Current Systemic Treatment Options for Advanced Pancreatic Cancer—An Overview Article

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Concrete, well-developed manuscript with clinical utility.

Clearly state that it is a narrative review. Although this type of review may not have a precisely defined methodology, I suggest including a brief methodological description, such as keywords used in the search, pubmed?, scopus?, years included, and criteria for selecting the manuscripts used, as well as, if possible, the number of manuscripts initially screened and those finally included. Or if they used criteria to select only relevant articles.

Although no plagiarism is detected, the similarity percentage is high (Percent match: 38%; iThenticate report), so it is suggested to lower this %.

Add a reference to this paragraph: Only 10% of pancreatic cancer cases are caused by genetic disorders, which primarily include Peutz-Jeghers syndrome (mutations in the STK11 tumor suppressor gene), mutations in the BRCA genes, the PALB gene, and the MLH1 and MSH2 genes (defects occurring in Lynch syndrome). Other genetic mutations (defects in the PRRS1 or p16/CDKN2A genes) are reported sporadically.

Lines 100-101: It is not clear which treatments the following paragraph refers to: Currently, there is no data available from large randomized clinical trials comparing the efficacy of the two regimens described above.

It would be desirable to summarize the results in a graph that shows the average survival of each therapeutic regimen (using the relevant selected reference), perhaps divided by first line, second line, and biological therapies, emphasizing if any of these treatments are only for particular subgroups.

I suggest adding a section on promising or future treatments that mark the current trend and possible future in treatment, such as gene therapy, immunotherapy, or something similar.

A section on radiotherapy would be relevant, as it is only mentioned in isolation, without clarifying its utility or role in the treatment of pancreatic cancer.

Author Response

Dear Reviewer Thank you for reading the article and reviewing it. Several comments have been addressed, and relevant sections have been added. The section "Currently, there is no data available from large randomized clinical trials comparing the efficacy of the two regimens described above" refers to the FOLFIRINOX and nab paclitaxel + gem regimens – I believe this is clearly stated in the text. The section on radiotherapy was omitted intentionally – last year, Current Oncology published my review paper on radiotherapy – hence, I do not wish to duplicate the work already done. My goal was to focus on systemic treatment. Sincerely,

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This article provides an overview of the current state of systemic therapy for advanced pancreatic cancer. Pancreatic cancer is a highly lethal malignancy, with 50% of patients presenting metastatic disease at diagnosis and a median survival time of 11 months. The preferred first-line treatment utilizes the FOLFIRINOX regimen (overall survival [OS] 11.1 months) or gemcitabine combined with nab-paclitaxel (OS 8.5 months), the latter being suitable for patients who cannot tolerate triplet combination therapy. For patients with BRCA mutations, olaparib maintenance therapy significantly extends progression-free survival (PFS: 7.4 vs. 3.8 months). The choice of second-line treatment depends on the initial regimen: gemcitabine monotherapy or combination regimens may be administered after disease progression on FOLFIRINOX, while modified FOLFIRINOX or oxaliplatin-containing regimens are options following progression on gemcitabine plus nab-paclitaxel. In targeted therapy, PD-1 inhibitors show an objective response rate of 34% in microsatellite instability-high (MSI-H) subtypes, although overall response rates remain limited in pancreatic cancer populations. Studies underscore the need to integrate patient performance status, molecular characteristics, and toxicity management into treatment strategies, emphasizing the importance of individualized therapeutic approaches. It is recommended that the author undertake the following revisions.

1. The author should allocate more space in the introduction section to present background information on pancreatic cancer.
2. The following references are closely related to the author's topic and are recommended for the author to cite.

[1] J. Li, A. Gu, N. Tang, G. Zengin, M.-Y. Li, Y. Liu, Patient-derived xenograft models in pan-cancer: From bench to clinic. Interdiscip. Med. 2025, 3, e20250016. DOI: 10.1002/INMD.20250016

[2] Uehara M, Domoto T, Takenaka S, Takeuchi O, Shimasaki T, Miyashita T, Minamoto T. Glycogen synthase kinase 3β: the nexus of chemoresistance, invasive capacity, and cancer stemness in pancreatic cancer. Cancer Drug Resist. 2024;7:4. http://dx.doi.org/10.20517/cdr.2023.84

[3] Liu, QQ., Dong, ZK., Wang, YF. et al. Reprogramming neural-tumor crosstalk: emerging therapeutic dimensions and targeting strategies. Military Med Res 12, 73 (2025). https://doi.org/10.1186/s40779-025-00661-9

3. While the article offers a comprehensive overview of various treatment regimens, it falls short in providing guidance for selecting suitable therapies for diverse patient populations, such as different age groups, those with comorbidities, and varying genetic mutation statuses. It would be beneficial to incorporate a summary section or flowchart at the conclusion of each chapter, delineating which patient types are best suited for specific therapeutic approaches, thereby bolstering its clinical applicability.
4. The article mentions adverse events related to regimens such as FOLFIRINOX and NALIRIFOX; however, it does not systematically compare the toxicity profiles of different treatment protocols. We suggest adding a comparative table of adverse events and briefly outlining the management principles for common adverse events.
5. The article mentions new drugs such as Darazoxane and others, but lacks sufficient analysis of their potential applications and limitations. It is recommended to add a paragraph discussing the challenges these new drugs may face.

The transitions between certain sections are abrupt. It is recommended to add brief transitional paragraphs between chapters to clarify the rationale and evidence base for treatment selections, thereby enhancing overall coherence of the manuscript.

Author Response

Dear reviewers, Thank you very much for reading this publication and for your many constructive comments. According to your comments: - the introduction has been expanded - the chapter on targeted drugs has been expanded - toxicities have been added to some of the described regimens - the chapters are more clearly separated Thank you Sincerely,
M Domagała-Haduch

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

1. Introduction paragraph:-

-Paragraph 4 on germline mutations needs to be significantly enhanced. This does not contain any references also based on the pancreatic cancer screening cohort give individual prevalence for each gene.

-Please add family history of pancreatic cancer in the risk factors as well

-Paragraph 5 again please add the prevalence of symptoms in brackets

-Talk about universal germline testing

2. First-line treatment for advanced pancreatic cancer paragraph

-Please add how hyperbilirubinemia impacts 1L chemotherapy choice

-Add how for patients with DNA repair mutations platinum based regimens are the first choice

3. Add a paragraph on resectable and borderline resectable PDAC management – In addition to surgery and radiation please add regarding neoadjuvant and adjuvant treatment regiment with al the trials
4. Please add a section on pancreatic cancer screening as that is the standard of care

Author Response

Dear reviewer, Thank you for reading the article and submitting your comments. In the publication, - the percentages of symptom occurrence have been updated - the testing and use of BRCA mutations have been briefly discussed - a paragraph regarding hyperbilirubinemia has been added Regarding the description of resectable pancreatic cancer, the aim of our article was to summarize current treatment methods for metastatic cancer. Describing the comprehensive treatment of this cancer would relegate palliative treatment to the background, and this discussion was our goal. Sincerely, M Domagała-Haduch

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors The manuscript added new information according to the comments of all reviewers. I recommend publishing it

Author Response

Thank you.

Reviewer 2 Report

Comments and Suggestions for Authors

ACCEPT

Author Response

Thank you.