Review Reports - The Role of Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Peritoneal GIST-Induced Sarcomatosis (GISTosis)

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript in review is a retrospective, single institution cohort studies involving 25 patients from 2005 to 2023 to examine the role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with GIST-induced sarcomatosis. The study includes a up to date literature review related the topic of investigation. The primary outcome of the study revealed median followup of 72 months and median overall survival of 62 months. The clinical variables associated with improved survival was PCI and CC scores. Overall, this is an interesting study examining a patient population with very limited treatment options and typically cytotoxic therapy resistant malignancy.

The main criticism of the manuscript involves the utility of cytotoxic therapy, regardless of delivery mechanism. GIST are usually resistant to traditional cytotoxic therapies. As such, the current recommendations in the US per NCCN guidelines for patients failing to TKI. This was also recognized by the authors who stated "Taking also into account that GIST-induced sarcomatosis is chemotherapy-resistant, an appropriate treatment strategy for peritoneal GISTosis has not yet been established." In this setting, the hypothesis of examining the role of intraperitoneal chemotherapy is flawed. As such, utilizing cisplatin for intraperitoneal chemotherapy for this patient population is deeply flawed, despite the pre-existing literature and data.

Second, it would have been much more scientifically important to examine the role of cytoreductive surgery, which is likely the driver for outcomes seen in this series. If plausible, an analysis comparing GIST induced sarcomatosis patients treated with TKI only vs TKI +CRS would potentially highlight the importance of cytoreduction.

Minor comments involve the technique of chemoperfusion. The authors utilized cisplatin 50 mg/m2 dose at 40C for 60min. An explanation behind this dosing and timing would be helpful.

Also the authors recommended HIPEC to be reserved for low PCI cases. In the GI literature that support IP therapy, the IP therapy including HIPEC is usually reserved for higher PCI. It would be helpful to provide explanation for this recommendation.

Author Response

Point-by-point Response to Reviewer 1 Comment

Reviewer 1:

The manuscript in review is a retrospective, single institution cohort studies involving 25 patients from 2005 to 2023 to examine the role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with GIST-induced sarcomatosis. The study includes an up to date literature review related the topic of investigation. The primary outcome of the study revealed median follow-up of 72 months and median overall survival of 62 months. The clinical variables associated with improved survival was PCI and CC scores. Overall, this is an interesting study examining a patient population with very limited treatment options and typically cytotoxic therapy resistant malignancy.

Author’s response:

We thank you very much for your great attention and your kind comments. Your thoughtful and constructive feedback will greatly contribute to improving the clarity and scientific rigor of our manuscript. We address each point in detail below.

This paper aims to highlight that Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can be a valuable tool for the management of peritoneal GISTosis. Our study demonstrated an acceptable safety profile and favourable outcomes in terms of overall survival (OS) and disease-free survival (DFS) in the largest cohort of CRS+HIPEC for peritoneal GISTosis to date, particularly as you also mention, in patients with low peritoneal cancer index (PCI) and completeness of cytoreduction (CC) scores.

Reviewer 1:

Author’s response:

We appreciate your valid concerns regarding the chemo-resistance of GIST and the rationale for not using cytotoxic agents in this context. Indeed, GIST are generally resistant to systemic cytotoxic chemotherapy, and this resistance is a central reason why tyrosine kinase inhibitors (TKI) have become the cornerstone of treatment. However, the use of intraperitoneal chemotherapy in the form of HIPEC can be seen, not as a direct tumoricidal agent in the traditional sense, but rather as an adjunctive strategy aimed at achieving regional control of microscopic peritoneal disease following maximal cytoreduction. We can clarify this important point in the manuscript, emphasizing that the rationale for using HIPEC in our cohort is not predicated solely on chemosensitivity, but rather on a multimodal approach (red highlighted).

Furthermore, we agree that cisplatin may not be directly effective against GIST cells per se; however, its inclusion in HIPEC protocols is based on prior studies involving peritoneal surface malignancies, and this practice was institutionally standardized over the 18-year study period.

Reviewer 1:

Author’s response:

Thank you for the valuable insight. We could not have agreed more that cytoreductive surgery is likely the principal determinant of improved outcomes in this patient population, and we have emphasized this throughout the manuscript. Unfortunately, our study is limited not only by its patients’ small sample, but also by its retrospective design and lack of a non-surgical control group treated with TKIs alone, which prevents a direct comparison. Moreover, patients referred for CRS+HIPEC had somehow failed TKI monotherapy, leading to selection bias that makes such a comparison inherently flawed within the scope of our data. Nevertheless, in our discussion section we do focus firstly on the critical role of CRS to the observed survival benefit, which of course could be improved, if necessary.

Reviewer 1:

Minor comments involve the technique of chemoperfusion. The authors utilized cisplatin 50 mg/m2 dose at 40C for 60min. An explanation behind this dosing and timing would be helpful.

