Cytoreduction (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

Anatomy and Physiology

Peritoneal Cavity 

The peritoneum is a serous membrane lining the abdominal cavity, composed of an outer connective tissue layer and an inner layer of mesothelial cells. These mesothelial cells provide the primary surface for tumor cell adhesion during the development of peritoneal metastases. The peritoneum is divided into the parietal peritoneum, which covers the abdominopelvic wall and diaphragm, and the visceral peritoneum, which envelops the intra-abdominal organs. The peritoneal cavity typically contains a small volume of fluid (10–100 mL) enriched with nutrients, signaling molecules, and immune cells that interact with the bloodstream. Diaphragmatic motion propels this fluid upward, while stomata in the diaphragmatic peritoneum connect to lymphatic vessels, facilitating the clearance of debris, bacteria, and cells into systemic circulation (see Image. Pathways of Peritoneal Fluid Movement).[10]

Pathophysiology of Peritoneal Malignancies 

Peritoneal malignancy develops through a sequential process that includes cancer cell detachment, dissemination within the peritoneal cavity, adhesion to mesothelial surfaces, and invasion of the submesothelial stroma. Increased tumor stiffness and elevated interstitial fluid pressure facilitate the release of cancer cells by disrupting cell–cell junctions and inducing epithelial-to-mesenchymal transition, thereby increasing cell motility and resistance to anoikis (detachment-induced cell death). Tumor rupture, surgical manipulation, or leakage of bile and blood may also introduce malignant cells into the peritoneal space. Certain tumor types, particularly right-sided or mucinous colorectal cancers, exhibit a greater tendency for peritoneal dissemination, likely due to stromal-rich molecular features.[11]

After entering the peritoneal cavity, tumor cells, frequently organized as multicellular clusters, are transported by peritoneal fluid flow, diaphragmatic movement, and gravity to preferred implantation sites, including the pelvis, paracolic gutters, and subdiaphragmatic regions. The omentum is a common site of implantation because its immune-rich structures, known as milky spots or fat-associated lymphoid clusters, provide a supportive environment through inflammatory and angiogenic signaling.[11][12] Free-floating cancer cells attach to mesothelial cells and extracellular matrix components through adhesion molecules. This process is amplified by inflammation, surgical trauma, or increased intraperitoneal pressure.

Neutrophil extracellular traps and fibrin deposition further promote tumor cell binding and survival on the peritoneal surface.[12][13] Following attachment, cancer cells penetrate the mesothelial layer by secreting proteolytic enzymes, including matrix metalloproteinases, and by inducing apoptosis in mesothelial cells. Within the submesothelial stroma, these cells remodel the local microenvironment into a tumor-promoting niche that facilitates cancer cell proliferation, angiogenesis, and immune evasion.[12][13]

Mechanism of Action of CRS-HIPEC

CRS-HIPEC constitutes a 2-step approach for treating peritoneal malignancies. The initial step, cytoreduction, involves surgical removal of all visible tumor deposits. Subsequently, HIPEC targets residual microscopic disease by circulating heated chemotherapy within the peritoneal cavity.[14][15]

During HIPEC, the peritoneal cavity is perfused with chemotherapy heated to 40 °C to 43 °C for 60 to 90 minutes, combining pharmacologic and thermal effects to enhance tumor cell destruction. The peritoneal–plasma barrier enables high local drug concentrations, resulting in prolonged exposure of residual tumor cells while minimizing systemic toxicity. Hyperthermia increases chemotherapy efficacy by enhancing tumor cell membrane permeability and drug penetration. Also, it potentiates the activity of agents such as platinum compounds and alkylating agents by promoting DNA adduct formation and transiently inhibiting DNA repair mechanisms, including BRCA2-mediated pathways. In addition to direct cytotoxic effects, hyperthermia induces the expression of heat shock proteins, which stimulate antitumor immune responses, particularly by activating natural killer cells.[16][15]

