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Intraperitoneal Hyperthermic Chemotherapy for Peritoneal Surface Malignancy: Current Status and Future Directions

Surgical Oncology Service, Department of General Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Correspondence: Address correspondence and reprint requests to: Edward A. Levine, MD; E-mail: elevine{at}wfubmc.edu.

ABSTRACT

Natural history studies have shown that peritoneal carcinomatosis is uniformly fatal, with a median survival in the range of approximately 6 months. For more than a decade, a handful of centers have pursued aggressive intraperitoneal cytoreductive surgery combined with intraperitoneal hyperthermic chemotherapy as an alternative approach to this disease. Strict selection criteria, variation in intraperitoneal chemotherapy, and the vagaries of what represents "cytoreductive surgery" make many of our colleagues, particularly those in medical oncology, reticent to refer patients for such an aggressive therapy. This article establishes a conceptual framework for understanding the role of intraperitoneal hyperthermic chemotherapy in the treatment of peritoneal surface malignancy. This procedure continues to make advancements in the oncological community despite formidable challenges. The advancement of centers of excellence and the initiation of further phase II trials will help to define the optimal treatment approach for peritoneal carcinomatosis.

Key Words: Peritoneal dissemination • Carcinomatosis • Intraperitoneal hyperthermic chemotherapy • Mitomycin C • Cytoreductive surgery

Peritoneal carcinomatosis (PC) is uniformly a terminal disease, with a median survival of 6 months.^1,2 Unfortunately, advanced disease is often present at the time the primary tumor is diagnosed.^1,3 Systemic chemotherapy is palliative and generally provides limited improvement in survival.^1,4,5 Cytoreductive surgery alone has long been used to treat macroscopic disease. The use of cytoreductive surgery along with intraperitoneal hyperthermic chemotherapy (IPHC), however, has evolved into a novel approach for peritoneal surface malignancy.^6,7 This review outlines the rationale, current practice, and future directions of IPHC.

RATIONALE

Tumor dissemination can occur in intra-abdominal malignancies and may be contained by the parietal peritoneum. Unchecked, such peritoneal surface disease inexorably progresses to bowel obstruction, malignant ascites, or both. Intraperitoneal tumors seem to spread according to three patterns. The first is that of direct extension. The second pattern involves distribution of tumor cells via peritoneal fluid. In his original article, Meyers⁸ investigated the flow of intraperitoneal contrast as a model for intraperitoneal tumor cell dissemination. Tumor cells were typically distributed into the pouch of Douglas, the inferior left pericolic gutter, and the space between the right diaphragm and liver. The third method of peritoneal tumor spread is surgical manipulation or trauma. Proponents of this theory suggest that viable exfoliated tumor cells become entrapped in avascular scar tissue, thus becoming relatively resistant to intravenous chemotherapy.^9–11

Such localization within the parietal peritoneum without distant metastasis makes an aggressive regional approach attractive. The foundation of treatment remains aggressive surgical cytoreduction, because even the most ambitious perfusion strategies penetrate but a few millimeters. Therefore, removal of bulk disease is imperative and allows perfusion to treat the microscopic or small-volume residual disease. The relative contribution of IPHC in addition to such surgery is unknown.

Systemic chemotherapy for peritoneal surface malignancies is largely ineffective because of its limited entry into the peritoneum. Early studies confirmed the presence of a peritoneal-plasma partition by demonstrating that drugs delivered into the peritoneal cavity have a clearance that is inversely proportional to the square root of its molecular weight.^12–14 Because of this partition, drugs without lipophilic properties and high molecular weights have optimal pharmacokinetic profiles for intraperitoneal application. The pharmacokinetic advantage of intraperitoneal perfusion can be expressed by the area under the curve ratios of peritoneal fluid to plasma, as shown in Table 1.^15–21

The timing of peritoneal perfusion is critical. Extensive evidence shows that the effect of postoperative versus intraoperative peritoneal perfusion is reduced by the rapid formation of intra-abdominal adhesions, as well as complications related to intra-abdominal catheters.^28–31 Intraoperative peritoneal perfusion not only allows the instillation of chemotherapeutic agents in an adhesion-free environment, but also minimizes the number of viable exfoliated tumor cells after resection.^32–34 Taken together, this represents the biologic foundation for the current use of IPHC in the treatment of peritoneal surface malignancies.

CHOOSING THE APPROPRIATE CANDIDATES FOR IPHC

Patient selection is an important aspect of planning for IPHC. We used the following criteria:

1. Patients must be medically fit to undergo the rigors of cytoreductive surgery and IPHC. 2. There must be no extra-abdominal disease.
   
