Efficacy of Different Interventions to Reduce Pre- or Perioperative Blood Transfusion Rate in Patients with Colorectal Cancer: A Network Meta-Analysis of Randomized Controlled Trials

Round 1

Reviewer 1 Report

In this network met-analysis, the authors study the efficacy of different interventions to reduce pre- or perio-operative blood transfusion rate in patients with colorectal cancer.  To my knowledge this is the first network meta-analysis of this type. 

The following suggestions may strengthen this paper: 

1. Introduction - the authors should site the Cochrane database review published in 2009 by Devon and McLeod on the use of pre and peri-operative erythropoeitin for reducing allogenic blood transfusion in colorectal surgery - noting the differences between this study and the current study.
2. Analysis - if possible, this study would be significantly strengthened if an analysis of the adverse effects of the different interventions were compared.  If this is not possible, at least a paragraph in the discussion should include the adverse events noted in the studies that looked at High dose EPO.  This may make this more clinically relevant/ acceptable as to my knowledge high dose EPO is not a common practice in this setting, at least in Canada (i.e. the readership of this journal). 
3. Minor comments:  Lines 128 and 148 - should include the initials of the authors who screened the studies.  Line 209 - include the word "studies" after double blind. 

Author Response

Reviewer 1

 

Open Review

(x) I would not like to sign my review report
( ) I would like to sign my review report

English language and style

( ) Extensive editing of English language and style required
( ) Moderate English changes required
(x) English language and style are fine/minor spell check required
( ) I don't feel qualified to judge about the English language and style

 

Comments and Suggestions for Authors

In this network met-analysis, the authors study the efficacy of different interventions to reduce pre- or perio-operative blood transfusion rate in patients with colorectal cancer. To my knowledge this is the first network meta-analysis of this type. 

=> Many thanks to your valuable comments. We truly appreciated your great comments and recommendation. We had rechecked the entire manuscript and made appropriate revisions on some of the text, tables, figures, and references throughout the whole manuscript according to all the reviewers’ comments. We had marked the revision with red-color in the manuscript. We believed that the revised manuscript would provide more comprehensive and scientifical information in the clinical practice.

 

 

The following suggestions may strengthen this paper: 

1. Introduction - the authors should site the Cochrane database review published in 2009 by Devon and McLeod on the use of pre and peri-operative erythropoeitin for reducing allogenic blood transfusion in colorectal surgery - noting the differences between this study and the current study.

=> Many thanks to your important comments. We had revised our statement in introduction and site the Cochrane database review published in 2009 by Devon and McLeod as “…In one recent Cochrane meta-analysis by Devon and McLeod, which merged different dosage of erythropoietin into one group, there were no statistically significantly different transfusion rate between the erythropoietin group and control group [27]…” (page 2 line 75-78) accordingly.

 

 

2. Analysis - if possible, this study would be significantly strengthened if an analysis of the adverse effects of the different interventions were compared.  If this is not possible, at least a paragraph in the discussion should include the adverse events noted in the studies that looked at High dose EPO. This may make this more clinically relevant/ acceptable as to my knowledge high dose EPO is not a common practice in this setting, at least in Canada (i.e. the readership of this journal). 

=> Many thanks to your excellent comments. The safety of high-dose EPO would have potential adverse events in the clinical practice, which was also the major concern for the clinicians. Therefore, we had added the thorough discussion about its safety as “…However, although there was no significantly different drop-out rate noted between high-dose recombinant human erythropoietin plus oral iron supplement group and the placebo/control groups, the safety of high-dose recombinant human erythropoietin in patients with colorectal cancer should be cautious. In the RCT by Qvist et al [17], one patient in the treatment group developed deep venous thrombosis, although in another study there was no evidence that the perioperative treatment with high-dose recombinant human erythropoietin would influent the hemostatic parameters [50]. In the RCT by Christodoulakis et al [7], there was only one study drug-related adverse event (i.e. incidence of grade 2 rash) noted, which was consistent with the findings in the review article of safety of erythropoietin [51]. Nevertheless, there was one major concern about the risk of potential enhancement of tumor growth by high-dose recombinant human erythropoietin in cancer patients. To be specific, in the mice study by Rupertus et al [52], administration of darbepoetin-alpha alone would slightly affect the tumor metastatic growth; however, in mice receiving both darbepoetin-alpha administration and partial hepatectomy, the colorectal liver metastatic growth would be enhanced significantly. Similarly, in another RCT of head/neck cancer patients receiving radiotherapy [53], loco-regional progression-free survival was poorer in patients receiving epoetin beta than those with placebo. Although these phenomena had not been seen in the included RCTs [7,10,11,15-17,42], the potential risk of potential enhancement of tumor growth by high-dose recombinant human erythropoietin still could not be excluded because the risk of potential enhancement of tumor growth need longer follow-up duration to approve its existence. The clinicians needed to be cautious about the potential risk of enhancement of tumor growth when applying the high-dose recombinant human erythropoietin in cancer patients. Therefore, future large-scale RCT with long term follow-up duration should be warranted to approve the long-term safety of high-dose recombinant human erythropoietin in cancer patients…” (page 9 line 307 – page 10 line 332) accordingly in the section of discussion. In addition, we had revised the statement as “…The combination of high-dose recombinant human erythropoietin and oral iron supplements might be considered as a choice for reducing the rate of blood transfusion in patients with colorectal cancer. However, future large-scale RCT with long term follow-up should be warranted to approve the long-term safety…” (page 1 line 36-39) in the section of abstract and “…Future larger-scale, long term follow-up, well-designed double-blind RCTs, with objective criteria to administer blood transfusion, are warranted to support or refute the present study results and to approve the long-term safety of high-dose recombinant human erythropoietin in cancer patients…” (page 10 line 374-377) in the section of conclusions.