Indications

CRS-HIPEC constitutes an aggressive locoregional treatment for peritoneal surface malignancies. Appropriate patient selection involves thorough assessment of tumor histology, disease extent as measured by the peritoneal cancer index, and the probability of achieving complete cytoreduction.[17] The efficacy of CRS-HIPEC depends on the removal of all macroscopic disease, as intraperitoneal chemotherapy penetrates only 2 to 3 mm into tissue and is ineffective against larger tumor deposits. Completeness of cytoreduction (CC) scoring determines resection adequacy: CC-0 indicates no visible residual disease; CC-1 indicates residual nodules of 2.5 mm or less; CC-2 (2.5 mm to 2.5 cm) and CC-3 (>2.5 cm) are associated with poorer outcomes and generally preclude HIPEC.[18]

Ovarian Cancer

HIPEC has demonstrated survival benefit specifically in patients with stage III epithelial ovarian cancer undergoing interval cytoreductive surgery following neoadjuvant chemotherapy.[17][19] The landmark OVHIPEC-1 trial randomized 245 patients to interval CRS with or without HIPEC using cisplatin and demonstrated improved recurrence-free survival (14.2 vs 10.7 months) and overall survival (45.7 vs 33.9 months) in the HIPEC arm, with no significant differences in adverse event rates.[20] These findings apply exclusively to patients achieving complete or optimal cytoreduction during interval surgery. Current evidence does not support HIPEC administration during primary debulking surgery, as the ongoing OVHIPEC-2 trial is evaluating this setting. Similarly, HIPEC for platinum-sensitive recurrent ovarian cancer lacks definitive evidence outside clinical trial protocols.[21]

Colorectal Cancer with Peritoneal Metastases

The role of HIPEC in colorectal peritoneal metastases remains controversial following publication of the PRODIGE 7 trial, which randomized 265 patients with colorectal peritoneal metastases to CRS alone versus CRS-HIPEC using oxaliplatin. The trial showed no difference in overall survival (41.7 vs 41.2 months) between the arms, while the HIPEC group had higher 60-day morbidity.[22] These results challenged the previously accepted role of HIPEC established by earlier studies and prompted reevaluation of treatment paradigms.

Current practice increasingly favors CRS combined with perioperative systemic chemotherapy rather than HIPEC for established colorectal peritoneal metastases. However, the HIPECT4 trial identified a potential prophylactic role, demonstrating that HIPEC added to CRS in patients with locally advanced T4 colon cancer at high risk for peritoneal recurrence reduced locoregional recurrence rates compared to surgery alone.[23] This prophylactic indication is an evolving area in which HIPEC may provide benefit by preventing, rather than treating, peritoneal metastases.[23] Patient selection for CRS, regardless of HIPEC administration, requires a limited peritoneal disease burden (generally a peritoneal cancer index <20), absence of extensive small-bowel involvement, and evidence of chemosensitivity, as demonstrated by stable or responding disease on systemic therapy.[24]

Gastric Cancer

Evidence supporting CRS-HIPEC for gastric cancer with peritoneal metastases remains limited, and indications are restricted to highly selected patients. Gastric peritoneal carcinomatosis historically carries a poor prognosis, with a median survival of 3 to 6 months with systemic therapy alone. CRS-HIPEC may be considered for patients with low-volume peritoneal disease (peritoneal cancer index ≤10), absence of distant metastases, and disease stability or response following at least 3 months of systemic chemotherapy.[17][25] Complete cytoreduction is paramount, as incomplete resection offers no survival advantage over systemic therapy alone.

The National Comprehensive Cancer Network recommends a multidisciplinary discussion before proceeding with CRS-HIPEC, emphasizing that treatment should be performed at high-volume centers with expertise in peritoneal surface malignancies. Prophylactic HIPEC following gastrectomy for serosa-positive gastric cancer has been evaluated in Asian populations with mixed results and is not standard practice in Western centers. Given the limited evidence base, enrollment in clinical trials is encouraged whenever possible.[25]

Appendiceal Neoplasms and Pseudomyxoma Peritonei

CRS-HIPEC represents the standard treatment for appendiceal mucinous neoplasms with peritoneal dissemination, including pseudomyxoma peritonei. Optimal candidates include patients with low-grade histology (low-grade appendiceal mucinous neoplasm or well-differentiated mucinous adenocarcinoma), absence of signet ring cell features, limited disease burden (peritoneal cancer index ≤21), and adequate performance status.[26] The Peritoneal Surface Oncology Group International consensus established histologic grade as the most important prognostic factor, with low-grade tumors achieving 10-year survival rates exceeding 70% following complete CRS-HIPEC. High-grade tumors, particularly those with signet ring cell differentiation, carry a significantly worse prognosis regardless of treatment approach.

