studies found that 10%~15% of cholangiocarcinomapatients had DNA repair mutations[53], and 40% of cholangiocarcinomapatients had positive programmed cell death receptor 1 (PDL1) expression[54], who might be the potential beneficiaries of immunotherapies. Recent clinical trials have exhibited promising results in the advanced cholangiocarcinoma, which would change the trajectory of ICC management[55, 56]. In future, promises of adjuvant targeted therapies and/or immunotherapies have been expected in the on-going trials.There were several restrictions of this meta-analysis. First, all the included studies were retrospective ones, indicating an obvious selection and recalling bias. Second, most of the studies were multi-centers or based on the database mainly due to the rare incidence of ICC, which meant that procedure of surgical resection and AT were different and bias was hard to avoid. Third, most of the cofounding factors such as radical resection and LNM were hard to be resorted in the original studies, which would weaken the conclusion. Fourth, RFS was evaluated in only six of the 22 included studies, which was insufficient to evaluate the effect of AT on recurrence. Fifth, considering that the span of the included studies was a little longer (1990~2019), during which the surgical techniques, chemotherapy agents and radiation approaches were different, our conclusion in this study deserved further validation. The last but not the least, publication bias was found in this meta-analysis, although the present result was found to be not changed after “trim and fill” analysis.
Conclusion
With the current data, we concluded that AT would benefit patients with ICC after resection, but it deserved further validation. Considering that not all AT strategies would bring benefit to patients with ICC, and not all patients would be benefited from AT, identifying the potential beneficiaries of different AT is a priority in future.
PRISMA 2009 checklist.
(DOC)Click here for additional data file.
The searching strategy of the pubmed database.
(DOCX)Click here for additional data file.30 Dec 2019PONE-D-19-27317The effect of adjuvant therapy for patients with intrahepatic cholangiocarcinoma after surgical resection: a systematic review and meta-analysisPLOS ONEDear Dr. Lei Wang,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.We would appreciate receiving your revised manuscript within 60 days. 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Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.Reviewer #1: YesReviewer #2: Yes**********2. Has the statistical analysis been performed appropriately and rigorously?Reviewer #1: YesReviewer #2: Yes**********3. Have the authors made all data underlying the findings in their manuscript fully available?The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. 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(Please upload your review as an attachment if it exceeds 20,000 characters)Reviewer #1: I read the manuscript Ke et al with great interest. The authors tried to answer the question whether adjuvant therapy (in different forms) for intrahepatic CCA would be useful or not using the meta-analysis of the published paper.With the large cohort of the meta-analysis and included study it looks like the statistical power seems adequate. However, the authors included studies which span over 30 years.I have several comments;1- Due to 30 years of span (1990-2019), as also can be seen by Table 2, some chemotherapy agents were different. Therefore, the response to chemotherapy could be different. This should be acknowledged in the discussion as the most limiting factor for chemotherapy and chemoradipotherapy. This long time span eventually impacts on the surgical techniques as well. The power of meta-analysis is the large cohort but different surgical techniques, (improved techniques most recently with improved diagnostics) change the overall survival of CCA patients. This should be also acknowledged as an important limitation.2- page 3, line 70 - Varies should be Various3- page 4 line 77, OMIT, "badly".Again, the authors should add limitations to the study and soften the conclusion based on these limitations.Reviewer #2: This manuscript by Qiao Ke et al. is a meta-analysis evaluating the effect of adjuvant therapy (AT) for patients with intrahepatic cholangiocarcinoma (ICC) after resection. Resection is still the only potentially curative treatment for patients with intrahepatic cholangiocarcinoma (ICC), but the prognosis remains far from satisfactory. The role of conventional therapies (transarterial chemoembolization, chemotherapy and radiotherapy) has yet to be fully defined, particularly in the adjuvant and second-line settings. This is the first systematic review evaluating the clinical value of AT in the treatment of ICC, including 22 studies with 10181 patients. Results showed that some patients could be benefited from AT in a whole. However, not all AT strategies would bring benefit to patients with ICC, and the benefit of adjuvant radiotherapy needs to be further validated. Identifying the selected patients and choosing the appropriate AT strategy is a major challenge for Clinics. The manuscript is well written and easy to follow. The topic of this manuscript is of great interest. The Reviewer has just some issues to address.MAJOR1. The major weaknesses of this study are well addressed by the Authors in the Discussion chapter: the studies are retrospective, indicating an obvious selection and recalling bias; most of the studies are multi-centers or based on the database mainly due to the rare incidence of ICC, which meant that procedure of surgical resection and AT were different and bias was hard to avoid; most of the cofounding factors such as radical resection and LNM are hard to be resorted in the original studies, which would weaken the conclusion; RFS is evaluated in only six of the 22 included studies, which is insufficient to evaluate the effect of AT on recurrence; publication bias is found in this meta-analysis.2. Since a number of pathway-targeted therapies, as well as modulation of the immune environment, hold promise for patients with intrahepatic cholangiocarcinoma, the Authors should add this topic in the discussion.**********6. 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Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdfResponse: Thank you for your kindly reminder. We are sure that our manuscript is well meet the requirements of PLOS ONE.2. At this time, we ask that you please provide the full search strategy and search terms for at least one database in the Supplementary information.Response: Thank you for your professional comment. Full search strategy and search terms for PubMed was uploaded as the Supplementary file. However, manually searching was repeated conducted through the references of the included studies, reviews, letters and comments.3. Thank you for stating the following beneath the Acknowledgments Section of your manuscript:"This study was supported by Startup Fund for scientific research, Fujian Medical University (Grant number: 2018QH1195)."We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:"Not application"a.Please provide an amended Funding Statement that declares *all* the funding or sources of support received during this specific study (whether external or internal to your organization) as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-nowb.Please state what role the funders took in the study. If any authors received a salary from any of your funders, please state which authors and which funder. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."c.Please include your amended statements within your cover letter; we will change the online submission form on your behalf.Response: Thank you for your kindly reminder. Lei Wang is the grantee of the funding, but "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." We removed funding-related text from the manuscript and update our Funding Statement as you suggested.4. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQResponse: Thank you for your kindly reminder. We have added all the authors’s ORCID and updated our information.Reviewer #1: I read the manuscript Ke et al with great interest. The authors tried to answer the question whether adjuvant therapy (in different forms) for intrahepatic CCA would be useful or not using the meta-analysis of the published paper.With the large cohort of the meta-analysis and included study it looks like the statistical power seems adequate. However, the authors included studies which span over 30 years.I have several comments;1- Due to 30 years of span (1990-2019), as also can be seen by Table 2, some chemotherapy agents were different. Therefore, the response to chemotherapy could be different. This should be acknowledged in the discussion as the most limiting factor for chemotherapy and chemoradipotherapy. This long time span eventually impacts on the surgical techniques as well. The power of meta-analysis is the large cohort but different surgical techniques, (improved techniques most recently with improved diagnostics) change the overall survival of CCA patients. This should be also acknowledged as an important limitation.Response: Thank you for your professional comment. Firstly, we admitted that the span of the included researches was a little longer. Considering that most of the included studies were after 2010, we conducted a subgroup analysis stratified by the publication year before and after 2010 as you suggested, and results showed that the results of two subgroup analysis were coincident with the whole, which indicated that the conclusion was robust to some extent. Secondly, as you indicated that “some chemotherapy agents were different “, and the relevant subgroup analysis was published previously, which was depicted in the “Discussion”. And, the emphasis and innovation were the subgroup analysis stratified by different adjuvant strategies including chemotherapy, TACE, radiotherapy, and chemoradiotherapy. Thirdly, as you pointed out that “different surgical techniques, (improved techniques most recently with improved diagnostics) change the overall survival of CCA patients”, but relevant subgroup analysis such as laparoscopic vs. open hepatectomy, major vs. minor hepatectomy, hepatectomy with or without lymphadenectomy were unable to conduct due to most of the data was unavailable. However, these limitations were emphasized in the “Discussion” as you suggested.2- page 3, line 70 - Varies should be VariousResponse: Thank you for kindly reminder, and we corrected it in the revised manuscript.3- page 4 line 77, OMIT, "badly".Response: Thank you for kindly reminder, and we corrected it in the revised manuscript.Again, the authors should add limitations to the study and soften the conclusion based on these limitations.Response: Thank you for kindly reminder, and we had softened our conclusion in the revised manuscript.Reviewer #2: This manuscript by Qiao Ke et al. is a meta-analysis evaluating the effect of adjuvant therapy (AT) for patients with intrahepatic cholangiocarcinoma (ICC) after resection. Resection is still the only potentially curative treatment for patients with intrahepatic cholangiocarcinoma (ICC), but the prognosis remains far from satisfactory. The role of conventional therapies (transarterial chemoembolization, chemotherapy and radiotherapy) has yet to be fully defined, particularly in the adjuvant and second-line settings. This is the first systematic review evaluating the clinical value of AT in the treatment of ICC, including 22 studies with 10181 patients. Results showed that some patients could be benefited from AT in a whole. However, not all AT strategies would bring benefit to patients with ICC, and the benefit of adjuvant radiotherapy needs to be further validated. Identifying the selected patients and choosing the appropriate AT strategy is a major challenge for Clinics. The manuscript is well written and easy to follow. The topic of this manuscript is of great interest. The Reviewer has just some issues to address.MAJOR1. The major weaknesses of this study are well addressed by the Authors in the Discussion chapter: the studies are retrospective, indicating an obvious selection and recalling bias; most of the studies are multi-centers or based on the database mainly due to the rare incidence of ICC, which meant that procedure of surgical resection and AT were different and bias was hard to avoid; most of the cofounding factors such as radical resection and LNM are hard to be resorted in the original studies, which would weaken the conclusion; RFS is evaluated in only six of the 22 included studies, which is insufficient to evaluate the effect of AT on recurrence; publication bias is found in this meta-analysis.Response: Thank you for your professional comments, and these limitations above were hardly avoided, and would weaken the conclusion of this study. Hence, we had softened the conclusion in the revised manuscript.2. Since a number of pathway-targeted therapies, as well as modulation of the immune environment, hold promise for patients with intrahepatic cholangiocarcinoma, the Authors should add this topic in the discussion.Response: Thank you for your professional comment. Considering the great advances in the pathway-targeted therapies and immunotherapies, prognosis of patients with intrahepatic cholangiocarcinoma following resection would be improved. Hence, we checked the latest reports on this topic, and added the progress in the revised “Discussion”.We are looking forward to receive your letter, and please contact me without any hesitation if you have any question.Best Regards,Yours sincerely,Qiao KeCorresponding to Lei Wang, E-mail: wangleiy001@126.comSubmitted filename: Response to Reviewers.docxClick here for additional data file.4 Feb 2020The effect of adjuvant therapy for patients with intrahepatic cholangiocarcinoma after surgical resection: a systematic review and meta-analysisPONE-D-19-27317R1Dear Dr. Lei Wang,We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.With kind regards,Gianfranco D. AlpiniAcademic EditorPLOS ONEAdditional Editor Comments (optional):Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.Reviewer #1: All comments have been addressedReviewer #2: All comments have been addressed**********2. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.Reviewer #1: YesReviewer #2: Yes**********3. Has the statistical analysis been performed appropriately and rigorously?Reviewer #1: YesReviewer #2: Yes**********4. Have the authors made all data underlying the findings in their manuscript fully available?The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.Reviewer #1: YesReviewer #2: Yes**********5. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********6. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)Reviewer #1: Authors responded to all my comments properly and appropriate changes were made. No further comments.Reviewer #2: The Authors answered satisfactorily to reviewers' comments.**********7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.Reviewer #1: NoReviewer #2: No7 Feb 2020PONE-D-19-27317R1The effect of adjuvant therapy for patients with intrahepatic cholangiocarcinoma after surgical resection: a systematic review and meta-analysisDear Dr. Wang:I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.For any other questions or concerns, please email plosone@plos.org.Thank you for submitting your work to PLOS ONE.With kind regards,PLOS ONE Editorial Office Staffon behalf ofDr. Gianfranco D. AlpiniAcademic EditorPLOS ONE
Authors: X-F Zhang; J Chakedis; F Bagante; Q Chen; E W Beal; Y Lv; M Weiss; I Popescu; H P Marques; L Aldrighetti; S K Maithel; C Pulitano; T W Bauer; F Shen; G A Poultsides; O Soubrane; G Martel; B Groot Koerkamp; A Guglielmi; E Itaru; T M Pawlik Journal: Br J Surg Date: 2018-04-14 Impact factor: 6.939
Authors: Liang-Shuo Hu; Xu-Feng Zhang; Matthew Weiss; Irinel Popescu; Hugo P Marques; Luca Aldrighetti; Shishir K Maithel; Carlo Pulitano; Todd W Bauer; Feng Shen; George A Poultsides; Oliver Soubrane; Guillaume Martel; B Groot Koerkamp; Endo Itaru; Timothy M Pawlik Journal: Ann Surg Oncol Date: 2019-04-24 Impact factor: 5.344
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