Hyperthermic Intraperitoneal Chemotherapy

Anatomy and Physiology

Like the tumor entity, the extent of intra-abdominal tumor invasion is crucial for operability and prognosis. Intra-abdominal tumor burden is determined using the Sugarbaker Peritoneal Carcinosis Index. The abdomen is divided into 12 regions, the last 4 of which describe the small intestine, and individual lesions are classified according to their size. 

After administration of cytotoxic drugs in the intra-abdominal cavity, a difference in the concentration of the cytotoxic agent is observed between the peritoneal cavity and the plasma, related to the relatively slow movement of the drug from the peritoneal cavity to the plasma (peritoneal clearance) and explained by the existence of a peritoneal-plasma barrier (Sugarbaker 1996).[8]

Curiously, the pharmacokinetics of intraperitoneal chemotherapy is not affected by surgical removal of the diseased peritoneum.[9]

Blood drainage from the peritoneal surface occurs via the portal vein to the liver, providing increased exposure of potential liver micrometastases to cytotoxic drugs.[10]

Higher drug concentrations in lymph than in plasma are observed because the lymphatics transport some drugs to the systemic circulation, representing a second beneficial effect of intraperitoneal chemotherapy.

Some authors (Van der Speeten K et al. ) refer to a three-compartment model that includes the tumor-bearing peritoneum as the third compartment, where the drug is incorporated by tissue penetration.[11]

The association of hyperthermia is justified by the fact that malignant cells are selectively destroyed by hyperthermia in the range of 41 to 43 degrees C.[12][13] Additionally, the microcirculation in most malignant tumors exhibits complete vascular stasis in response to hyperthermia. The combination of heat and cytotoxic drugs results in increased cytotoxicity resulting in increased drug absorption into malignant cells due to increased membrane permeability.[14] The most important effect of hyperthermia is, therefore, the synergistic effect with certain cytostatics. A synergistic effect has been described for doxorubicin, cytostatics containing platinum, mitomycin C, melphalan, docetaxel, irinotecan, and gemcitabine (Sugarbaker PH et al.)[15]

Indications

In addition to the surgical operability criteria and the comorbidity factors taking into account ASA classification (ASA score [American Society of Anesthesiologists] <3), hepatic and renal function and the cumulative dose of chemotherapy treatments must be considered.

• In gastric adenocarcinoma, peritoneal carcinomatosis is very common; even after radical surgery, cytoreduction surgery with CHIP seems to delay oncological progression without affecting long-term survival. The procedure remains in the experimental field and should be reserved for younger patients under the age of 60, who are active, with a PCI <10 and small nodules, without ascites, extraperitoneal metastasis, or hepatic invasion that has responded well to neoadjuvant chemotherapy.[16][17]

• According to a review of the literature and meta-analysis, cytoreduction surgery with HIPEC prolongs overall survival and up to eight years after the gesture in ovarian neoplasia with peritoneal carcinosis.[18]

• In colorectal cancer: the peritoneum is the second site most common metastatic after the liver, about 7 to 15% of colorectal cancer patients have synchronous PC, and 4 to 19% will develop one afterward.

An improvement in patient prognosis has been noticed since the introduction of cytoreduction surgery with HIPEC and modern chemotherapy regimens (capecitabine, oxaliplatin, irinotecan) combined with immunotherapy (bevacizumab, cetuximab, panitumumab).[19][20] 

• Peritoneal pseudomyxoma and mucinous tumors of the appendix: Cytoreduction surgery (CRS)  with HIPEC has been well established as the only treatment for mucinous tumors with peritoneal dissemination, based on retrospective and comparative studies (Chua et al.).[21]

• Mesothelioma: Mesothelioma is a rare tumor of peritoneal origin. Cytoreduction surgery combined with HIPEC improves mean survival by up to 4 years but with repeated procedures.[22]

Contraindications

It has been shown by several studies that when the surgical cytoreduction is incomplete, there is no longer any benefit from HIPEC on survival.[23]

Medically, in addition to comorbid factors such as severe cardiovascular disorders and serious lung disease, hepatic and renal failure may complicate the procedure and should contraindicate the operation.

Allergy to cytotoxic agents is a formal contraindication to the HIPEC.

The threshold value of the PCI score to perform a HIPEC in the PC of colorectal origin is 20. Indeed, the survival overall at five years is virtually zero for patients with a PCI greater than 20.[24]

Surgically and in addition to a too high PCI score, the invasion of some surgical sites also contraindicates the HIPEC. These are the root of the mesentery, the hepatic pedicle, retroperitoneum, and the bladder. Impairment of small intestinal function that potentially could induce a short bowel syndrome is also a contraindication.