Mitomycin C-based HIPEC regimens are most commonly employed for appendiceal neoplasms.[27] Repeat CRS-HIPEC may be considered for recurrent disease in carefully selected patients, particularly those with low-grade histology, prolonged disease-free interval following initial surgery, and limited peritoneal disease burden at recurrence. For high-grade recurrences, the interval since prior surgery and extent of recurrent disease should be carefully evaluated, with shorter intervals and extensive disease generally precluding repeat cytoreduction.[27][28]

Peritoneal Mesothelioma

CRS-HIPEC represents the preferred treatment for medically operable individuals with epithelioid peritoneal mesothelioma and unicavitary disease confined to the peritoneal cavity. Epithelioid histology is associated with significantly better outcomes compared to sarcomatoid or biphasic subtypes, with 5-year survival rates of 50% to 60% achievable at experienced centers. Optimal candidates have a peritoneal cancer index of less than 17, adequate performance status, and no pleural or extraperitoneal involvement. Cisplatin-based HIPEC regimens are most commonly employed, including cisplatin combined with doxorubicin, cisplatin alone, carboplatin, or cisplatin with mitomycin C.

The combination of CRS, HIPEC, and early postoperative intraperitoneal chemotherapy (EPIC) has been utilized at some centers, though comparative data are limited. CRS-HIPEC is not recommended as initial therapy for patients with sarcomatoid or biphasic histology, given poor outcomes; these patients should be treated with systemic therapy, with surgery considered only in highly selected cases demonstrating exceptional response. Bicavitary disease involving both pleural and peritoneal surfaces generally precludes curative-intent surgery, though sequential cytoreduction has been reported in isolated cases.[29]

Contraindications

Contraindications for CRS-HIPEC include inability to achieve complete cytoreduction, presence of extra-abdominal metastases, poor performance status, significant comorbidities, unresectable disease, elevated peritoneal cancer index, and high-risk histological features. Increased morbidity is associated with advanced age, frailty, poor nutritional status, hypoalbuminemia, and an American Society of Anesthesiologists score of 3 or higher.[30][31] Invasion of critical surgical sites such as the root of the mesentery, porta hepatis, and retroperitoneal structures also contraindicates CRS-HIPEC.

Impaired small bowel function with risk of short bowel syndrome is similarly a contraindication. These criteria are applicable across tumor types and are essential for appropriate patient selection.[32] Approximately one-quarter of patients undergoing exploratory surgery are ultimately found unsuitable for CRS-HIPEC, most commonly due to more extensive peritoneal disease than preoperative imaging suggested.[31]

Equipment

Prior to initiating this procedure in a hospital setting, it is essential to establish a chemotherapy approval system supported by surgical facilities and integrated with a medical-surgical resuscitation unit for patient monitoring. HIPEC may be performed using either an open or a closed l technique. In both approaches, the abdominal cavity is continuously perfused with a cytostatic solution heated to 40 °C  to 43 °C via a drainage system with inlet and outlet catheters. Various pieces of equipment are required to perform this procedure.[15][33][34] This includes:

• A heat exchanger connected to a thermostat maintains a stable temperature of 40 °C  to 43 °C  in the inflow and outflow catheters to facilitate the infusion and distribution of the cytotoxic agent within the abdominal cavity.
• Temperature probes for monitoring temperatures within both the extracorporeal circuit and the peritoneal cavity.
• A roller pump to sustain the extracorporeal circulation of the cytotoxic agent.
• A reservoir for the cytotoxic agent.
• A computer system to regulate the heat exchanger and drainage pumps based on feedback from thermal probes.
• A timer to monitor the duration of infusion.
• Cytotoxic drugs for intra-abdominal chemotherapy, with mitomycin C, cisplatin, oxaliplatin, and paclitaxel being the most commonly used. 
• The chemotherapeutic agent is administered with a carrier solution, typically 0.9% sodium chloride or 5% glucose. The volume of the carrier solution is determined according to the patient's body surface area, with typical infusion volumes ranging from 1.5 to 2 liters per square meter.