2. Peritoneal disease must be potentially completely resectable or could be significantly reduced.
   
3. There must be no parenchymal hepatic metastases.
   
4. There must be no bulk retroperitoneal disease.
   

The common indications for IPHC are listed in Table 2.^35–45

ASSESSMENT OF INTRA-ABDOMINAL TUMOR BURDEN

Preoperative Imaging
Accurate preoperative imaging of peritoneal surface malignancy not only assists in planning cytoreduction, but also prevents unwarranted laparotomy in patients who have unresectable disease. The modern armamentarium of preoperative imaging includes computed tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET). Patients found to have extraperitoneal disease by any modality are excluded from IPHC. CT of the solid organs and retroperitoneum has demonstrated great accuracy in detecting primary or recurrent lesions. However, its sensitivity in evaluating disease within the peritoneal cavity and pelvis is limited. In a recent study from the Netherlands Cancer Institute, helical spiral CT scans in 25 consecutive patients with carcinomatosis were compared with intraoperative findings. The overall sensitivity of CT scans in this study was between 25% and 37%, with a negative predictive value that ranged between 47% and 51%.⁴⁸ These data highlight the limitations of CT scans in detecting and determining the size and location of peritoneal implants. Conversely, MRI with dilute oral barium and intravenous gadolinium has been shown to be superior to CT scans in detecting peritoneal metastasis, with a sensitivity of 84% to 100%.^49,50 We use either CT or MRI but do not routinely obtain both. Although PET imaging is very sensitive for high-volume disease, in contrast to numerous other tumor systems, it has been shown to have decreased sensitivity (10%) for low-volume disease in patients with PC.⁵¹ Moreover, PET is of very limited value for low-grade or predominantly mucinous lesions, such as pseudomyxoma. Further studies are indicated to improve preoperative imaging of PC.

Intraoperative Staging
Intraoperative staging allows for a standard assessment of tumor burden. At present, four systems are used to quantitate the extent of peritoneal disease. The Japanese Research Society for Gastric Cancer originally classified peritoneal disease from gastric primary tumors according to location.⁵² This classification is as follows: P0, no peritoneal disease; P1, implants adjacent to the stomach; P2, minimal metastasis only to the peritoneum and ovaries; and P3, multiple metastases to just the peritoneum.⁵² Several studies of cytoreductive surgery followed by IPHC for gastric cancer have demonstrated survival stratification based on this intraoperative staging classification.^53–55 A subsequent staging system for peritoneal surface malignancies was described by Gilly in 1994 (Table 3). This original study and others^56–59 have suggested a correlation between the Gilly Carcinomatosis Index and prognosis.

View larger version (26K): [in this window] [in a new window]   FIG. 1. Peritoneal Carcinomatosis Index (PCI) staging system for peritoneal carcinomatosis.

The IPHC must be preceded by a complete cytoreduction to maximize its therapeutic benefit. The goal of cytoreduction is not simply debulking, but resection of all gross tumor. A generous midline incision is used for all explorations. Significant tumor burden typically necessitates resection of the peritoneum by stripping it off the abdominal wall combined with multivisceral resections (such as splenectomy, large and small bowel resection, and hysterectomy). Any tumor adherent to vital structures that cannot be resected may be cytoreduced with the cavitronic ultrasonic surgical aspirator device (Valleylab, Bolder, CO). If a bowel resection is performed, any anastomoses may be completed before or after IPHC; ostomies are completed at the end of the entire procedure.

IPHC can be performed via either an open or closed technique. The open abdominal cavity technique involves covering the abdomen with a plastic sheet during the circulation of hyperthermic chemotherapeutic agents.⁶⁶ Proponents of the open abdominal cavity technique believe that it provides optimal thermal homogeneity and spatial diffusion. However, supporters of the closed technique suggest that the increased intra-abdominal pressure of the closed abdomen drives deeper penetration of agents.^67,68 Furthermore, the closed-cavity technique minimizes the surgical team’s exposure to liquid-phase and aerosolized chemotherapy in the operating room. To date, no prospective trials have compared the two techniques. The following describes the closed technique used at Wake Forest University.