Ultimately, surgical cytoreduction will remove as many tumors as possible, while the associated HIPEC  will make it possible to "sterilize" the tumor residues not visible to the naked eye. The purpose of CHIP is to obtain a high local concentration of chemotherapy and a low systemic concentration.[16]

Equipment

Before starting this procedure in a hospital, it is mandatory to have a chemotherapy approval infrastructure equipped with a surgical infrastructure linked to the medical-surgical resuscitation unit for patient monitoring.

HIPEC can be performed on the open and closed abdomen. In both perfusion models, the abdominal cavity is continuously perfused with cytostatic solution heated to 41 to 43 degrees C through a drainage system consisting of inlet and outlet catheters.

This procedure, therefore, requires the following equipment:

• A heat exchanger connected to a thermostat to maintain a stable temperature at 42 degrees in the extracorporeal circulation
• Outflow and inflow catheter to ensure the infusion and absorption of the cytotoxic drug in the abdominal cavity
• Temperature probes which measure the temperature in the circuit and the peritoneum
• Roller pump to maintain the extracorporeal circulation of the cytotoxic drug
• The reservoir of the cytotoxic agent
• A computer system that controls the heat exchanger and the drainage pumps according to the thermal probes
• A timer that measures the infusion time
• Cytotoxic drugs used for intra-abdominal chemotherapy are mitomycin C, Platine, doxorubicin, paclitaxel, and irinotecan.
• The chemotherapeutic agent is applied with a carrier solution (mainly 0.9% NaCl or 5% glucose). The volume of the carrier solution is calculated based on the body surface area. Usually, infusion volumes between 1.5 and 2 liters/ m^2 of body surface areas are used.

Personnel

HIPEC is an intraperitoneal chemotherapy technique that should only be performed by qualified physicians who have received sufficient training in surgical oncology. Nursing staff in the operating room must be qualified, trained in medical oncology, and manage the extracorporeal circulation of cytotoxic drugs during this procedure to perform the procedure safely.

Hospital pharmacists must prepare cytotoxic drugs at the pharmacy in a specific room under constant laminar flow to strictly reduce any bacterial contamination of the preparation.

Preparation

Before initiating the procedure, a preoperative evaluation is necessary according to WHO guidelines. This evaluation must include the medical-surgical history, the assessment of tumor generalization, the history of preoperative or neoadjuvant chemotherapy, and the analysis of cardiopulmonary examinations. Current treatment should also be noted, including the consumption of anti-coagulants to minimize the risk of bleeding during surgical cytoreduction because it is a major surgery that will precede the act of HIPEC.

The patient must understand the advantages and disadvantages of the operation as well as the benefit/risk ratio of HIPEC because the procedure must be able to improve the survival of the oncological patient. A detailed description of the procedure is required to obtain informed consent from the patient.

The role of the anesthetist is essential during cytoreduction and HIPEC. Specific training is desirable.

Finally, this procedure must be performed in a qualified university center specializing in medico-surgical oncology and equipped with an appropriate medical surveillance infrastructure.

Technique or Treatment

Generally, two methods for HIPEC are described: open abdomen technique and closed abdomen technique.

Open abdomen technique: as described by Sugarbaker, at the end of the surgical cytoreduction, a Tenckhoff catheter and four closed suction drains are sutured to the skin and placed through the abdominal wall. The temperature probes are attached to the skin edge for intraperitoneal temperature monitoring. The skin edges at the level of the abdominal incisions are suspended until the Thompson self-retaining retractor by a monofilament to maintain open space in the abdominal cavity. For preventing the leakage of the chemotherapy solution, a plastic sheet is inserted into this suture.

Continuous manipulation by the surgeon of the perfusion allows the uniform exposure of all anatomical structures to heat and chemotherapy during the procedure. A pumping system injects the chemotherapy infusion into the abdomen through the Tenckhoff catheter and pulls it through the drains with a constant flow. The heat exchanger keeps the intraperitoneal fluid temperature at 41 to 43 degrees, the drug is then administered in the circuit, and the timer for the perfusion is started. The duration varies from 30 min to 1 hour, depending on the type of cancer.

A disadvantage of the open technique is the heat dissipation, making it more difficult to have a hyperthermic state.

Closed abdomen technique: Thermal catheters and probes are placed in the same way, but the skin edges of the laparotomy are tightly sutured to allow perfusion in a closed circuit. The abdominal wall is shaken manually by the surgeon during the infusion for uniform heat distribution. The volume of perfusate is greater in this technique to establish the circuit, and higher abdominal pressure is obtained during the perfusion, which facilitates tissue penetration of the drug. After infusion, the abdomen is reopened to remove the perfusate and the preparation of the anastomosis. This technique allows maintaining rapid attainment of hyperthermia because there is minimal heat loss.

