Precision Medicine for Peritoneal Carcinomatosis—Current Advances in Organoid Drug Testing and Clinical Applicability
, Josephine A. Wright 2, Daniel L. Worthley 3, Elizabeth Murphy 4 and Susan L. Woods 1,2,*
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
This is a timely review on the potential benefits of organoid technology for improving treatment of patients with peritoneal metastases from GI origin. The review is well-written and comprehensively discusses many relevant aspects of this topic.
I have the following suggestions for improving the manuscript:
In the introduction the authors only mention PIPAC as an alternative treatment for unresectable PM. (“On the other hand, patients with a high PCI, where a curative outcome is less feasible, are considered for palliative intraperitoneal chemotherapy”). However, systemic chemotherapy is still the standard of care in most countries for patients with inoperable PM (as far as I know), while PIPAC is still experimental. This paragraph could be revised to better distinguish clinical routine from experimental approaches like PIPAC and port-a-cath-based chemo-infusion (e.g. PMID: 37467389).
The statement that “organoids closely mimic primary tissues in both architecture and function” is a bit misleading as in most cases they consist only of the epithelial compartment, at least when derived from GI cancers. This is better described in the last part of section 3.3.
In the section on the importance of hyperthermia during HIPEC it could be mentioned that this is not relevant for PIPAC or port-a-cath-based i.p. chemo delivery
In paragraph 3.2 on the methodologies of (optimizing) PDO response assessment the authors may want to refer to a recent paper on this topic (PMID: 38414064).
In the first section of paragraph 4 (“Correlating patient clinical outcomes with organoid drug responses”) I would emphasize the difficulty of measuring PM using standard CT, and therefore the challenge of using RECIST for adequate response evaluation. Without a reliable clinical measurement of response, establishing correlations with PDO responses will always be difficult. Alternative imaging tools that may be better suited to detect PM and their response to therapy may be mentioned as a possible solution in future studies (i.e. DW-MRI, FAPI-PET).
In addition, in the same paragraph it may be mentioned that the value of PDOs to predict drug responses in patients could be drug-dependent (PMID: 31597751).
In the very last paragraph of section 4 on including cells from the microenvironment, alternative strategies may be mentioned, such as MOS (PMID: 35508177; PMID: 36270276). Or maybe better in section 5 as a future direction.
In the ‘challenges’ section the authors may want to refer to PMID: 33887686
Author Response
Review article titled ‘Precision Medicine for Peritoneal Carcinomatosis–Current Advances in Organoid Drug Testing and Clinical Applicability. Manuscript ID: organoids-3417996
Summary:
Thank you very much for taking the time to review this manuscript. We truly appreciate your feedback, which has helped clarify and significantly improve the overall quality of our work. Below, you will find our responses and alterations to manuscript text in red.
Response to Reviewer 1 comments
This is a timely review on the potential benefits of organoid technology for improving treatment of patients with peritoneal metastases from GI origin. The review is well-written and comprehensively discusses many relevant aspects of this topic.
I have the following suggestions for improving the manuscript:
In the introduction the authors only mention PIPAC as an alternative treatment for unresectable PM. (“On the other hand, patients with a high PCI, where a curative outcome is less feasible, are considered for palliative intraperitoneal chemotherapy”). However, systemic chemotherapy is still the standard of care in most countries for patients with inoperable PM (as far as I know), while PIPAC is still experimental. This paragraph could be revised to better distinguish clinical routine from experimental approaches like PIPAC and port-a-cath-based chemo-infusion (e.g. PMID: 37467389).
Line 54-55 On the other hand, patients with a high PCI, where a curative outcome is less feasible, palliative intraperitoneal chemotherapy can be considered alongside systemic chemotherapy (9). One form of experimental treatment is known as pressurised intraperitoneal aerosol chemotherapy (PIPAC) (1).
The statement that “organoids closely mimic primary tissues in both architecture and function” is a bit misleading as in most cases they consist only of the epithelial compartment, at least when derived from GI cancers. This is better described in the last part of section 3.3.
Line 96-98 Cultivated in ECM-based medium with high success rates for gastrointestinal tissues, organoids closely mimic the epithelial component of primary tissues. in both architecture and function.
In the section on the importance of hyperthermia during HIPEC it could be mentioned that this is not relevant for PIPAC or port-a-cath-based i.p. chemo delivery
Line 161-64 HIPEC involves delivery of heated chemotherapy, typically at 42°C directly into the peritoneal cavity to enhance chemotherapeutic efficacy [30]. Heat is a distinctive feature of HIPEC and is not present in PIPAC or other forms of intraperitoneal chemotherapy. Mimicking this condition in vitro may be important to ensure an accurate representation of the in vivo treatment regime [15,16].
In paragraph 3.2 on the methodologies of (optimizing) PDO response assessment the authors may want to refer to a recent paper on this topic (PMID: 38414064).
The insufficiency of clinical HIPEC doses in eradicating residual microscopic disease have also prompted further investigations into optimizing treatment regimens, including increased MMC doses in trials such as GECOP-MMC (43).
Line 227-235 Another study optimized drug screening methods using PDOs from 23 CRC metastases to correlate organoid responses with clinical outcomes. PDOs were exposed to 5-fluorouracil (5-FU), irinotecan, and oxaliplatin-based chemotherapy, with optimisation involving the exclusion of N-acetylcysteine (NAC) from the medium, biphasic curve fitting for combination screens, and testing different readouts and treatment setups. Area under the curve was identified as the most robust drug response metric, and correlations between PDO sensitivity and patient response were demonstrated (coefficients of 0.58 for 5-FU, 0.61 for irinotecan, and 0.60 for oxaliplatin). PDO resistance to oxaliplatin was associated with shorter patient progression-free survival (3.3 vs. 10.9 months), and prior patient exposure to 5-FU/capecitabine was reflected in PDO resistance (p = 0.003) (44).