Patients are cooled to a core temperature of approximately 34°C to 35°C by passive measures (i.e., not warming airway gases or intravenous solutions) during cytoreduction. After the completion of cytoreductive surgery, peritoneal perfusion catheters are placed percutaneously. Two inflow catheters (22F) are directed beneath the left and right hemidiaphragms. One or two outflow catheters (32F) are placed in the pelvis. Drainage bulbs are attached to the end of the outflow cannulas to avoid suction injury to the bowel. Temperature probes are placed on the inflow and outflow catheters (Fig. 2). The abdominal skin incision is temporarily closed with a running suture to prevent leakage of peritoneal perfusate. A perfusion circuit is typically established with 3 L of crystalloid solution. Flow rates of approximately 800 to 1000 mL/min are maintained by using a roller pump managed by a perfusionist. The pelvic catheters drain to a standard cardiotomy reservoir containing a coarse filter to catch debris and reduce foaming. The circuit continues through a single roller pump and a heat exchanger to the patient. Heated water is pumped to the heat-exchanger device from a Blanketrol (Cincinnati Sub-Zero Products, Inc., Cincinnati, OH) heating/cooling blanket reservoir. The temperature of the fluid in the patient-return and patient-directed tubing is monitored with stainless-steel couplers with temperature probe connectors and needle probes at the tips of one inflow and one outflow cannula.

View larger version (67K): [in this window] [in a new window]   FIG. 2. Inflow and outflow catheters for intraperitoneal hyperthermic chemotherapy.

ASSESSMENT OF COMPLETENESS OF CYTOREDUCTION

All trials of IPHC have demonstrated a correlation between the completeness of cytoreduction (CC) and survival. Presently, two classification systems are used to describe the extent of cytoreduction. The resection classification system used at Wake Forest includes complete (R0, no gross disease with negative microscopic margins; R1, no gross disease with positive microscopic margins) versus incomplete (R2a–c) cytoreduction. A resection classification of R2a indicates residual tumor of up to 5 mm, R2b designates 6 to 20 mm of gross disease, and R2c identifies >20 mm of gross residual disease. Data from our institution and others demonstrate a significant survival advantage for patients undergoing R0/R1 resection compared with R2 resections.^46,69,70 When it is not possible to perform a significant cytoreduction, IPHC is rarely indicated; the 1-year survival in these individuals is exceedingly low. A recent study of 56 patients with PC demonstrated a 79% 2-year survival rate in patients undergoing complete cytoreduction and IPHC, whereas those undergoing incomplete cytoreduction had a 2-year survival of only 44.7%.⁷¹ Similarly, Yonemura et al.⁷² demonstrated a 40% 3-year survival in patients with gastric carcinomatosis treated with complete cytoreduction and IPHC. This is a dramatic improvement over the 3-year survival rate of 10% seen in a similar group of patients treated with IPHC only. In our experience, patients undergoing R0 resection followed by IPHC experienced 3-year survival rates of 72.4%, whereas those undergoing R1, R2a, R2b, and R2c resections experienced 5-year survival rates of 50%, 44%, 22.2%, and 9.3%, respectively.⁴⁶

Sugarbaker and colleagues have also devised a CC score. A CC of 0 indicates that no peritoneal disease was present after cytoreduction. A CC of 1 represents cytoreduction that resulted in <2.5 mm of residual disease, a CC of 2 indicates residual tumor between 2.5 and 2.5 cm, and a CC of 3 indicates >2.5 cm of residual tumor or the presence of a sheet of unresectable tumor nodules. The CC has been correlated with survival in pseudomyxoma peritonei, mesothelioma, colorectal carcinomatosis, and sarcomatosis.^60,62,73,74

RESULTS

Morbidity and Mortality
Because of the extent of surgery necessary to obtain optimal cytoreduction, the morbidity and mortality of IPHC are significant.^46,75,76 Current morbidity rates experienced by centers that perform IPHC range between 27% and 56%. The most common complications of IPHC include abscess, fistula, prolonged ileus, pneumonia, and hematological toxicity. Multivariate analysis by the group at the Washington Hospital Center has suggested that the rate of postoperative complications is related to the stage of carcinomatosis, the duration of the operation, and the number of anastomoses.⁷⁵

Although a minority of patients are long-term survivors, most patients eventually die of their disease. Therefore, it is important to consider its effect on the individual’s quality of life (QOL). Two recent studies from our institution examined short- and long-term QOL outcomes after cytoreductive surgery and IPHC. Sixty-four patients in the short-term study reported decreased overall QOL after surgery compared with baseline but then returned to baseline or better within 3 to 6 months of surgery.⁴¹ A follow-up study of 17 patients who survived >3 years after cytoreductive surgery and IPHC reported that >90% had minimal to no limitations of activity and had functional assessments that compared favorably to national reference values for their respective age groups.⁷⁷ In a similar study, the National Cancer Institute demonstrated improved QOL scores at 3, 6, and 9 months after cytoreductive surgery and IPHC.⁷⁸ Currently, all patients who undergo cytoreductive surgery and IPHC at Wake Forest University Baptist Medical Center are encouraged before surgery to participate in an ongoing QOL study.

