Special Review I Redefining the Treatment Paradigm for Peritoneal Metastases: The Clinical Value and Recent Advances of CRS + HIPEC

Peritoneal carcinomatosis has long been regarded as a hallmark of advanced progression in various solid tumors. Due to the widespread dissemination of tumor cells across the peritoneum, omentum, mesentery, and pelvic cavity, patients often present with ascites, bowel obstruction, and malnutrition. Traditional treatment has predominantly relied on palliative chemotherapy and supportive care, with overall prognosis remaining poor.

In recent years, advances in the biological understanding of peritoneal tumors, the maturation of cytoreductive surgical techniques, and the evolution of regional chemotherapy concepts have driven a paradigm shift in the management of peritoneal carcinomatosis. The comprehensive treatment model represented by cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has transitioned select patients from purely palliative care toward a more proactive, multimodality management approach.

The core value of CRS+HIPEC lies in the maximal macroscopic tumor removal through surgery, followed by the localized control of residual microscopic disease and free tumor cells using hyperthermia, regional chemotherapy, and intraperitoneal perfusion. It is not a single device or a standalone procedure, but rather a systematic therapeutic framework built upon patient selection, surgical cytoreduction, hyperthermic perfusion, and comprehensive postoperative management.

I. Why Is Peritoneal Carcinomatosis Difficult to Treat?

Peritoneal metastasis is not simply a form of 'distant metastasis.' Given the large volume and extensive surface area of the peritoneal cavity, once tumor cells enter the abdomen, they tend to implant at multiple sites on the peritoneal surface, forming diffuse lesions.

Compared with solid organ metastases such as those to the liver or lungs, peritoneal carcinomatosis often presents with three distinctive features:

First, lesions are scattered.
Tumor deposits can be distributed across multiple regions, including the peritoneum, omentum, small bowel mesentery, and pelvic cavity, making surgical clearance highly challenging.

Second, imaging detection is difficult.
Some small lesions, miliary nodules, or early peritoneal implants are not easily identifiable on imaging studies.

Third, there is a strong need for locoregional treatment.
Systemic chemotherapy alone has limited drug exposure to peritoneal surface lesions, thus requiring regional therapeutic strategies to complement it.

For these reasons, the treatment paradigm for peritoneal carcinomatosis is gradually shifting from 'systemic therapy alone' toward a comprehensive model that integrates systemic therapy, locoregional treatment, and precision cytoreductive surgery.

II. What Is the Treatment Rationale Behind CRS+HIPEC?

CRS+HIPEC typically consists of two core components.

CRS, or cytoreductive surgery, aims to remove all macroscopically visible tumor deposits within the peritoneal cavity to the greatest extent possible, including peritoneal surface lesions, involved omentum, locally affected organs, and associated adhesive tissues. The key to CRS is not merely 'resection,' but rather achieving a status of no macroscopic residual disease or only minimal residual disease.

HIPEC, or hyperthermic intraperitoneal chemotherapy, involves circulating heated chemotherapeutic agents within the peritoneal cavity immediately following CRS, allowing the drugs—potentiated by hyperthermia—to act directly on the peritoneal surface, microscopic residual disease, and free-floating tumor cells.

In simpler terms, CRS addresses the 'visible' lesions, while HIPEC targets the 'potentially residual' microscopic disease and free cancer cells.

The advantages of HIPEC derive primarily from three aspects: first, it achieves high local drug concentrations that directly target intraperitoneal disease; second, systemic toxicity is relatively manageable; and third, hyperthermia itself can enhance the cytotoxic effects of certain chemotherapeutic agents while improving local tissue penetration.

Therefore, the clinical value of CRS+HIPEC lies not merely in the 'hyperthermic perfusion' itself, but rather in its integration of surgical cytoreduction, locoregional highdose chemotherapy, and comprehensive perioperative management into a unified treatment strategy.

III. Which Patients Are More Suitable for CRS+HIPEC?

CRS+HIPEC is not applicable to all patients with peritoneal carcinomatosis. Its efficacy is highly dependent on patient selection, with particular attention to two core indicators: the PCI score and the CC score.

PCI, i.e., the Peritoneal Cancer Index, divides the abdominal cavity into 13 regions and scores each region based on the size of tumor lesions, with a total score ranging from 0 to 39. A higher PCI score generally indicates a greater intraperitoneal tumor burden, increased surgical complexity, and a lower likelihood of achieving complete cytoreduction.

CC, i.e., the Completeness of Cytoreduction score, is used to evaluate the extent of residual disease after CRS. Generally, CC0 indicates no macroscopic residual disease, and CC1 indicates only minimal residual disease—both of which are considered favorable cytoreductive outcomes. CC2–3, on the other hand, suggests more significant residual disease, with potentially diminished treatment benefit.

Therefore, the key prerequisite for CRS+HIPEC is that, following multidisciplinary evaluation, the patient is considered to have a reasonable chance of achieving optimal cytoreduction and is medically fit to tolerate the treatment.

IV. Progress in Application Across Different Tumor Types

Peritoneal carcinomatosis is not a single disease entity. The biological behavior, metastatic patterns, and treatment sensitivity vary across different primary tumors, so the applicability of CRS+HIPEC must be understood on a tumor-type basis.