Personnel

CRS-HIPEC necessitates a multidisciplinary team comprising specialized surgical oncologists, anesthesiologists with expertise in complex oncologic procedures, perfusionists or trained surgical staff to operate the HIPEC delivery system, and intensive care specialists for postoperative management.[6] Surgeons with specialized training in cytoreductive techniques and peritonectomy procedures are essential. These operations frequently involve multivisceral resections and extensive peritoneal stripping, which require expertise beyond standard oncologic surgery. Due to the complexity and duration of these procedures, participation of multiple surgeons is often necessary.[35][36]

Anesthesiologists experienced in prolonged, complex oncologic procedures are required, as patients may undergo extended operations involving significant fluid shifts, challenges in temperature management during the hyperthermic phase, and the potential for substantial blood loss necessitating transfusion.[37] A perfusionist or specially trained surgical personnel is required to operate the HIPEC perfusion device, which functions similarly to a heart bypass system. This individual manages the circulation of heated chemotherapy solution through the abdominal cavity, maintaining temperatures between 40 °C and 43 °C during the 30- to 120-minute perfusion period.

The perfusion team is responsible for monitoring inflow and outflow catheters and ensuring adequate heating of the peritoneal surface.[36] Intensive care specialists and nursing staff with experience in managing postoperative complications from major oncologic surgery are essential, given the reported morbidity rates of 23% to 44% and the potential for serious complications such as fistulas, abscesses, bowel perforation, and renal failure. Specialized intensive care unit management is particularly important during the first 30 to 60 days postoperatively, when most major complications are likely to occur.[36]

Preparation

Patient Selection and Multidisciplinary Evaluation

A multidisciplinary tumor board should determine candidacy for CRS-HIPEC to ensure that decisions incorporate input from all relevant specialties.[34]

Prehabilitation and Optimization

Prehabilitation should commence once surgery is planned and continue throughout the recovery period. This approach enhances functional capacity and postoperative outcomes.[38][39] Key modifiable factors to optimize:

• Nutrition
  • Poor nutritional status is associated with worse HIPEC outcomes; nutritional status should be optimized preoperatively.
• Physical fitness
  • Preoperative exercise programs can improve patient performance status.
• Psychological health
  • Counseling and mental health support services facilitate improved coping mechanisms.
• Smoking
  • Active smoking should be identified and addressed before surgery.

Prehabilitation is particularly important given the significant nutritional, physical, and psychological burdens associated with advanced peritoneal disease.

Laboratory and Organ Function Assessment 

Baseline laboratory assessment should be performed within 1 week before surgery and should include a complete blood count and evaluation of renal and hepatic function. Careful assessment of renal function is particularly important because HIPEC often involves high-dose cisplatin administration. Contraindications to proceeding include a creatinine clearance below 30 mL/min or a serum creatinine greater than 1 mg/dL.

Additional caution is warranted in patients with diabetes, preexisting neuropathy, hearing loss, or advanced age due to increased susceptibility to cisplatin toxicity. Perioperative exposure to nephrotoxic agents, including contrast media and nonsteroidal anti-inflammatory drugs, should be minimized. Prophylactic administration of sodium thiosulfate is recommended to mitigate the risk of cisplatin-induced nephrotoxicity.[40]

Institutional and Procedural Preparation 

CRS-HIPEC should be performed at high-volume centers with experienced, multidisciplinary teams, as delivering intraperitoneal chemotherapy requires close coordination among surgical, anesthesia, nursing, and pharmacy personnel. While many high-volume institutions have developed formalized preoperative and perioperative pathways, there remains variability in practice patterns internationally. Key perioperative considerations include routine antiemetic prophylaxis and goal-directed fluid therapy to maintain hemodynamic stability and adequate tissue perfusion.