The national mortality rate for IPHC has been reported to be between 0% and 11%. At our institution, the most common causes of death after IPHC are bowel perforation, bone marrow suppression, respiratory failure, methicillin-resistant Staphylococcus aureus infection, and pulmonary embolism. Factors that predict mortality include malignant ascites, poor performance status, and bowel obstruction.⁴⁶ Although these morbidity and mortality rates are significant, they must be compared with the dismal outcomes without such therapy.

Clinical Outcomes for IPHC by Tumor Type
Colorectal Cancer
Several trials have investigated the utility of cytoreductive surgery and IPHC for carcinomatosis from colorectal carcinoma. These studies, which included relatively small numbers of patients, showed a 3-year survival rate of 25% to 39% (Table 4), which is clearly superior to that achieved by systemic chemotherapy alone.^46,79–82 Single-institution results of a phase III randomized study of IPHC with MMC have been reported by the Netherlands Cancer Center. Patients with colorectal carcinomatosis were randomized to undergo systemic 5-fluorouracil/leucovorin therapy with or without palliative surgery or cytoreduction, IPHC, and systemic chemotherapy. A median survival of 12.6 months was seen in the palliative chemotherapy arm, whereas the median survival of the experimental arm was 22.3 months (P = .032). The trial was stopped prematurely because of the large survival difference in favor of IPHC.⁸³ Recently, Glehen et al.⁸⁴ presented data from an international registry of 506 patients undergoing IPHC for PC from colorectal cancer at 28 institutions. The overall median survival was 19.2 months after IPHC. Moreover, the 3- and 5-year survival rates were 39% and 19%, respectively. The 5-year survival in this setting is indeed remarkable, because such survivors without IPHC are extremely rare.

Pseudomyxoma Peritonei
Pseudomyxoma peritonei has been considered the classic indication for IPHC. Pseudomyxoma peritonei is an extremely rare lesion with a median survival of 6 years in surgically treated patients. Ronnett et al.⁵⁶ evaluated 109 cases of pseudomyxoma peritonei and categorized them into disseminated peritoneal adenomucinosis (DPAM; 58%), peritoneal mucinous carcinomatosis (PMCA; 28%), and intermediate histologies (14%). DPAM is marked by its abundant extracellular mucin; scant, focally proliferative mucinous epithelium; and lack of cytological atypia or mitotic activity. PMCA has histological characteristics that include an abundant mucinous epithelium with architectural and cytological features of carcinoma. The remainder of patients with pseudomyxoma will have intermediate or hybrid histology. The outcome with DPAM and intermediate histology is significantly better than that with PMCA. Whether pseudomyxoma peritonei is from the benign DPAM or malignant PMCA etiology, it is important to remember that these lesions are uniformly fatal if untreated.

Four series have evaluated IPHC for pseudomyxoma peritonei. Five-year survivals have ranged between 66% and 97%.^60,80,89,90 However, aggressive cytoreduction and IPHC resulted in morbidity rates between 27% and 44% and mortality rates between 2.7% and 13%.^60,80,89,90 The largest series to date evaluated 385 patients with pseudomyxoma secondary to appendiceal primary cancers. Of these, 205 underwent IPHC with MMC followed by postoperative intraperitoneal 5-fluorouracil, whereas 180 patients underwent exploratory laparotomy, cytoreduction, and perioperative intraperitoneal chemotherapy. This work suggests that patients with DPAM have a better prognosis than patients with mucinous adenocarcinoma or intermediate histology after exploratory laparotomy and cytoreduction. However, it is unclear whether this survival difference persists after IPHC.⁶⁰ A subsequent study revealed a borderline statistically significant difference in 5-year survival between DPAM (64%) and hybrid/PMCA (54%) with IPHC (P = .05). There were, however, very few PMCAs (3 of 36) in the follow-up study.⁸⁹ We recently completed a study of 110 patients treated with IPHC for pseudomyxoma peritonei, and this study did not support a difference in survival between DPAM and the intermediate histology after IPHC.⁹¹ Patients with pseudomyxoma peritonei should undergo cytoreduction and IPHC as primary therapy, if they are acceptable surgical candidates, because of its poor response to systemic therapy.

