Prospective evaluation of percutaneous hepatic perfusion with melphalan as a treatment for unresectable liver metastases from colorectal cancer

T. Susanna Meijer; Jan H. N. Dieters; Eleonora M. de Leede; Lioe-Fee de Geus-Oei; Jaap Vuijk; Christian H. Martini; Arian R. van Erkel; Jacob Lutjeboer; Rutger W. van der Meer; Fred G. J. Tijl; Ellen Kapiteijn; Alexander L. Vahrmeijer; Mark C. Burgmans

doi:10.1371/journal.pone.0261939

Peer Review History

Original SubmissionApril 5, 2021
12 Apr 2021 Decision Letter - Stefano Guadagni, Editor PONE-D-21-02466 Prospective evaluation of percutaneous hepatic perfusion with melphalan as a treatment for unresectable liver metastases from colorectal cancer PLOS ONE Dear Dr. Meijer, 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. ACADEMIC EDITOR: This is a prospective study on a complex locoregional chemotherapy procedure named percutaneous hepatic perfusion. Percutaneous hepatic perfusion was performed with melphalan (high-dosage - approximately 200 mg) and hemofiltration. The sample size is small (8 patients) and the primary endpoint is response. Considering the small sample size, it is not possible to investigate about the effect of selected variables on response (logistic regression analysis). Secondary endpoints include adverse events that resulted very limited (probably in relation to the use of hemofiltration and the skill of the Authors). The scientific contribution is important but, in my opinion, the Authors should support with more emphasis the reasons to perform this locoregional chemotherapy procedure. The indications for M-PHP are still not defined in the international scientific literature. International guidelines consider locoregional chemotherapy as third line for unresectable CRCLM. The Authors protocol (as reported in the supporting information file), considers M-PHP for the CRCLM patients for whom “No other standard systemic treatment options (are) available”, but, at same time, include patients “Candidate for neoadjuvant chemotherapy as determined during the multidisciplinary meeting to down size the tumor.” and “Patients (they had) received no, one or more courses of systemic therapy”. *Minor changes* Abstract page 3, line 6: please, added “with hemofiltration”. Materials and Methods, Procedure details, page 7, line 12: please, clarify if the 16-F double-balloon catheter was positioned percutaneously or by surgical preparation of the femoral (or saphenous) vein. Table 4: please, precise if patients with grade 3/4 leukopenia/neutropenia received granulocyte colony-stimulating factors. Table 4: please, re-format line 4 (gr). In Discussion, the Authors should clarify with more details the reasons for believing and choosing a complex procedure such as M-PHP. In particular the Authors should clarify the reasons to propose percutaneous hepatic perfusion in CRCLM patients not previously submitted to systemic therapy or after failure of the first line. In Discussion, the Authors should elaborate on the reasons of the very limited adverse events. In Discussion, as concerning the limitations paragraph, page 12, line 8, please added: “…definitive conclusions. In relation to this problem, the importance of multi-center recruitment, as performed in other locoregional chemotherapy trials […please cite this reference… Mambrini A, Sanguinetti F, Pacetti P, Caudana R, Iacono C, Guglielmi A, Guadagni S, Del Freo A, Fiorentini G, Cantore M. Intra-arterial infusion of 5-fluorouracil, leucovirin, epirubicin, and carboplatin (FLEC regimen) in unresectable pancreatic cancer: results of a ten-year experience. In vivo. 2006; 20: 751-6.], must be emphasized. ============================== Please submit your revised manuscript by 20 April, 2021. 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Revision 1
1 Jun 2021 Author Response Respone to the reviewers Thank you for reviewing our manuscript. We have appreciated your comments and tried to incorporate them in our manuscript. Academic editor: This is a prospective study on a complex locoregional chemotherapy procedure named percutaneous hepatic perfusion. Percutaneous hepatic perfusion was performed with melphalan (high-dosage - approximately 200 mg) and hemofiltration. The sample size is small (8 patients) and the primary endpoint is response. Considering the small sample size, it is not possible to investigate about the effect of selected variables on response (logistic regression analysis). Secondary endpoints include adverse events that resulted very limited (probably in relation to the use of hemofiltration and the skill of the Authors). The scientific contribution is important but, in my opinion, the Authors should support with more emphasis the reasons to perform this locoregional chemotherapy procedure. Reply: Although systemic therapy is currently considered the first-line treatment modality in patients with unresectable CRLM, it can be accompanied by serious side-effects. We hypothesised that M-PHP would be a good alternative with limited systemic side-effects for metastatic CRC patients with liver-only disease. It has already been demonstrated that M-PHP is a safe, well-tolerated procedure in patients with liver metastases from ocular melanoma (Cardiovasc Intervent Radiol. 