Advanced hemodynamic monitoring is recommended during the procedure, given the significant physiologic shifts associated with CRS-HIPEC. Multimodal analgesia strategies should be employed, often incorporating thoracic epidural analgesia when appropriate. Implementation of standardized, evidence-based perioperative care pathways, including enhanced recovery protocols, has been shown to improve outcomes, particularly in high-risk or complex cases.[40][41]

Technique or Treatment

CRS

CRS is an extensive operative procedure designed to remove all visible peritoneal tumor burden, with HIPEC administered subsequently to eradicate microscopic residual disease. The fundamental principle underlying treatment efficacy is achieving complete or near-complete macroscopic tumor removal, as intraperitoneal chemotherapy penetrates only 2 to 3 mm into tissue and cannot effectively treat larger deposits. Optimal cytoreduction leaves no gross residual disease or only nodules measuring 2.5 mm or less.[29][42]

Peritoneal Cancer Index Assessment

The peritoneal cancer index provides a standardized method for quantifying peritoneal tumor burden and guides both preoperative planning and intraoperative decision-making (see Image. Peritoneal Cancer Index). The abdominopelvic cavity is divided into 13 regions: 9 abdominopelvic regions (numbered 0–8) and 4 small bowel regions (numbered 9–12). Each region receives a lesion size score from 0 to 3, where 0 indicates no visible tumor, 1 denotes tumor deposits up to 0.5 cm, 2 indicates deposits between 0.5 and 5 cm, and 3 represents deposits exceeding 5 cm or confluent disease.

The sum of all regional scores yields a total peritoneal cancer index ranging from 0 to 39. A higher peritoneal cancer index is associated with a lower likelihood of achieving complete cytoreduction and a worse overall prognosis across tumor types. Peritoneal cancer index thresholds for surgical candidacy vary by histology, with appendiceal neoplasms tolerating higher scores (peritoneal cancer index [PCI] ≤20–21) than colorectal (PCI ≤15–20) or gastric malignancies (PCI ≤10).[25][29][42][43]

Peritonectomy Procedures

The surgical approach employs systematic peritonectomy tailored to tumor distribution, as initially described by Sugarbaker. Six distinct peritonectomy regions are addressed sequentially based on disease involvement. Anterior parietal peritonectomy involves resection of the peritoneum from the anterior abdominal wall, including the umbilicus and any prior surgical scars that may harbor tumor deposits. Electrosurgical dissection facilitates the separation of the peritoneum from the underlying musculature while maintaining hemostasis. The falciform ligament and round ligament are excised en bloc with the surrounding peritoneum.

Right upper quadrant peritonectomy addresses disease on the right hemidiaphragm, liver capsule, and hepatoduodenal ligament. Right subphrenic peritonectomy requires mobilization of the right hepatic lobe and careful dissection along the diaphragmatic surface, preserving the phrenic veins and avoiding diaphragmatic perforation. Glisson capsule resection may be necessary for tumor implants on the liver surface, performed using ball-tip electrocautery to strip the involved capsule while preserving the underlying parenchyma. Cholecystectomy is routinely performed to facilitate access and remove a common site of occult disease.

Left upper quadrant peritonectomy addresses the left hemidiaphragm, splenic hilum, and greater curvature of the stomach. Splenectomy is frequently required when the tumor involves the splenic hilum or capsule, and is performed en bloc with greater omentectomy. The greater omentum is resected from the transverse colon and the gastric greater curvature, ligating the gastroepiploic vessels. Careful attention to the short gastric vessels and splenic flexure of the colon is essential to avoid iatrogenic injury.

Pelvic peritonectomy addresses tumors within the pelvis, including disease on the bladder peritoneum, cul-de-sac, and pelvic sidewalls. In women, total hysterectomy with bilateral salpingo-oophorectomy is commonly performed, with en bloc resection of the rectosigmoid when involved. Careful dissection along the pelvic sidewalls identifies and preserves the ureters while removing the involved peritoneum.

