Anesthesia and Surgery for Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

Introduction

Cytoreductive surgery (CRS) was initially described in the 1930s for patients with locally advanced gynecologic cancers, especially those with local and peritoneal spread, in an attempt to reduce symptoms arising from tumor burden. The subsequent extensive debulking surgeries developed in the 1960s and 1970s demonstrated an improvement in patient survival in conjunction with postoperative chemotherapy and improved tumor response to adjuvant treatment.

Seeding of tumor cells to the peritoneum is believed to occur as a result of inherent tumor biology; however, spillage of microscopic tumor cells into the peritoneum during surgery is also inevitable. The development of metastatic disease within the abdomen is thought to occur due to the “sticky surface” of the peritoneum, which provides a beneficial environment in which tumor deposits can flourish.

Hyperthermic intraperitoneal chemotherapy (HIPEC) was first reported in 1955 when intraperitoneal nitrogen mustard was administered to seven patients with ovarian cancer. In a landmark paper, Dedrick et al. examined the pharmacokinetic properties of intraperitoneal chemotherapy and found a positive impact on transport across the peritoneal-plasma barrier. Intraperitoneal chemotherapy was found to offer a survival benefit to patients with appendiceal tumors, and phase I and II trials commenced in the 1980s.

HIPEC is thought to improve tumor response in a number of ways. Intraperitoneal perfusion of chemotherapeutic agents was found to have a slower rate of clearance from the body than intravenous chemotherapy. The drugs used are hydrophilic and have a high molecular weight, thereby sequestering the active agent in the peritoneal cavity more effectively.

Tumor cells have less ability to repair DNA and exhibit increased apoptosis when heat is applied, and specific chemotherapeutic agents including cisplatin, doxorubicin, and mitomycin C demonstrate improved cytotoxicity and penetration when combined with hyperthermia, which adds to the effectiveness of the treatment. The application of HIPEC is most effective when administered immediately following the cytoreductive portion of the procedure and prior to reconstruction.

Epidemiology and Cancer Subtypes

CRS combined with HIPEC is predominantly used to treat patients with peritoneal carcinomatosis from appendiceal, colorectal, ovarian, and mesothelioma primary cancers.

Pseudomyxoma peritonei (PMP) primarily arises from mucinous tumors of the appendix or ovary, which rupture and seed within the peritoneal cavity. Systemic treatment is often ineffective for these cancers, and morbidity and mortality are often a result of relentless tumor progression, resulting in intestinal obstruction. Prior to the development of CRS and HIPEC, low-grade appendiceal malignancies were invariably fatal. Low-grade appendiceal tumor recurrence primarily recurs at the original resection site and peritoneal surfaces, while aggressive cancers can also exhibit metastases to the lymph nodes and liver.

Epithelial ovarian cancer affects over 200,000 women worldwide on a yearly basis. Minimal symptoms in the early stages of the disease often result in the presence of distal spread on presentation. Overall survival is poor, with a rate of only 50% at 5 years. A recent analysis highlighted increased survival in patients with ovarian cancer who received HIPEC with CRS compared with those without HIPEC.

Malignant mesothelioma is a neoplasm of the serosal lining of the body cavities, including the abdomen. Diffuse malignant peritoneal mesothelioma is an aggressive form of the disease and has an annual occurrence rate of 300–400 cases annually in the United States, with many patients dying within a year of diagnosis. HIPEC and CRS have offered an alternative treatment strategy and improved median survival up to 60 months in some patients.

Approximately 10% of patients presenting with colorectal carcinoma will have coexisting peritoneal metastases, while one-quarter of those with recurrent disease have peritoneal metastases. Aggressive treatment with CRS and HIPEC targeting peritoneal metastases has demonstrated significantly improved survival rates.

The incidence of peritoneal dissemination of primary gastric cancer is estimated to be 20%. Patients with peritoneal spread of the disease have an extremely poor prognosis, with median survival estimated at 1–3 months. In select patients HIPEC and CRS can almost double the survival time.

Strategy in Cytoreductive Surgery and HIPEC

CRS involves both visceral and peritoneal resections. CRS can be either primary, intended to completely remove tumors prior to commencement of chemotherapeutic regimens, or secondary, intended to remove residual tumor following chemotherapy. CRS is aimed at removing all macroscopic deposits of the tumor, i.e., >2.5 mm, while HIPEC is designed to target microscopic disease. Palliative debulking surgery can also be performed to relieve symptoms due to disease.