 

 

3. Minor comments:  Lines 128 and 148 - should include the initials of the authors who screened the studies.  Line 209 - include the word "studies" after double blind. 

=> Many thanks to your great comments. We had added the initials of the authors who screened the studies as “…Two authors (MK Wu and PT Tseng) independently screened…” (page 3 line 132) accordingly. In addition, we had revised our statement of result as “…which were both well-designed double-blind studies [16,17]…” (page 6 line 213-214) according to reviewer’s suggestion.

Author Response File: Author Response.docx

Reviewer 2 Report

This review is of good quality. Methodology is well done. I do not have specific remarks. I do beleive that this is worth of publication although there are some potential sources of significant bias such as different tumor stages, different protocols for transfusion, heterogenous population, relatively small number of studies included in analysis etc. that may interfer with final results. It s up to the Editor to decide wether the study with listed limitations is worth of publication in their Journal.

Author Response

Reviewer 2

 

Open Review

(x) I would not like to sign my review report
( ) I would like to sign my review report

English language and style

( ) Extensive editing of English language and style required
( ) Moderate English changes required
(x) English language and style are fine/minor spell check required
( ) I don't feel qualified to judge about the English language and style

 

Comments and Suggestions for Authors

This review is of good quality. Methodology is well done. I do not have specific remarks.

=> Many thanks to your valuable comments. We truly appreciated your great comments and recommendation. We had rechecked the entire manuscript and made appropriate revisions on some of the text, tables, figures, and references throughout the whole manuscript according to all the reviewers’ comments. We had marked the revision with red-color in the manuscript. We believed that the revised manuscript would provide more comprehensive and scientifical information in the clinical practice.

 

 

I do believe that this is worth of publication although there are some potential sources of significant bias such as different tumor stages, different protocols for transfusion, heterogenous population, relatively small number of studies included in analysis etc. that may interfere with final results. It’s up to the Editor to decide whether the study with listed limitations is worth of publication in their Journal.