The presacral space may require dissection in cases of posterior cul-de-sac disease. Lesser omentectomy removes the gastrohepatic ligament and provides access to the lesser sac, which frequently harbors tumor deposits. Complete lesser sac peritonectomy may require stripping of the peritoneum from the posterior stomach, pancreatic capsule, and transverse mesocolon.[44][45]

Visceral Resections

Visceral resections are performed based on tumor involvement and follow oncologic principles. Omentectomy (greater and lesser) is performed in nearly all cases, as the omentum serves as a preferential site for peritoneal metastases. Bowel resections are performed for tumors involving the intestinal serosa, mesentery, or bowel wall, with primary anastomosis or stoma creation depending on the extent of resection, nutritional status, and anastomotic reliability. Multiple bowel resections may be necessary, though preservation of intestinal length is prioritized to avoid short bowel syndrome. Small bowel involvement, pervasive serosal disease, or mesenteric retraction represents a relative contraindication to cytoreduction, given the difficulty of achieving complete resection while maintaining adequate intestinal function.

Additional visceral resections may include appendectomy (routine in most cases), partial hepatectomy for parenchymal invasion, distal pancreatectomy for tail involvement, partial gastrectomy for serosal or transmural disease, and segmental ureterectomy with reconstruction for ureteral involvement. The decision to proceed with extensive visceral resections requires careful consideration of the likelihood of achieving complete cytoreduction, balanced against operative morbidity and functional outcomes.[44][46]

Technical Considerations

Electrosurgical technique is fundamental to cytoreductive surgery, with ball-tip electrocautery used extensively for peritoneal stripping. High-voltage cutting current facilitates tissue separation while coagulation current achieves hemostasis. Argon beam coagulation provides superficial tissue destruction in areas of minimal residual disease and aids hemostasis on raw peritonectomy surfaces. Careful attention to tissue planes minimizes blood loss and facilitates identification of residual tumor deposits.

Systematic exploration of all abdominopelvic regions ensures comprehensive tumor assessment. Adhesiolysis is performed to expose all peritoneal surfaces, and inspection includes the diaphragmatic surfaces, paracolic gutters, small bowel mesentery, pelvis, and omental bursa. Palpation of the small bowel from the ligament of Treitz to the ileocecal valve identifies serosal implants that may not be visually apparent.[44][45][47]

Completeness of Cytoreduction Scoring

The CC score quantifies residual disease following surgical resection and represents the strongest independent prognostic factor across all peritoneal surface malignancies. CC-0 indicates no visible residual disease, while CC-1 denotes residual nodules measuring 2.5 mm or less, both considered optimal outcomes amenable to HIPEC efficacy. CC-2 describes residual nodules between 2.5 mm and 2.5 cm, and CC-3 indicates nodules exceeding 2.5 cm; neither score is associated with a meaningful survival benefit from HIPEC administration. Achieving CC-0 or CC-1 cytoreduction should be the operative goal, and cases where complete cytoreduction appears unattainable may warrant abandonment of the procedure or conversion to palliative resection, depending on clinical circumstances.[29][42]

HIPEC Administration

HIPEC can be delivered using open (coliseum) or closed techniques, both of which demonstrate acceptable safety and efficacy when properly executed. Technique selection depends on institutional experience, surgeon preference, and patient factors. The open coliseum technique elevates the skin edges using a self-retaining retractor system to create an exposed abdominal cavity resembling a coliseum. Heated perfusate maintained at 40 °C to 43 °C circulates through the peritoneal cavity via a pump system that delivers 3 to 4 liters of chemotherapy solution through strategically placed inflow and outflow catheters.