In the first section of paragraph 4 (“Correlating patient clinical outcomes with organoid drug responses”) I would emphasize the difficulty of measuring PM using standard CT, and therefore the challenge of using RECIST for adequate response evaluation. Without a reliable clinical measurement of response, establishing correlations with PDO responses will always be difficult. Alternative imaging tools that may be better suited to detect PM and their response to therapy may be mentioned as a possible solution in future studies (i.e. DW-MRI, FAPI-PET).
Line 385-93 Additionally, RECIST (Response Evaluation Criteria in Solid Tumours) is frequently used to evaluate radiologic tumour responses, providing an objective measure of treatment efficacy (61). However, peritoneal metastases may not be measurable lesions on staging CT, therefore applying the RECIST criteria is not always feasible or uniform (62, 63). In the absence of a reliable clinical measurement of response, establishing correlations with PDO responses will always be challenging. Alternative imaging tools such as diffuse weight magnetic resonance imaging (DW-MRI) or fibroblast activation protein inhibitor positron emission tomography (FAPI-PET) may be better suited to detect PM and should be considered as a possible solution in future studies.
In addition, in the same paragraph it may be mentioned that the value of PDOs to predict drug responses in patients could be drug-dependent (PMID: 31597751).
Line 375-79 Assessing the correlation of PDO drug responses in vitro with clinical outcomes for peritoneal disease following treatment presents significant challenges, largely due to varying extents of cytoreductive surgery (CRS) completion, types of chemotherapeutics used, the influence of residual disease on progression, limitations in imaging modalities, and differential responses to HIPEC and systemic treatments depending on the site of the metastatic deposits (39, 60).
In the very last paragraph of section 4 on including cells from the microenvironment, alternative strategies may be mentioned, such as MOS (PMID: 35508177; PMID: 36270276). Or maybe better in section 5 as a future direction.
Section 5 While PDOs offer potential for personalised drug testing, creating these models is still time-intensive and challenging due to the complex structure of some peritoneal tumours, often delaying results needed for timely clinical decisions (60, 73). To address these limitations, droplet emulsion microfluidics with temperature control and dead-volume minimization are now emerging to generate thousands of Micro-Organospheres (MOS) from low-volume patient tissues, providing a rapid, scalable, and clinically relevant model for precision oncology (74).
In the ‘challenges’ section the authors may want to refer to PMID: 33887686
Section 5 While PDOs offer potential for personalised drug testing, creating these models is still time-intensive and challenging due to the complex structure of some peritoneal tumours, often delaying results needed for timely clinical decisions (60, 73).
Reviewer 2 Report
Comments and Suggestions for Authors
The authors present an interesting review on the advances in Organoid drug testing and its clinical applicability in order to deliver a personalised chemotherapy in cancer patients with peritoneal carcinomatosis.
The topic is pertinent, as patient-dericed orgaoid culture can provide a relevant new tools for personalised treatment for patients with peritoneal carcinomatosis which is characterised with sensibility to systemic chemotherapautic agents.
The manuscript is quite informative as it gathers a complete review of the published information on this topic.
The references are appropiate, and the Tables and Figures are quite informative.
Only some query:
In order to make the manuscript attractive to clinicians interested in the treatment of peritoneal carcinomatosis it would be very important ot add in the Introduction section an explanation of what are the patient-derived organoid cultures, differences with the more traditional cell culture techniques, advantages. how the biologic material is obtained and managed.
Author Response
Review article titled ‘Precision Medicine for Peritoneal Carcinomatosis–Current Advances in Organoid Drug Testing and Clinical Applicability. Manuscript ID: organoids-3417996
Summary:
Thank you very much for taking the time to review this manuscript. We truly appreciate your feedback, which has helped clarify and significantly improve the overall quality of our work. Below, you will find our responses and alterations to manuscript text in red.
Response to Reviewer 2 Comments
The authors present an interesting review on the advances in Organoid drug testing and its clinical applicability in order to deliver a personalised chemotherapy in cancer patients with peritoneal carcinomatosis.
The topic is pertinent, as patient-dericed orgaoid culture can provide a relevant new tools for personalised treatment for patients with peritoneal carcinomatosis which is characterised with sensibility to systemic chemotherapautic agents.
The manuscript is quite informative as it gathers a complete review of the published information on this topic.
The references are appropiate, and the Tables and Figures are quite informative.
Only some query:
In order to make the manuscript attractive to clinicians interested in the treatment of peritoneal carcinomatosis it would be very important ot add in the Introduction section an explanation of what are the patient-derived organoid cultures, differences with the more traditional cell culture techniques, advantages. how the biologic material is obtained and managed.
Line 81-89 Patient-derived xenograft models (PDXs) while reproducible, present long term genomic stability along with clinical applicability however, encounter limitations such as sample accessibility, time required to generate xenograft models, economic constraints, and ethical concerns, hindering their extensive use in basic research and personalised medicine [17,18]. Considering the limitations of traditional models like 2D cell lines and PDXs, organoids offer a promising alternative for assessing drug sensitivity and advancing personalised therapy. Patient derived organoid cultures are three-dimensional structures grown from patient tissue samples, obtained through a biopsy or surgery. These organoids retain genetic, histological and functional characteristics of the epithelial compartment over multiple passages and can be cryopreserved for storage without losing their fidelity to the original tissue (20).
Round 2
Reviewer 2 Report
Comments and Suggestions for Authors
The authors have modified the text of the original version to include a paragrapgh detailing the organoid technique of culture cells. In my opinion the text is suitable for publication