=> Many thanks to your important comments. The current meta-analysis was the first one to evaluate the issue of comparison of different pharmacologic interventions to reduce the blood transfusion rate, which still had inconclusive evidence. In order to increase the strength of the current study, we tried to apply strict inclusion criteria so that the numbers of overall included RCTs would be relatively small. To address this issue, we had revised our statement in the limitation as “…Although we tried to enhance the strength of the current meta-analysis with strict inclusion criteria (i.e. only included RCTs, only included colorectal cancer), several limitations of our study should be considered when interpreting the results…” (page 10 line 357-359) accordingly. Also, based on the reviewers’ suggestion, the safety of high-dose EPO would have potential adverse events in the clinical practice, which was also the major concern for the clinicians. Therefore, we had added the thorough discussion about its safety as “…However, although there was no significantly different drop-out rate noted between high-dose recombinant human erythropoietin plus oral iron supplement group and the placebo/control groups, the safety of high-dose recombinant human erythropoietin in patients with colorectal cancer should be cautious. In the RCT by Qvist et al [17], one patient in the treatment group developed deep venous thrombosis, although in another study there was no evidence that the perioperative treatment with high-dose recombinant human erythropoietin would influent the hemostatic parameters [50]. In the RCT by Christodoulakis et al [7], there was only one study drug-related adverse event (i.e. incidence of grade 2 rash) noted, which was consistent with the findings in the review article of safety of erythropoietin [51]. Nevertheless, there was one major concern about the risk of potential enhancement of tumor growth by high-dose recombinant human erythropoietin in cancer patients. To be specific, in the mice study by Rupertus et al [52], administration of darbepoetin-alpha alone would slightly affect the tumor metastatic growth; however, in mice receiving both darbepoetin-alpha administration and partial hepatectomy, the colorectal liver metastatic growth would be enhanced significantly. Similarly, in another RCT of head/neck cancer patients receiving radiotherapy [53], loco-regional progression-free survival was poorer in patients receiving epoetin beta than those with placebo. Although these phenomena had not been seen in the included RCTs [7,10,11,15-17,42], the potential risk of potential enhancement of tumor growth by high-dose recombinant human erythropoietin still could not be excluded because the risk of potential enhancement of tumor growth need longer follow-up duration to approve its existence. The clinicians needed to be cautious about the potential risk of enhancement of tumor growth when applying the high-dose recombinant human erythropoietin in cancer patients. Therefore, future large-scale RCT with long term follow-up duration should be warranted to approve the long-term safety of high-dose recombinant human erythropoietin in cancer patients…” (page 9 line 307 – page 10 line 332) accordingly in the section of discussion. In addition, we had revised the statement as “…The combination of high-dose recombinant human erythropoietin and oral iron supplements might be considered as a choice for reducing the rate of blood transfusion in patients with colorectal cancer. However, future large-scale RCT with long term follow-up should be warranted to approve the long-term safety…” (page 1 line 36-39) in the section of abstract and “…Future larger-scale, long term follow-up, well-designed double-blind RCTs, with objective criteria to administer blood transfusion, are warranted to support or refute the present study results and to approve the long-term safety of high-dose recombinant human erythropoietin in cancer patients…” (page 10 line 374-377) in the section of conclusions.

Author Response File: Author Response.docx

Reviewer 3 Report

Erythropoietin is contra indicated in patiënts with colorectal cancer due to direct tumor growth. please see. 

 Rupertus K, Sperling J, Corsten M, et al. Darbepoetin-alpha enhances hepatectomy-associated stimulation of colorectal liver metastatic growth. Ann Surg. 2010;252:131–141.  Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet. 2003;362:1255–1260.

 

The poor prognosis in colorectal cancer patients related to blood transfusion is known after long term follow up studies and by majority related to extensiveness of disease. Using EPO as an alternative will only be justified after a long term follow up safety study.

At least a dicussion point for long term should be included

Author Response

Reviewer 3

Open Review

(x) I would not like to sign my review report
( ) I would like to sign my review report

English language and style

( ) Extensive editing of English language and style required
( ) Moderate English changes required
( ) English language and style are fine/minor spell check required
(x) I don't feel qualified to judge about the English language and style

=> Many thanks to your valuable comments. We truly appreciated your great comments and recommendation. We had rechecked the entire manuscript and made appropriate revisions on some of the text, tables, figures, and references throughout the whole manuscript according to all the reviewers’ comments. We had marked the revision with red-color in the manuscript. We believed that the revised manuscript would provide more comprehensive and scientifical information in the clinical practice.

 

 

Comments and Suggestions for Authors

Erythropoietin is contra indicated in patiënts with colorectal cancer due to direct tumor growth. please see: Rupertus K, Sperling J, Corsten M, et al. Darbepoetin-alpha enhances hepatectomy-associated stimulation of colorectal liver metastatic growth. Ann Surg. 2010;252:131–141.  Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet. 2003;362:1255–1260. The poor prognosis in colorectal cancer patients related to blood transfusion is known after long term follow up studies and by majority related to extensiveness of disease. Using EPO as an alternative will only be justified after a long term follow up safety study. At least a discussion point for long term should be included

