Cytoreductive Surgery and Intraperitoneal Hyperthermic Chemotherapy for Peritoneal Surface Malignancy: Experience with 501 Procedures

Edward A Levine, MD, FACS, John H Stewart IV, MD, Gregory B Russell, MS, Kim R Geisinger, MD, Brian L Loggie, MD, FACS, Perry Shen, MD, FACS
Peritoneal dissemination of abdominal malignancy (PSD) has a clinical course marked by bowel obstruction and death. We have been using aggressive cytoreductive surgery with intraperitoneal hyperthermic chemotherapy (IPHC) to treat PSD. The purpose of this article was to review our experience with IPHC. STUDY DESIGN: A prospective database of patients undergoing IPHC has been maintained since 1991. Patients were uniformly evaluated and treated. Demographics, performance status, resection status, primary site, and experience quartile were compared with outcomes. Univariate and multivariate analyses were performed. RESULTS: A total of 460 patients underwent 501 IPHC procedures. Average age was 53.0 years, and 50.4% were women. The 30-day mortality rate was 4.8%, the complication rate was 43%, and median hospital stay was 9 days. Median followup was 55.4 months, median survival was 22.2 months, and 5-year survival rate was 27.8%. Factors correlating with improved survival were performance status (p 0.0001), primary tumor (p 0.0001), resection status (p 0.0001), complications (p 0.002), previous IPHC (p 0.006), and experience quartile (p 0.031). On multivariate analysis, primary tumor site, performance status, resection status, and development of complications (p 0.001) predicted outcomes. CONCLUSIONS: Our experience demonstrated that preoperative criteria for better outcomes include primary tumor site and performance status. Completeness of resection and development of postoperative complications are also crucial, and outcomes have improved over time. Cytoreductive surgery and IPHC represent substantial improvements in outcomes compared with historic series and best-available systemic therapy. Longterm survival is possible for selected patients who undergo the procedure. (J Am Coll Surg 2007;204:943955. 2007 by the American College of Surgeons)
BACKGROUND:

Disseminated malignant peritoneal surface disease (PSD), or carcinomatosis, has traditionally and justifiably been approached with therapeutic nihilism. Patients typically progress to death from bowel obstruction in less than a
Competing Interests Declared: None. A portion of this work was supported by the Robert Welborne fund. Presented at the Southern Surgical Association 118th Annual Meeting, West Palm Beach, FL, December 2006. Received December 2, 2006; Accepted December 15, 2006. From the Surgical Oncology Service, Department of General Surgery (Levine, Stewart, Shen), the Section on Biostatistics, Department of Public Health Sciences (Russell), and the Department of Pathology (Geisinger), Wake Forest University School of Medicine, Winston-Salem, NC; and the Surgical Oncology Section, Department of General Surgery, Creighton University School of Medicine, Omaha, NE (Loggie). Correspondence address: Edward A Levine, MD, Department of General Surgery, Surgical Oncology Service, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157.

year.1 PSD results from intracavitary dissemination of tumor from a variety of primary pathologic lesions. Such findings are all too common for gastrointestinal and ovarian carcinomas, and are also seen with unusual malignancies such as sarcoma, mesothelioma, and urachal carcinoma. Frequently, PSD is confined to the peritoneal cavity without extraabdominal disease. So, a regional approach to selected patients with PSD is reasonable. In the 1980s, aggressive treatments of peritoneal surface malignancies were explored in an attempt to benefit through multimodality techniques. Centers explored treatment options such as peritonectomy procedures,2 IP injection of anticancer drug OK432,3 intracavitary immunotherapy, photodynamic therapy,4,5 IP hyperthermic chemotherapy (IPHC), and early postoperative IP chemotherapy.6-8 Over the past decade, there has been ever increasing interest in such regional therapy for PSD. This

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Abbreviations and Acronyms

CS GIST IPHC MMC OS PMP PSD

cytoreductive surgery gastrointestinal stromal tumor intraperitoneal hyperthermic chemotherapy mitomycin C overall survival pseudomyxoma peritonei peritoneal surface malignant disease