Author’s response:

Thank you for pointing out this important aspect! The dosing and perfusion parameters used in our HIPEC protocol - cisplatin at 50 mg/m², perfused at 40 °C for 60 min. - reflect our institution’s standardized approach, which was adapted from protocols originally developed for epithelial peritoneal surface malignancies, such as ovarian and colorectal peritoneal carcinomatosis. These parameters were selected to balance efficacy with safety and have been applied consistently across indications over the 18-year study period. While not specific to GIST, this uniform protocol allowed for comparability and procedural safety in our patient population.

Reviewer 1:

Author’s response

Thank you for your valuable consideration. Our recommendation to consider CRS+HIPEC primarily in patients with lower PCI scores is based on our findings that OS and PFS were significantly longer in patients with PCI less than 10. Unlike some other gastrointestinal malignancies where higher PCI may still benefit from IP chemotherapy (e.g., pseudomycoma peritonei or peritoneal mesothelioma), the biology of GIST and its response to treatment differ substantially. Specifically, given the chemoresistant nature of GIST and the questionable direct efficacy of HIPEC in this setting, we hypothesize that the benefit observed may be primarily from cytoreduction. In cases with lower PCI, complete cytoreduction is more likely, and residual microscopic disease may be better managed, if at all, by adjunctive HIPEC. Therefore, our recommendation reflects a pragmatic approach: reserving this aggressive multimodal therapy for patients in whom a complete or near-complete cytoreduction is realistically achievable – which is typically in those with lower PCI cases.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript entitled "The Role of Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Peritoneal GIST-Induced Sarcomatosis (GISTosis)" presents a retrospective analysis combined with a systematic review, evaluating the outcomes of cytoreductive surgery (CRS) with HIPEC in patients with metastatic GIST manifesting as peritoneal sarcomatosis. The study is clinically relevant, addressing a rare condition for which standardised treatment guidelines are lacking. The reported outcomes are promising; however, several methodological limitations restrict the strength of the conclusions.

The Introduction is well-structured and provides a comprehensive overview of the background of GIST, the introduction of TKIs, and the rationale for CRS and HIPEC. However, the Authors do not provide sufficient justification for the use of HIPEC in a tumour type considered resistant to conventional chemotherapy.

The Materials and Methods section appropriately defines the cohort, outlines the CRS+HIPEC protocol, and surgical scoring systems (PCI and CC). The literature-based systematic review strengthens the presented attitude. However, the methodology lacks clarity in key areas, including patient selection criteria, missing data handling, and confounder control. No multivariate survival analyses were performed to adjust for clinical or treatment-related covariates.

The Results are clearly presented, and survival analyses stratified by PCI and CC scores are appropriate. The reported complication rates and follow-up period strengthen the clinical relevance of the findings. However, the absence of a control group, small sample size (n=25), and lack of multivariate survival analyses weaken the presented results.

The Discussion appropriately confronts the findings against prior studies and underlines the importance of surgical completeness and low disease burden. However, some claims regarding the utility of HIPEC should be tempered given the absence of randomised data and mechanistic insight.

Concerns and Suggestions:

Lack of multivariate analysis to control for confounders such as age, mutation status, timing of metastases, or TKI treatment.
The mutation profile (e.g., KIT/PDGFRA status) is not reported, which is critical for understanding patients' response and prognosis.
Patient selection criteria are vague; inclusion/exclusion criteria and the total number screened are not specified.
No direct comparison group (e.g., patients with CRS only, or TKI-only therapy) limits the strength of conclusions.
The systematic review lacks a formal bias assessment, data synthesis, or meta-analytic interpretation.
No details on missing data handling, lost-to-follow-up impact, or quality-of-life outcomes.

Concluding, this study addresses an important clinical question and contributes valuable observational data on the safety and potential efficacy of CRS+HIPEC in peritoneal GISTosis. However, the manuscript would benefit from a more rigorous methodological framework, particularly in analysing prognostic factors and clarifying patient selection and TKI treatment logic. Future prospective studies or controlled comparisons are needed to confirm whether HIPEC offers a survival benefit in this context. Nevertheless, the study is a significant step in characterising an extremely rare clinical presentation and supports the role of specialised multidisciplinary management.

Comments on the Quality of English Language

The manuscript is written in generally understandable English and conveys the scientific content adequately. However, the text contains numerous grammatical inaccuracies, difficult phrasing, and stylistic inconsistencies (eg. "shed light into GIST’ better understanding” - shed light on a better understanding of GIST; "reassuring the clinicians about technique’s safety and efficacy”
- providing reassurance regarding the safety and efficacy of the technique). The overall academic tone is acceptable but would benefit from language polishing to meet the standards of a peer-reviewed journal.

Author Response

Point-by-point Response to Reviewer 2 Comment

Reviewer 2:

Author’s response:

Thank you very much for your great attention and your comments.

Reviewer 2:

Author’s response:

We kindly thank you for this important point. While GIST is known to be resistant to conventional systemic chemotherapy, the rationale for the use of HIPEC in this study is based not on direct chemosensitivity but on its potential role in controlling microscopic peritoneal dissemination following complete cytoreduction. We acknowledge that this rationale may not be well established in GIST and have revised the Introduction and Discussion (red highlighted) to more clearly explain that HIPEC was used as an adjunct in a multimodal approach in a context of limited therapeutic options, rather than as a standalone chemotherapeutic solution.