Peritoneal Mesothelioma
To date, five noncontrolled trials have evaluated IPHC for peritoneal mesotheliomas.^3,92–95 These studies demonstrate median survival times of 34 to 67 months (Table 6), which is a significant improvement over the previously reported median survival times of 12 to 17 months.^39,40,42,45 Furthermore, palliation of ascites is an essential consideration in the treatment of peritoneal mesothelioma. The current studies show an 86% to 99% relief from ascites after IPHC for malignant mesothelioma (Table 6). The National Cancer Institute group recently delineated the factors associated with outcome in individuals undergoing IPHC with cisplatin for peritoneal mesotheliomas. This analysis demonstrated that previous debulking surgery, absence of deep tissue invasion, and maximum cytoreduction at an age younger than 60 years were associated with improved survival.⁹⁶ Together, these data suggest that patients with mesothelioma are excellent candidates for IPHC.

FUTURE DIRECTIONS

Several issues surround the future of IPHC. Chief among them is how to make such therapy standardized and available to large numbers of patients. At present there are approximately 25 active centers in the United States and only half a dozen with experience of >100 cases. The operative procedures required for aggressive cytoreduction are lengthy, challenging, and morbid and use a great deal of hospital, blood bank, and surgical house officer resources. Further, the use (and safety) of chemotherapy in the operating room is daunting for many centers. Additionally, great care needs to be taken in selecting patients to undergo this procedure. It is estimated that only a handful of patients who are potential candidates for this therapy actually receive it, and this is underscored by the relatively small number of patients accrued to the phase II studies even at large "perfusion centers." It is clear that expanding the number of centers should be performed by surgical oncologists who have more than a passing knowledge of systemic chemotherapy and who are comfortable with the rigors of aggressive operative procedures in the abdomen.

Although reported results from "perfusion centers" represent a substantial improvement in survival and, likely, QOL,^41,77,78 most patients who undergo these procedures will experience tumor recurrence. Evaluating patients for second cytoreduction and additional chemoperfusion will become an ever more common problem as these procedures move into the mainstream. Most failures after IPHC occur exclusively at intra-abdominal sites. This certainly supports the contention that a subset of patients will manifest intra-abdominal disease without manifesting hematogenous metastases. We, and others, believe that in selected patients, a second cytoreductive procedure and chemoperfusion may be of value. In evaluating patients for second cytoreduction, the same criteria that are used to select patients for the first remain important. Specifically, the patients must remain medically fit to tolerate a major operative procedure, be free of extra-abdominal or hepatic parenchymal metastases, and have disease that seems amenable to complete cytoreduction. Additionally, the time to recurrence after initial cytoreduction and the completeness of the initial cytoreduction should be considered in deciding to proceed with another procedure. Patients with bulk residual disease after an initial cytoreduction for colorectal carcinoma should not be considered candidates for second cytoreductive procedures.^73,101

At present, large cooperative group trials of IPHC have been proposed to the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the American College of Surgeons Oncology Group (ACOSOG). The trials are designed to evaluate many of the fundamental questions regarding cytoreduction and intraperitoneal hyperthermic chemoperfusion (Figs. 3 and 4). The proposed NSABP trial stratifies patients according to previous treatment and resection status. Enrollees who have optimal cytoreduction will undergo IPHC with MMC. The primary end points in the NSABP proposal are time to assessable peritoneal progression and overall survival. The secondary end points are progression-free survival and QOL. A similar study is under consideration by the ACOSOG. Patients will be similarly stratified; however, participants will be randomized to debulking with or without IPHC. All patients will receive postoperative systemic chemotherapy. This proposal will evaluate time to peritoneal progression as its primary end point. Secondary end points will be overall survival, progression-free survival, and QOL measures.

View larger version (16K): [in this window] [in a new window]   FIG. 3. Protocol submitted to the National Surgical Adjuvant Breast and Bowel Project phase II protocol design to evaluate the benefit of intraperitoneal hyperthermic chemotherapy (IPHC) after resection/cytoreductive surgery for patients with peritoneal carcinomatosis secondary to colorectal and appendiceal malignancy. QOL, quality of life.

View larger version (15K): [in this window] [in a new window]   FIG. 4. Protocol submitted to the American College of Surgeons Oncology Group protocol design to evaluate the benefit of intraperitoneal hyperthermic chemotherapy (IPHC) after resection/cytoreductive surgery for patients with peritoneal carcinomatosis secondary to colorectal malignancy. MMC, mitomycin C; 5-FU, 5-fluorouracil; LV, leucovorin; QOL, quality of life.

Received for publication December 2, 2004. Accepted for publication May 11, 2005.

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