Transforming hyperthermic intraperitoneal chemotherapy: using computer simulation to improve HIPEC treatments

Hyperthermic intraperitoneal chemotherapy (HIPEC) is a well-established treatment for patients with peritoneal surface malignancies (1). HIPEC targets microscopic tumor deposits that cannot be removed by cytoreductive surgery (2). Since the location of the tumor deposits is often invisible, drug and heat delivery during HIPEC must be homogeneous despite the irregular geometry of the peritoneal cavity (3). Unfortunately, many authors have highlighted the wide variability and lack of consistent scientific rationale for many HIPEC parameters in routine practice (4,5). These knowledge gaps on HIPEC fluid and temperature dynamics limit our ability to improve clinical outcomes. Currently, expert consensus recommendations constitute the main method to standardize care for patients undergoing HIPEC (6).

To bridge these gaps, recent studies have incorporated computer simulation (3,7,8). Simulation studies in HIPEC use computational fluid dynamics (CFD) to reproduce certain in vivo conditions. Moreover, they can incorporate different types of flow, measure variables at pre-specified areas, and simulate heat transfer. This approach is appealing as it provides a sound scientific rationale for the HIPEC regimen, allowing researchers to refine hypotheses used in preclinical and clinical studies. While still being developed, CFD models in HIPEC have been reported to have an acceptable correlation with clinical data (8).

In the August issue of the Journal of Gastrointestinal Oncology, Cooney et al. reported the results of a simulated HIPEC model to evaluate the fluid flow dynamics at specific intra-abdominal at-risk locations (7). Their model included the main intrabdominal organs, two flow rates (800 and 1,120 mL/min), and two fluid directions. Moreover, it resembled several conditions of a clinical case, such as the number and locations of catheters and the duration of treatment. Assuming them as rigid, the authors highlighted how organs can impede homogeneous fluid and temperature distribution in certain locations. Specifically, this was described in probe 2, inferior to small bowel mesentery, where forward flow was blocked by the transverse colon mesentery. Furthermore, the results showed improved dynamics with a reversed flow configuration (lower pelvis to upper abdomen direction) and higher flow rates. Interestingly, the authors reported that even in the best combination tested, certain locations did not reach the target temperature by 30 minutes. Finally, the authors concluded that the outflow temperature may not accurately represent the actual temperature at many intraabdominal locations.

The results from Cooney et al. add to a growing body of literature on computer simulation of HIPEC treatments. Previously, Loke et al. developed and validated CFD models of HIPEC treatments (3). Their model was first developed using rat computed tomography images to create an anatomical model of the abdominal cavity. Both heat transfer and chemotherapy models were made and compared to published experimental data. Their findings suggested the superiority of a four-inflow approach to achieve temperature homogeneity. These CFD models have also studied the effect of several treatment parameters (e.g., catheter configuration, changes in temperature, etc.) in temperatures and flows during HIPEC. In another simulation study, Loke et al. created a three-dimensional CFD model using human data and produced a realistic representation of the abdominal cavity (8). Subsequently, a life-size, anatomically correct 3D phantom was used to validate the thermal model of an open HIPEC setup (9).

Significant differences can be appreciated between the CFD models created and validated by Loke et al. and those by Cooney et al. These include anatomical accuracy, the higher number of catheter setups, chemotherapy modules, and different software. Notably, we can also appreciate similitudes between them. For instance, changing flow direction can improve temperature heterogeneity in regions where forward flow is insufficient. In clinical practice, however, flow reversal is only used to relieve an obstruction. Moreover, modifying the catheter setup and flow direction in the middle of treatment can risk brief flow interruptions and result in decreased fluid temperatures. Furthermore, catheter positioning must minimize the risk of thermal or mechanical tissue injury. Simulation studies also agree on a period of temperature stabilization. We consider time an essential variable in ensuring an optimal HIPEC treatment, as it determines an adequate thermal dose. These findings agree with the results of the PRODIGE-7 trial, where a 30-minute course of HIPEC did not alter survival in patients with metastatic colorectal cancer (10). Finally, another common characteristic of both approaches is their comparison to published clinical or preclinical data. This is encouraging, as it generates some validity in the findings. Still, considerable validation is required using more experiments and a priori definitions of accuracy.