2019;42(6):841–852). Unfortunately, the current study was terminated prematurely due to slow recruitment. Several factors such as the availability of alternative therapies (e.g. systemic chemotherapy or radioembolization) and competing trials with systemic drugs or intra-arterial therapies probably contributed to this slow recruitment. This, together with a tumor response rate and median OS that did not meet our expectations (unfavorable compared to the study by Rothbarth et al. in which patients with CRLM were treated with isolated hepatic perfusion using a high dose of melphalan (Br J Surg. 2003;90(11):1391–1397)) implies that there is currently no clear role for M-PHP in patients with CRLM outside of clinical trials. The indications for M-PHP are still not defined in the international scientific literature. International guidelines consider locoregional chemotherapy as third line for unresectable CRCLM. The Authors protocol (as reported in the supporting information file), considers M-PHP for the CRCLM patients for whom “No other standard systemic treatment options (are) available”, but, at same time, include patients “Candidate for neoadjuvant chemotherapy as determined during the multidisciplinary meeting to down size the tumor.” and “Patients (they had) received no, one or more courses of systemic therapy”. Reply: It is correct that relatively few exclusion criteria were incorporated in the study protocol whereby most patients with histologically proven, unresectable CRLM were indeed eligible for inclusion. As was shown in Fig. 1, in 4/16 patients that were discussed during a multidisciplinary team meeting prior to possible inclusion, were excluded from participation because first-line systemic therapy was preferred. Table 2 shows that all patients in the current study had received one or more types of systemic therapy before receiving M-PHP. The ability to perform PHP may increase the role of hepatic perfusion for treatment of multiple tumor histologies since this procedure allows for sequential treatments to be delivered with lower morbidity. The management of unresectable liver metastases is a significant clinical problem that requires the combined efforts of multiple providers to develop an integrated approach for each patient. Continued evaluation of hepatic perfusion in these patients is necessary so that its role in this integrated approach can be more clearly defined. Minor changes Abstract page 3, line 6: please, added “with hemofiltration”. Reply: We added these words. Materials and Methods, Procedure details, page 7, line 12: please, clarify if the 16-F double-balloon catheter was positioned percutaneously or by surgical preparation of the femoral (or saphenous) vein. Reply: We made alterations accordingly. Table 4: please, precise if patients with grade 3/4 leukopenia/neutropenia received granulocyte colony-stimulating factors. Reply: All patients received a subcutaneous injection of granulocyte-colony stimulating factor within 72h after each M-PHP procedure. We added a sentence in the caption of Table 4. Table 4: please, re-format line 4 (gr). Reply: We re-formatted Table 4. In Discussion, the Authors should clarify with more details the reasons for believing and choosing a complex procedure such as M-PHP. In particular the Authors should clarify the reasons to propose percutaneous hepatic perfusion in CRCLM patients not previously submitted to systemic therapy or after failure of the first line. Reply: See also one of the replies to the academic editor. We believe that there is currently no clear role for M-PHP in patients with CRLM outside of clinical trials. In an attempt to clarify this, some changes were made to the manuscript. In Discussion, the Authors should elaborate on the reasons of the very limited adverse events. Reply: In a pharmacological study that was conducted in 2017, de Leede et al. demonstrated that the mean extraction rate of the GEN 2 hemofiltration system is 86%. (Cardiovasc Intervent Radiol. 