Sugarbaker’s Five Peritonectomy Procedures

The cytoreductive surgical technique has been standardized by Sugarbaker et al. ( Table 29.1 ). Current evidence suggests that the removal of all visible tumors should be operative intent. The completeness of cytoreduction is a major prognostic factor in all peritoneal surgeries. The survival advantage of macroscopically complete cytoreduction has been demonstrated in the treatment of sarcomatosis, abdominal mesothelioma, and peritoneal metastases of ovarian, gastric, and colorectal origin. Near-complete cytoreduction, leaving behind small volume residual tumor, should be pursued only when complete CRS is not feasible, and to preserve postoperative organ function. After initial laparotomy, assessment was performed using a standardized scoring system, the peritoneal carcinomatosis index (PCI). PCI is a clinical assessment of both the size and distribution of nodules on the peritoneal surface ( Fig. 29.1 ).

Table 29.1

Compartmentalization of the Cytoreductive Surgical Approach

Abdominal Region	Peritonectomies	Visceral Resections
Right upper	Right subphrenic	Glisson’s capsule dissection
Left upper	Left subphrenic	Splenectomy
Anterolateral	Stripping of paracolic gutters Greater omentectomy	Appendectomy Right colectomy
Subhepatic	Lesser omentectomy Stripping of omental bursa	Gastric antrectomy/total gastrectomy, cholecystectomy
Pelvis	Pelvic peritonectomy	Sigmoidectomy Hysterectomy Bilateral salpingo-oopherectomy

The abdominal cavity is divided into nine regions, while the area of the small bowel from the duodenojejunal flexure to the terminal ileum is subdivided into four areas. The greatest possible extent of tumor burden is assessed within these specific regions and is given a score of 0 to 3 depending on the lesion size (LS). An LS score of 0 means no malignant deposit is visible macroscopically, rising to LS 3, which indicates a cumulative tumor burden of greater than 5.0 cm. A maximum PCI score of 39 is attainable. Regardless of the primary cause of peritoneal carcinomatosis, a lower PCI score is associated with a higher chance of complete CRS and hence curative intent at the time of surgery. A radiographically derived PCI score can be used as a prognostic indicator in advance of surgery, although it can be difficult to accurately assess tumor burden, and consequently PCI, with imaging alone. PCI may also be calculated at staging laparoscopy; however, it remains the case that the most accurate PCI score is obtained during traditional open surgery. ^,

Completeness of Cytoreduction Score

The most definitive assessment used to assess the prognosis of patients with peritoneal surface malignancy is the completeness of the cytoreduction (CC) score ( Fig. 29.2 ). The CC score has been shown to accurately predict outcomes in PMP, peritoneal metastases from colorectal, ovarian, and gastric malignancies, and sarcomatosis and peritoneal ­mesothelioma. A CC score of 0 indicates that no visible peritoneal seeding exists following cytoreduction, while a CC score of 3 indicates tumor nodules >2.5 cm or a confluence of unresectable tumor nodules at any site within the abdominal cavity. CC-2 and CC-3 cytoreductions are considered incomplete.

HIPEC Rationale

Locoregional administration of chemotherapy increases the local concentration of the chemotherapeutic agent at the site of action, thereby reducing systemic toxicity. In HIPEC, the carrier solution for chemotherapy is initially heated to a temperature between 40°C and 43°C. The HIPEC solution is administered for 30–120 min depending on the institutional protocol, and the desired chemotherapy agent utilized. For example, in our institution (Peritoneal Malignancy Institute at Mater Misericordiae University Hospital, Dublin, Ireland), heated mitomycin C is administered for 60 min to treat PMP and colorectal and gastric peritoneal metastases. Ovarian peritoneal metastases are commonly treated with cisplatin for 90 min, while a combination of doxorubicin and cisplatin for 60 min is used to treat abdominal mesothelioma. Following HIPEC, the abdominal cavity is lavaged prior to the creation of any anastomoses and abdominal ­closure with placement of intraabdominal drains. ^,

The Dedrick Diffusion Model

The pharmacokinetic rationale of perioperative intraperitoneal chemotherapy is based on dose intensification provided by the direct instillation of chemotherapy into the peritoneal cavity and delayed clearance caused by the peritoneal plasma barrier. The peritoneal permeability of a number of hydrophilic anticancer drugs may be less than that of the same drug. ^,