=> Many thanks to your important comments. The safety of high-dose EPO would have potential adverse events in the clinical practice, which was also the major concern for the clinicians. The potential risk of enhancement of tumor growth would be a major concern in cancer patients. To remind the clinicians of this potential risk was one of the responsibility of meta-analysis. Therefore, we had revised our statement in discussion, cited these two references, and added a thorough discussion about its safety as “…Therefore, the combination of high-dose recombinant human erythropoietin and oral iron supplements might be a potential choice to manage anemia in patients with colorectal cancer. However, although there was no significantly different drop-out rate noted between high-dose recombinant human erythropoietin plus oral iron supplement group and the placebo/control groups, the safety of high-dose recombinant human erythropoietin in patients with colorectal cancer should be cautious. In the RCT by Qvist et al [17], one patient in the treatment group developed deep venous thrombosis, although in another study there was no evidence that the perioperative treatment with high-dose recombinant human erythropoietin would influent the hemostatic parameters [50]. In the RCT by Christodoulakis et al [7], there was only one study drug-related adverse event (i.e. incidence of grade 2 rash) noted, which was consistent with the findings in the review article of safety of erythropoietin [51]. Nevertheless, there was one major concern about the risk of potential enhancement of tumor growth by high-dose recombinant human erythropoietin in cancer patients. To be specific, in the mice study by Rupertus et al [52], administration of darbepoetin-alpha alone would slightly affect the tumor metastatic growth; however, in mice receiving both darbepoetin-alpha administration and partial hepatectomy, the colorectal liver metastatic growth would be enhanced significantly. Similarly, in another RCT of head/neck cancer patients receiving radiotherapy [53], loco-regional progression-free survival was poorer in patients receiving epoetin beta than those with placebo. Although these phenomena had not been seen in the included RCTs [7,10,11,15-17,42], the potential risk of potential enhancement of tumor growth by high-dose recombinant human erythropoietin still could not be excluded because the risk of potential enhancement of tumor growth need longer follow-up duration to approve its existence. The clinicians needed to be cautious about the potential risk of enhancement of tumor growth when applying the high-dose recombinant human erythropoietin in cancer patients. Therefore, future large-scale RCT with long term follow-up duration should be warranted to approve the long-term safety of high-dose recombinant human erythropoietin in cancer patients…” (page 9 line 305 – page 10 line 332) accordingly in the section of discussion. In addition, we had revised the statement as “…The combination of high-dose recombinant human erythropoietin and oral iron supplements might be considered as a choice for reducing the rate of blood transfusion in patients with colorectal cancer. However, future large-scale RCT with long term follow-up should be warranted to approve the long-term safety…” (page 1 line 36-39) in the section of abstract and “…Future larger-scale, long term follow-up, well-designed double-blind RCTs, with objective criteria to administer blood transfusion, are warranted to support or refute the present study results and to approve the long-term safety of high-dose recombinant human erythropoietin in cancer patients…” (page 10 line 374-377) in the section of conclusions.

Author Response File: Author Response.docx

Round 2

Reviewer 3 Report

My earlier conserns are mentioned well in the paper. Although, the English of the revision must be improved. In my opinion EPO and iron might be an alternative for blood transfusion only when there are no other alternatives. Still there is no clear evidence of the worsening of prognosis due to transfusion only. Anaemic patients and patients needed transfusion have a worse malignant disease and need more extensive blood transfusion

Author Response

Reviewer 3

Open Review

(x) I would not like to sign my review report
( ) I would like to sign my review report

English language and style

(x) Extensive editing of English language and style required
( ) Moderate English changes required
( ) English language and style are fine/minor spell check required
( ) I don't feel qualified to judge about the English language and style

=> Many thanks to your valuable suggestion. We truly appreciated your great suggestion and recommendation. We had rechecked the entire manuscript and made appropriate revisions on some of the text, tables, figures, and references throughout the whole manuscript according to all the reviewers’ comments. We had marked the revision with red-color in the manuscript. We believed that the revised manuscript would provide more comprehensive and scientifical information in the clinical practice.

 

 

My earlier concerns are mentioned well in the paper. Although, the English of the revision must be improved. In my opinion EPO and iron might be an alternative for blood transfusion only when there are no other alternatives. Still there is no clear evidence of the worsening of prognosis due to transfusion only. Anaemic patients and patients needed transfusion have a worse malignant disease and need more extensive blood transfusion

=> Many thanks to your important suggestion. In order to remind the clinicians about the potential risk of EPO/iron and to preserve the EPO/iron to patients without other alternative choices, we had added one statement of “…Third, although there was no severe adverse event associated with the treatment in the current meta-analysis, the concerns about the risk of potential enhancement of tumor growth by high-dose recombinant human erythropoietin in cancer patients still should be kept in mind. Since there is no clear and conclusive evident association between the worsening prognosis and transfusion only, the high-dose recombinant human erythropoietin and iron supplementation in cancer patients still should be preserved to those without other alternative choices…” in the section of limitation (page 10 line 363-369) accordingly.

 

 

Author Response File: Author Response.docx

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.