2017;40:1196–1205). This means that only a small fraction of melphalan that is administered in the hepatic artery will eventually reach the systemic circulation. Additionally, all patients receive a subcutaneous injection with granulocyte colony-stimulating factor after each M-PHP procedure in an attempt to limit any systemic side-effects as much as possible. We made some changes to the Discussion section. In Discussion, as concerning the limitations paragraph, page 12, line 8, please added: “…definitive conclusions. In relation to this problem, the importance of multi-center recruitment, as performed in other locoregional chemotherapy trials […please cite this reference… Mambrini A, Sanguinetti F, Pacetti P, Caudana R, Iacono C, Guglielmi A, Guadagni S, Del Freo A, Fiorentini G, Cantore M. Intra-arterial infusion of 5-fluorouracil, leucovirin, epirubicin, and carboplatin (FLEC regimen) in unresectable pancreatic cancer: results of a ten-year experience. In vivo. 2006; 20: 751-6.], must be emphasized. Reply: We made alterations accordingly. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0261939.r002
29 Jun 2021 Decision Letter - Stefano Guadagni, Editor PONE-D-21-02466R1 Prospective evaluation of percutaneous hepatic perfusion with melphalan as a treatment for unresectable liver metastases from colorectal cancer PLOS ONE Dear Dr. Meijer, 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. Please submit your revised manuscript by Aug 13 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. 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Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments (if provided): The revision 1 is good but the paper needs further Minor changes. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. 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 addressed Reviewer #2: All comments have been addressed ******** 2. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The manuscript entitled ‘Prospective evaluation of percutaneous hepatic perfusion with melphalan as a treatment for unresectable liver metastases from colorectal cancer’ with the aim to prospectively evaluate the efficacy and safety of M-PHP in patients with unresectable CRLM. The manuscript can be further improved. Sample size calculation Page 9. the write up on the sample size requires further improvement. Information on margin of error, power of study to be stated. The statement of ‘16.5% around the observed proportion’ not clear. Page 10, what range refers to, min – max or IQR to be clearly stated. All percentage figures to be at least 1 decimal point. For Figure 1, more information could be added such as intervention, assessment, outcome variables, duration/period etc. For Table 2, 3, 4, dash (-) to be denoted in the table footnote. For Table 3, days to be stated as the initial measurements which then converted to months. This needs to be stated in the methodology. mo to be denoted in table footnote. In the Reference list, reference number 28 and 29 to conform with the journal format i.e journal name. Reviewer #2: The paper is very interesting but this is a very complex type of locoregional chemotherapy for hepatic metastases. In 8 patients the procedure has been performed percutaneously. The sample size is too small to demonstrate that the introduction of a 16F catheter is always possible without complications in all types of femoral arteries (also arteries with a diameter lower than 7 mm). Minor changes suggested: The authors should elaborate the previous concepts in Material and Methods and in Discussion. ****** 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: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. Attachments Attachment Submitted filename: Clementi Review.docx https://doi.org/10.1371/journal.pone.0261939.r003
Revision 2
1 Nov 2021 Author Response Response to the reviewers Thank you for reviewing our manuscript. We have appreciated your comments and tried to incorporate them in our manuscript. Trying to keep things comprehensive, we responded to the academic editor and reviewer(s) in blue. ---------------------------------------------------------------------------------------------------------------- Reviewer #1: The manuscript entitled ‘Prospective evaluation of percutaneous hepatic perfusion with melphalan as a treatment for unresectable liver metastases from colorectal cancer’ with the aim to prospectively evaluate the efficacy and safety of M-PHP in patients with unresectable CRLM. The manuscript can be further improved. Sample size calculation Page 9. the write up on the sample size requires further improvement. Information on margin of error, power of study to be