Peritoneal Metastasis from Appendiceal Cancer

Appendiceal tumors, particularly mucinous neoplasms, often present primarily with peritoneal dissemination. For lowgrade appendiceal mucinous neoplasms with peritoneal involvement, CRS+HIPEC represents one of the important treatment modalities. If optimal cytoreduction can be achieved, patients may experience substantial survival benefits. For high-grade pathological subtypes, systemic therapy is typically required as part of a comprehensive management approach.

Peritoneal Metastasis from Colorectal Cancer

Colorectal cancer is one of the major sources of peritoneal metastases. Studies have shown that select patients with a lower tumor burden and those in whom complete cytoreduction is achievable may benefit from CRS+HIPEC. However, it is also noted that complete cytoreduction serves as the foundation for benefit in colorectal peritoneal metastases, and the optimization of HIPEC—including drug selection, perfusion duration, and treatment protocol—remains an area requiring further refinement.

Peritoneal Metastasis from Ovarian Cancer

Ovarian cancer has a pronounced propensity for intraperitoneal dissemination, with many patients already presenting with peritoneal involvement at initial diagnosis. Interval cytoreductive surgery following neoadjuvant chemotherapy combined with cisplatin-based HIPEC has emerged as an important treatment paradigm in recent years. With the development of maintenance strategies such as PARP inhibitors, HIPEC is increasingly being discussed within the comprehensive treatment framework for advanced ovarian cancer.

Malignant Peritoneal Mesothelioma

Malignant peritoneal mesothelioma is relatively rare, but because the disease primarily involves the peritoneal surface, locoregional therapy is strongly justified. For patients with epithelioid subtype, low PCI, good performance status, and in whom optimal cytoreduction can be achieved, CRS+HIPEC can provide clear survival benefits.

Peritoneal Metastasis from Gastric Cancer

Peritoneal metastasis from gastric cancer is highly aggressive, with a high risk of systemic progression, making it particularly challenging to treat. Therefore, CRS+HIPEC is used with a strong emphasis on high selectivity in gastric cancer. Typically, patients with low PCI, sensitivity to systemic therapy, no extensive distant metastases, and in whom CC0/1 cytoreduction is achievable are considered suitable candidates. Emerging approaches, such as laparoscopic neoadjuvant HIPEC and bidirectional intraperitonealsystemic chemotherapy, are also under active investigation.

V. Key Technical Aspects of HIPEC Therapy

The standardized delivery of HIPEC is critical to both treatment efficacy and safety.

First, temperature control. HIPEC must be performed within a specific therapeutic temperature window—sufficient to achieve hyperthermic sensitization and cytotoxicity, while avoiding tissue damage from excessive temperatures.

Second, perfusion stability. During the procedure, it is essential to maintain stable circulation of the perfusate, uniform temperature distribution, and consistent flow rate, ensuring adequate exposure across all regions of the peritoneal cavity.

Third, drug selection and perfusion duration. Perfusion protocols vary by tumor type and chemotherapeutic agents. Clinical decisions should be guided by current guidelines, available evidence, and individual patient conditions.

Fourth, perioperative safety management. CRS+HIPEC is a complex treatment that requires close collaboration among surgical, anesthesia, medical oncology, nursing, and technical support teams. Renal function, coagulation status, infection risk, nutritional status, and postoperative recovery all require meticulous management.

This underscores that HIPEC is not simply 'heated drug infusion,' but rather a comprehensive therapeutic technology that is highly dependent on standardized protocols, equipment reliability, and team expertise.

VI. Future Trends: From a Single Treatment Episode to Comprehensive Disease Management

The evolution of CRS+HIPEC is moving beyond a 'single regional treatment modality' toward a more holistic approach—comprehensive management of peritoneal tumors.

In the future, patient selection will become more precise. PCI scoring, imaging assessment, laparoscopic exploration, pathological subtyping, and molecular testing will collectively aid clinicians in identifying patients most likely to benefit from the treatment.

The therapeutic approach will also become increasingly integrated. CRS+HIPEC will be combined with systemic chemotherapy, targeted therapy, immunotherapy, PARP inhibitor maintenance therapy, and other strategies to form a more complete treatment pathway.

In addition, emerging technologies such as organoid-based drug sensitivity screening, liquid biopsy, and circulating tumor cell (CTC) detection may help clinicians detect recurrence risk earlier and optimize individualized treatment regimens.

However, regardless of how the technology advances, standardization remains at the core. The broader adoption of CRS+HIPEC relies not only on equipment, but also on center accreditation, team training, process management, and quality control.

Reference:

[1] Foster JM, Zhang C, Rehman S, Sharma P, Alexander HR. The contemporary management of peritoneal metastasis: A journey from the cold past of treatment futility to a warm present and a bright future. CA: A Cancer Journal for Clinicians. 2023;73(1):49–71. doi:10.3322/caac.21749.

Disclaimer:

This article is intended for academic exchange and knowledge sharing purposes. The content is primarily organized based on the abovecited review article. The accompanying illustrations are provided for supplementary understanding only and should not be construed as specific diagnostic or therapeutic recommendations. All treatment decisions should be made by clinicians based on individual patient conditions in conjunction with clinical judgment.