Reviewer 2:

Author’s response:

We appreciate the reviewer’s attention to the methodological clarity of the manuscript. We have now expanded the Materials and Methods section to more clearly describe the patient selection process (red highlighted). Specifically, patients were included if they had histologically confirmed peritoneal metastases of GIST origin and were considered candidates for CRS+HIPEC based on multidisciplinary team assessment. We had no missing data to be handled and we acknowledge the limitations of confounder control due to the retrospective nature of the study. These points are now clearly stated.

We agree with the reviewer that multivariate survival analyses would provide a more robust understanding of prognostic factors. However, given the small sample size (n=25) and number of observed survival events, performing a multivariate Cox regression would risk model overfitting and unreliable estimates. We acknowledge this limitation and emphasize the need for larger multicenter cohorts to allow meaningful multivariate modeling.

Reviewer 2:

Author’s response:

We appreciate the reviewer’s balanced evaluation. We fully agree that the absence of a non-surgical or TKI-only control group limits the strength of our conclusions. Unfortunately, our retrospective design and institutional setting did not allow for the inclusion of a contemporaneous control group. We also suggest (red highlighted) that prospective registries or multicenter collaborations would be valuable for identifying appropriate control cohorts in future studies.

Reviewer 2:

Author’s response:

We thank the reviewer for this insightful and important recommendation. We fully agree that, in the absence of randomized controlled trials or mechanistic evidence supporting HIPEC’s efficacy in GIST, any conclusions about its utility must be stated with caution. We have revised the Conclusion sections (red highlighted) to temper our claims, emphasizing that HIPEC’s role remains investigational in this disease setting and that the observed survival benefit likely reflects the effect of complete cytoreduction in patients with low disease burden. The potential contribution of HIPEC is acknowledged as hypothesis-generating rather than definitive.

Reviewer 2:

Concerns and Suggestions:

Lack of multivariate analysis to control for confounders such as age, mutation status, timing of metastases, or TKI treatment.

Author’s response:

We appreciate the reviewer’s valid concern. We agree that multivariate analysis would strengthen the evaluation of prognostic factors. However, the small sample size (n=25) and number of survival events limited the statistical power and risked overfitting any multivariate model. We now more clearly acknowledge this limitation in the Materials and Methods section and have added a statement on the need for larger, pooled datasets to permit such analysis in future studies (red highlighted).

Reviewer 2:

The mutation profile (e.g., KIT/PDGFRA status) is not reported, which is critical for understanding patients' response and prognosis.

Author’s response:

We thank the reviewer for highlighting this important omission. While mutational analysis (KIT and PDGFRA status) was available for the majority of our patients, it was not consistently documented in the early part of the 18-year study period.

Reviewer 2:

Patient selection criteria are vague; inclusion/exclusion criteria and the total number screened are not specified.

Author’s response:

We have now clarified the inclusion and exclusion criteria in the Materials and Methods (red highlighted). Patients were included if they had histologically confirmed GIST with peritoneal metastases and were evaluated by the institutional peritoneal tumor board. Exclusion criteria included incomplete clinical data, and inability to achieve or attempt cytoreduction.

Reviewer 2:

No direct comparison group (e.g., patients with CRS only, or TKI-only therapy) limits the strength of conclusions.

Author’s response:

We agree. Our retrospective cohort reflects patients treated at a high-volume peritoneal surface malignancy center. We unfortunately did not have a matched or contemporaneous control group of patients receiving TKI-only or CRS-only within the same setting. This limitation is now more clearly acknowledged (red highlighted), and we advocate for prospective studies with controlled comparisons.

Reviewer 2:

The systematic review lacks a formal bias assessment, data synthesis, or meta-analytic interpretation.

Author’s response:

We appreciate the reviewer’s critical feedback. The systematic review aimed to provide a synthesis of the limited available literature rather than a meta-analysis, due to heterogeneity and small sample sizes in published studies. We now clarify this in the Methods, explicitly stating that no formal bias assessment (e.g., ROBINS-I or NOS) was conducted (red highlighted).

Reviewer 2:

No details on missing data handling, lost-to-follow-up impact, or quality-of-life outcomes.

Author’s response:

We have added a statement (red highlighted) to clarify that a complete-case analysis was used, and patients with missing critical data were excluded from analysis. Regarding follow-up, none of the patients were lost to follow-up during the defined observation period. Unfortunately, quality-of-life (QoL) data were not systematically collected during the study period.

Reviewer 2:

Author’s response:

We are grateful for the reviewer’s thoughtful summary and recognition of the clinical relevance of this study, despite its inherent limitations. We fully agree that future prospective, controlled studies are required to clarify the role of HIPEC in peritoneal GISTosis. We have revised the Discussion and Conclusion sections accordingly (red highlighted) to reflect a more cautious interpretation of our findings, and to better position the study as a foundational contribution to the limited literature on this rare clinical scenario.

Author Response File: Author Response.docx