Temperature probes monitor perfusate and tissue temperatures to ensure therapeutic hyperthermia. The primary advantage of the open technique is the ability to perform manual stirring throughout perfusion, promoting uniform distribution of chemotherapy across all peritoneal surfaces and preventing pooling in dependent areas. Disadvantages include greater heat loss, which requires higher inflow temperatures, and potential exposure of operating room personnel to aerosolized cytotoxic agents, necessitating appropriate protective equipment and ventilation.[15]

The closed technique involves placement of inflow and outflow catheters along with temperature probes, followed by temporary skin closure to create a sealed perfusion circuit. This approach minimizes heat loss, allowing more consistent maintenance of target temperatures, and substantially reduces operating room staff exposure to chemotherapy. Newer systems incorporating carbon dioxide recirculation have been developed to improve perfusate distribution within the closed abdomen. The primary disadvantage is the inability to perform manual manipulation during perfusion, which may limit the uniform distribution of chemotherapy throughout the peritoneal cavity, particularly in areas with adhesions or complex anatomy.[15][48]

Complications

CRS-HIPEC carries substantial perioperative risk, with contemporary series reporting major morbidity rates of 19% to 44% and mortality rates of 0% to 2.3%. The most frequent complications involve the gastrointestinal, infectious, renal, and hematologic systems. Serious (grade ≥3) complications occur in 9% to 40% of patients, with 32% to 42% experiencing severe events within 30 days.[22][49][50][51]

Gastrointestinal 

• Digestive fistulas: 7% to 11%, among the most severe complications
• Anastomotic leaks: 5% to 10.5%
• Abscesses: 3%to 5%
• Bowel perforation and ileus
• Surgical site infections: ~7%
• Broader infectious complications include wound infections, sepsis, pneumonia, central line infections, and intra-abdominal abscesses

Renal

Particularly associated with cisplatin-based HIPEC:

• Elevated creatinine: ~15% (median onset 5 days postop)
• Renal insufficiency/failure requiring intervention
• Age 58 and older is an independent risk factor

Hematologic

These are more common with HIPEC, especially oxaliplatin-based regimens.

Other Major Complications

• Hemorrhage requiring transfusion 
• Venous thromboembolism
• Myocardial infarction
• Pleural effusion, pneumothorax
• Pulmonary complications
• Wound dehiscence

Clinical Significance

Peritoneal surface malignancies historically carried a dismal prognosis, with median survival measured in months when treated with systemic chemotherapy alone. The development of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy fundamentally transformed the treatment paradigm for selected patients with peritoneal carcinomatosis, converting a previously terminal diagnosis into a potentially curable condition. This aggressive locoregional approach exploits the pharmacokinetic advantage of intraperitoneal drug delivery, achieving peritoneal drug concentrations 20 to 1000 times higher than plasma levels while minimizing systemic toxicity. Hyperthermia enhances chemotherapy cytotoxicity by increasing cellular drug uptake, impairing DNA repair mechanisms, and directly injuring tumor cells. The combination of complete macroscopic tumor removal with high-dose regional chemotherapy addresses both visible disease and microscopic residual tumor deposits that would otherwise serve as sources of recurrence.[15]

The clinical impact of CRS-HIPEC varies substantially by tumor histology, with the most significant benefit observed in appendiceal neoplasms and pseudomyxoma peritonei. Patients with low-grade appendiceal mucinous neoplasms treated with complete cytoreduction and HIPEC achieve 10-year survival rates of 70% to 80%, representing a dramatic improvement over historical outcomes with debulking surgery alone.[52] Peritoneal mesothelioma, previously uniformly fatal, demonstrates 5-year survival rates of 50% to 60% following CRS-HIPEC in patients with epithelioid histology and limited disease burden.[53]

Women with ovarian cancer undergoing interval CRS-HIPEC following neoadjuvant chemotherapy experience improved recurrence-free and overall survival compared to surgery alone, as demonstrated in the OVHIPEC-1 trial.[20] The role of colorectal peritoneal metastases remains more controversial following the PRODIGE 7 trial. However, CRS with perioperative systemic therapy continues to offer survival benefits over systemic chemotherapy alone in selected patients.[22]