Although disease-specific, the recurrence rate for any peritoneal malignancy is expectedly high. In appendiceal cancer, Kong et al. observed a recurrence rate of 25% with a median time to recurrence of about 20 months (11). In a mixed cancer sample, Wong et al. reported 1-, 3-, and 5-year progression-free survival rates of 64.4%, 24.8%, and 16.1%, respectively (12). Previously, we observed that failure to reach bladder hyperthermia during HIPEC was associated with worse progression-free and overall survival (13). Thus, it remains paramount to understand the role of HIPEC if we are to improve the survival of these patients. As of today, the certainty of evidence behind the survival advantage of HIPEC continues to be rated low (6).

Evaluating the performance of HIPEC treatments is a very complex endeavor. We commend Cooney et al. for their efforts to advance the knowledge of HIPEC. CFD simulations are complex tasks requiring multidisciplinary collaboration, advanced knowledge of bioengineering and physics, and significant computational power. As such, we consider them a step forward to improve HIPEC treatments worldwide.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-755/coif). C.E.G.L. reports previous research relationship with GE Healthcare for investigator-initiated research, unrelated to the topic of this manuscript; and ongoing relationship with Edwards Lifesciences and Vena Vitals for sponsored research, unrelated to the topic of this manuscript. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy of integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bushati M, Rovers KP, Sommariva A, et al. The current practice of cytoreductive surgery and HIPEC for colorectal peritoneal metastases: Results of a worldwide web-based survey of the Peritoneal Surface Oncology Group International (PSOGI). Eur J Surg Oncol 2018;44:1942-8. [Crossref] [PubMed]
2. Kusamura S, Barretta F, Yonemura Y, et al. The Role of Hyperthermic Intraperitoneal Chemotherapy in Pseudomyxoma Peritonei After Cytoreductive Surgery. JAMA Surg 2021;156:e206363. [Crossref] [PubMed]
3. Löke DR, Helderman RFCPA, Rodermond HM, et al. Demonstration of treatment planning software for hyperthermic intraperitoneal chemotherapy in a rat model. Int J Hyperthermia 2021;38:38-54. [Crossref] [PubMed]
4. Yurttas C, Hoffmann G, Tolios A, et al. Systematic Review of Variations in Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Peritoneal Metastasis from Colorectal Cancer. J Clin Med 2018;7:567. [Crossref] [PubMed]
5. Helderman RFCPA, Löke DR, Kok HP, et al. Variation in Clinical Application of Hyperthermic Intraperitoneal Chemotherapy: A Review. Cancers (Basel) 2019;11:78. [Crossref] [PubMed]
6. Kusamura S, Bhatt A, van Der Speeten K, et al. Review of 2022 PSOGI/RENAPE Consensus on HIPEC. J Surg Oncol 2024; Epub ahead of print. [Crossref] [PubMed]
7. Cooney OS, Goodin DA, Mouw TJ, et al. Intra-abdominal temperature variation during hyperthermic intraperitoneal chemotherapy evaluated via computational fluid dynamics modeling. J Gastrointest Oncol 2024;15:1847-60. [Crossref] [PubMed]
8. Löke DR, Kok HP, Helderman RFCPA, et al. Application of HIPEC simulations for optimizing treatment delivery strategies. Int J Hyperthermia 2023;40:2218627. [Crossref] [PubMed]
9. Löke DR, Kok HP, Helderman RFCPA, et al. Validation of thermal dynamics during Hyperthermic IntraPEritoneal Chemotherapy simulations using a 3D-printed phantom. Front Oncol 2023;13:1102242. [Crossref] [PubMed]
10. Quénet F, Elias D, Roca L, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:256-66. [Crossref] [PubMed]
11. Kong JC, Flood MP, Guerra GR, et al. Appendiceal pseudomyxoma peritonei: predictors of recurrence and iterative surgery. Colorectal Dis 2021;23:2368-75. [Crossref] [PubMed]
12. Wong JSM, Tan GHC, Cheok SHX, et al. Implications of peritoneal cancer index distribution on patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Pleura Peritoneum 2022;7:95-102. [Crossref] [PubMed]
13. Guerra-Londono CE, Owusu-Agyemang P, Corrales G, et al. Risk of Intraoperative Hyperthermia and Outcomes in Adults Undergoing Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC). Ann Surg Oncol 2022;29:2089-99. [Crossref] [PubMed]