stated. The statement of ‘16.5% around the observed proportion’ not clear. Reply: Unfortunately, no standard power calculation was performed since no clear null-hypothesis could be formulated. We choose a sample size that allows the response percentage to be determined with sufficient accuracy, i.e. with a sufficiently narrow confidence interval. Assuming a true response percentage of 60%, a sample size of 34 patients will yield a two-sided confidence interval of length 0.33 (± 16.5% around the observed proportion). Adjustments were made to our manuscript to clarify this. Page 10, what range refers to, min – max or IQR to be clearly stated. Reply: We changed made alterations accordingly, e.g. see page 10: ‘Median melphalan dose was 220 mg (ranging from 190 to 220) for the first cycle and 220 mg (ranging from range 160 to 220) for the second cycle.’ All percentage figures to be at least 1 decimal point. Reply: We made alterations accordingly. e.g. see page 10: ‘The one-, two-, and three-year OS was 50.0%, 50.0%, and 0% respectively. For Figure 1, more information could be added such as intervention, assessment, outcome variables, duration/period etc. Reply: Figure 1 is in our opinion to show the enrolment of patients, and why patients were not eligible for study inclusion. This is all provided in the figure. Elaborating on for instance intervention or outcome variables obtained distracts, in our opinion, from the information currently given in Figure 1. For Table 2, 3, 4, dash (-) to be denoted in the table footnote. Reply: Changes were made accordingly. See Table 2, 3 and 4. For Table 3, days to be stated as the initial measurements which then converted to months. This needs to be stated in the methodology. mo to be denoted in table footnote. Reply: Changes were made accordingly. See page 9: ‘Median OS, median PFS, and hPFS were measured in days and subsequently converted into months.’ Also changes were made accordingly in the footnote of Table 3. In the Reference list, reference number 28 and 29 to conform with the journal format i.e journal name. Reply: Changes were made accordingly. See reference 28 and 29 Reviewer #2: The paper is very interesting but this is a very complex type of locoregional chemotherapy for hepatic metastases. In 8 patients the procedure has been performed percutaneously. The sample size is too small to demonstrate that the introduction of a 16F catheter is always possible without complications in all types of femoral arteries (also arteries with a diameter lower than 7 mm). Minor changes suggested: The authors should elaborate the previous concepts in Material and Methods and in Discussion. Reply: This study aimed to evaluate the outcome in patients with colorectal liver metastases treated with percutaneous hepatic perfusion with Melphalan. The safety of this procedure has already been reported by Meijer et al. (Cardiovasc Intervent Radiol. 2019;42(6):841-852.) and is referred to in the last paragraph of the discussion. Until now, arterial access has not been a reason for exclusion of patients for this procedure in our hospital. Therefore, we do not elaborate extensively on this topic in the current paper. Additional changes: Figure one has been replace. The first box had a textual error, it said: ‘accessed for eligibility.’ It has now been changed to: assessed for eligibility.’ Attachments Attachment Submitted filename: Response to reviewers - 2 docx.docx https://doi.org/10.1371/journal.pone.0261939.r004
15 Dec 2021 Decision Letter - Stefano Guadagni, Editor Prospective evaluation of percutaneous hepatic perfusion with melphalan as a treatment for unresectable liver metastases from colorectal cancer PONE-D-21-02466R2 Dear Dr. Meijer, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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 help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- 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. Kind regards, Stefano Guadagni Academic Editor PLOS ONE Additional Editor Comments (optional): Good revision addressing all my concerns. Reviewers' comments: https://doi.org/10.1371/journal.pone.0261939.r005
Formally Accepted
6 Jan 2022 Acceptance Letter - Stefano Guadagni, Editor PONE-D-21-02466R2 Prospective evaluation of percutaneous hepatic perfusion with melphalan as a treatment for unresectable liver metastases from colorectal cancer Dear Dr. Meijer: I'm 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 let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Stefano Guadagni Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0261939.r006

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