Patient selection represents the most critical determinant of outcomes, as the substantial morbidity associated with CRS-HIPEC is justified only when complete cytoreduction is achievable and durable disease control is anticipated. The completeness of cytoreduction consistently emerges as the strongest prognostic factor across all tumor types, with incomplete resection conferring no survival advantage over palliative approaches while exposing patients to significant surgical risk. Tumor histology, peritoneal cancer index, and response to preoperative systemic therapy further stratify outcomes and guide treatment decisions. Centralization of care at high-volume centers with multidisciplinary expertise has improved outcomes through refined patient selection, surgical technique, and perioperative management. The learning curve for CRS-HIPEC is substantial, with institutional experience correlating directly with morbidity, mortality, and oncologic outcomes.[41]

The morbidity profile of CRS-HIPEC reflects the extensive nature of the procedure, with major complication rates of 30% to 50% reported across large series. Common complications include anastomotic leak, intra-abdominal abscess, wound infection, venous thromboembolism, and prolonged ileus. Perioperative mortality ranges from 1% to 5% at experienced centers, with higher rates observed during institutional learning curves and in patients with extensive disease requiring multiple visceral resections.[50] The physiologic stress of prolonged surgery, large-volume fluid shifts, and chemotherapy exposure necessitates careful patient selection based on performance status, nutritional parameters, and comorbid conditions. Despite this morbidity, quality-of-life studies demonstrate a return to baseline function in most patients within 6 to 12 months, with long-term survivors reporting satisfactory quality of life comparable to that of the general population.[54]

The integration of CRS-HIPEC into the broader oncologic treatment algorithm requires coordination with systemic therapy, with sequencing dependent on tumor type and clinical circumstances. Neoadjuvant chemotherapy serves multiple purposes: assessing tumor biology through treatment response, controlling micrometastatic disease, and potentially reducing peritoneal tumor burden to facilitate complete cytoreduction. Adjuvant systemic therapy following CRS-HIPEC targets distant micrometastatic disease and may reduce the risk of peritoneal recurrence, although optimal regimens and durations remain areas of active investigation. The expanding role of targeted therapies and immunotherapy in peritoneal malignancies presents opportunities for integration with locoregional treatment, with ongoing clinical trials evaluating novel combinations.

Enhancing Healthcare Team Outcomes

Interprofessional collaboration in CRS-HIPEC relies on structured multidisciplinary tumor board decision-making, coordinated preoperative planning, standardized perioperative protocols, and continuous communication to optimize patient selection, surgical outcomes, and complication management. Surgical oncologists, medical oncologists, radiologists, pathologists, anesthesiologists, intensivists, pharmacists, and specialized nursing staff collectively assess disease biology, resectability, peritoneal cancer index, imaging, and patient fitness to determine candidacy and guide preparation. Radiologists refine staging and operative planning, anesthesia teams manage complex physiologic demands with goal-directed therapy and advanced monitoring, and all personnel require dedicated HIPEC training to ensure safe chemotherapy delivery.

Centers benefit from standardized pathways, including prehabilitation, nephrotoxicity prevention, antiemetic strategies, and multimodal pain control, to reduce variability and improve safety. Intraoperatively, real-time communication supports perfusion management and confirmation of complete cytoreduction before HIPEC administration. Postoperatively, experienced intensive care unit teams manage high-risk complications and implement early recovery measures. At the same time, long-term surveillance and decisions on systemic therapy or repeat CRS-HIPEC are coordinated through ongoing multidisciplinary review. High-volume centers with established multidisciplinary team models consistently demonstrate higher rates of complete cytoreduction, fewer complications, and shorter learning curves, underscoring the critical role of institutional experience and sustained team-based collaboration.

Nursing, Allied Health, and Interprofessional Team Interventions

To perform a HIPEC safely, a qualified nursing team for the operating room and postoperative recovery is needed. Nurses must be trained in intensive care units and the operating room to manage intraoperative and postoperative complications without difficulty.

Nursing, Allied Health, and Interprofessional Team Monitoring

HIPEC must be carried out in university centers equipped with invasive vital signs monitoring and management of complications related to both surgery and the toxicity of cytotoxic drugs. This involves invasive monitoring of arterial pressure, central venous pressure, cardiac output, and peripheral vascular resistance.