Complications

According to recent studies (meta-analysis), Cytoreductive surgery and HIPEC are associated with morbidity and mortality of approximately 33% and 2.8%, respectively.[25] It should be remembered that heavy and complex surgical procedures likely lead to increased toxicity of HIPEC through changes in pharmacokinetics, protein losses, hepatic and renal metabolic restrictions, and stress-related bone marrow suppression.[26] According to the literature, this increased toxicity is manifested by hematotoxicity and nephrotoxicity with respective frequencies of 5.6% and 1.7%.[25]

Particular complications associated with the procedure are prolonged intestinal atony, increased fluid movement over the abdomen, delayed wound healing, and prolonged hospitalization.

Cases of intrathoracic chemotherapy have been described in cases of major surgery with diaphragm perforation.

Have been identified as risk factors for this procedure's serious complications: the general condition of the patient, age, the extent of peritoneal carcinoma, duration of the intervention, number of peritonectomy procedures, number of anastomoses, the quality of cytoreduction, and the dosage of intraperitoneal chemotherapy.

Other complications have been observed which are not related only to the HIPEC but are well associated with cytoreduction: Pancreatitis, fistula, Pulmonary embolism, and thrombosis.

Clinical Significance

According to several clinical studies, infiltration of the abdominal cavity by neoplastic cells is inevitable following surgical manipulation during peritonectomy. The main goal of intraperitoneal chemotherapy is to eliminate these free tumor cells and any micrometastases that are not visible to the naked eye. Classically, HIPEC is performed after surgical resection and before reconstruction of the gastrointestinal tract. This potentially curative therapeutic option completes the concept of multimodal therapy, and it is increasingly needed for patients with peritoneal metastatic gastrointestinal and gynecological tumors and mainly peritoneal malignancies.

Several prospective studies have proven the superiority of the concept of multimodal therapy over a single systemic therapy in the treatment of metastatic cancers.[27][28][29]

Van Driel et al. published in the New England journal of medicine the results of a multicenter randomized study on the treatment of peritoneal carcinoma in ovarian carcinoma. A statistically significant advantage was clearly demonstrated for the combined treatment compared to cytoreduction alone, especially in improving patient survival.[29]

For peritoneal carcinoma of colorectal origin, Quenet et al. included a prospective randomized study of 265 patients over a period of 6 years who should benefit from HIPEC versus a comparator group with simple cytoreduction; the results are statistically significant.  The survival of patients who underwent HIPEC with a PCI score between 11 and 15 was better.[30] It should be noted that many oncological centers consider that PCI> 20 is considered an exclusion criterion for HIPEC in colorectal cancer, and the PCI value of 15 is currently considered the upper limit of sensitive multimodal therapy.[31]

Despite the widespread use of HIPEC by several oncology centers, there is no consensus described on the method used, particularly the combinations of cytostatics, the concentration of cytostatics, the application time, the temperature, the infusion volume, and infusion duration, and optimal infusion mode.[32]

According to several retrospective studies, the combination of chemotherapy, whether systemic or peritoneal, with surgical cytoreduction is still beneficial.[33][34][35]

However, perioperative systemic chemotherapy's benefits in initially resectable peritoneal metastases of colorectal cancer remain a subject of discussion. According to a recent study (Deborah J Reppulo et al., 2021), a retrospective analysis of 125 patients treated with complete CRS  and HIPEC for Peritoneal malignancy (PM) from the colorectal origin with or without perioperative systemic chemotherapy (PCT).  In this study, the authors do not show any clear benefit of PCT in carefully selected patients undergoing  CRS and HIPEC for colorectal PM.[36]

Concerning gastric tumors with peritoneal carcinomatosis, the prognosis is limited. The median survival of only 7 months improved after cytoreductive surgery to 12 months on average; in some studies, additional HIPEC has shown beneficial effects on survival.[37][38][39]

For mucinous tumors with peritoneal dissemination, CRS / HIPEC has been well defined as the only effective treatment, based on retrospective and comparative studies (Chua TC et al. 2012), with an improvement in median survival up to 16.3 years.[21]

Enhancing Healthcare Team Outcomes

HIPEC, often combined with surgical cytoreduction, is a heavy procedure with a non-negligible morbidity and mortality rate even in the most efficient centers; it must be performed in university centers specializing in oncological surgery with multimodal and multidisciplinary care. This also implies collaboration between inter-professional teams.

The oncologist must respect the correct selection of patients in agreement with the surgeon to perform this procedure by taking into account the beneficial effects of HIPEC on the long-term survival of the oncological patient without forgetting the benefit/risk ratio.

The anesthesiologist should perform a preoperative evaluation necessary for the patient's operability. The resuscitator in charge of the intensive care unit must be informed of the procedure and its complications before admission to the intensive care unit.

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 in the operating room to be able 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 devices for optimal monitoring of vital parameters and management of complications related to both surgery and the toxicity of cytotoxic drugs.This involves invasive monitoring of the arterial pressure curve, monitoring of central venous pressure, cardiac output, and peripheral vascular resistance.