has been additionally stimulated by publication of a prospective randomized trial for PSD from colorectal sources9 and recent successes with IP chemotherapy for PSD from ovarian cancer.10,11 The optimal management of patients with PSD is a matter of intense debate. Systemic chemotherapy for PSD is limited, in part, to its limited entry into the peritoneum. Localization of tumor within the peritoneum without distant metastasis makes an aggressive regional approach attractive. Several groups have treated peritoneal surface extension of appendiceal tumors with debulking procedures.12-14 But it is clear that these procedures are frequently unable to remove all microscopic tumors. Our approach to selected patients with PSD has been to combine aggressive cytoreductive surgery (CS), with the goal of resecting all gross disease, with chemoperfusion to address microscopic residual tumor. A chemotherapy perfusion done at the same time as CS has several advantages. First, intracavitary chemotherapy achieves drug levels far greater than can be obtained with even the most aggressive systemic administration, which may overcome relative intrinsic drug resistance. Next, after CS, all peritoneal surfaces are exposed, allowing for better drug distribution (versus postoperative) as all adhesions are lysed. Additionally, the single intraoperative dose eliminates major compliance and tolerance issues encountered with postoperative administration of several cycles of treatment.10,11,15 The rationale for hyperthermia is based on laboratory studies showing synergy with certain drugs. We have previously reported our early experience8 and subsets of patients treated with CS and IPHC for PSD from appendiceal,16,17 colorectal,18,19 gastric,20 and small bowel21 carcinomas and mesothelioma.22 This article reviews our prospective database of patients undergoing CS and IPHC for PSD to evaluate our experiences with the first 501 procedures.

database. This database and analysis has been approved by the Institutional Review Board at Wake Forest University. All patients were evaluated in the surgical oncology clinics preoperatively. Evaluations included, at a minimum, a complete history, examination, pathologic review, CT imaging, blood counts, and renal and liver functions. To be considered for CS and IPHC, patients needed to have normal organ function (serum creatinine 2 mg/dL, alkaline phosphatase and serum aspartate transaminase or alanine transaminase less than 3 times the upper limit of normal, white blood cell count 4,000/mm3, and platelet count 100,000 mm3. Evaluation of preoperative CT imaging focused on the absence of extraabdominal metastasis, parenchymal hepatic metastasis (hepatic surface lesions allowed), bulky small bowel disease, multistation bowel obstruction, and ureteral or biliary obstruction. Tumors were categorized according to the primary site of origin. Before CS and IPHC, patients had their pathology reviewed by the Wake Forest University Department of Pathology. This was compared with final pathology from specimens garnered at the time of CS to reach a final diagnosis for the database. Patients with bulky pelvic disease or multiple previous pelvic procedures were routinely considered for urologic consultation for ureteral stent placement at the start of the procedure to facilitate retroperitoneal dissection. Clinical data on all patients were recorded in a database and maintained by a dedicated data management unit.
Cytoreductive surgery

METHODS Patients who underwent CS and IPHC for PSD at Wake Forest University School of Medicine Baptist Hospital between 1991 and 2006 were identified from a prospective

The goal of cytoreductive surgery was removal of all gross disease in all patients. CS consisted of the removal of gross tumor and involved organs, peritoneum, or tissue deemed technically feasible and safe for the patient. This included routine supracolic omentectomy in all patients when it had not been previously performed. Peritonectomy procedures were performed as indicated.2 Any tumors adherent or invasive to vital structures that could not be removed were cytoreduced using the cavitational ultrasonic surgical aspirator (CUSA, Valleylab). The resection status of patients was judged after CS using the following classification: R0, complete removal of all visible tumor and negative cytologic findings or microscopic margins; R1, complete removal of all visible tumor and positive postperfusion cytologic findings or microscopic margins; R2a, minimal residual tumor, nodule(s) measuring 0.5 cm; R2b, gross residual tumor, nodule 0.5 cm but 2 cm; and R2c, extensive disease remaining, nodules 2 cm.
Intraperitoneal hyperthermic chemotherapy

Near the completion of CS, patients were passively cooled to a core temperature of approximately 34 C to 35 C by

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passive measure (ie, not warming airway gases or IV solutions and cooling the room). After CS was completed, peritoneal perfusion inflow and outflow catheters were placed percutaneously into the abdominal cavity. Temperature probes were placed on the inflow and outflow catheters just outside the exit sites from the abdomen. The abdominal skin incision was closed temporarily with a running cutaneous suture to prevent leakage of peritoneal perfusate. A perfusion circuit was established with approximately 3 L of Ringers lactate. Flow rates of approximately 600 to 1,000 mL/min were maintained using a roller pump managed by the perfusionist. The circuit continued through a single roller pump, through a heat exchanger, and then to the patient. Constant temperature monitoring was performed at all temperature probes. Once a stable perfusion circuit was established and outflow temperature exceeded 38.5 C, the chemotherapy was introduced into the perfusion circuit. A maximum inflow temperature of 42.5 C was tolerated during perfusion, with a target outflow temperature at the pelvis of 40 C. The abdomen was gently massaged throughout perfusion to improve drug distribution to all peritoneal surfaces. Total planned perfusion time after the initial addition of mitomycin C (MMC) was 120 minutes. Although several chemotherapeutic agents were used, most patients received MMC. The MMC was dosed based on volume of perfusate necessary to establish a stable circuit (typically 3 L). When MMC was used, 30 mg was added to the perfusate at initiation of the IPHC; at 60 minutes, an additional 10 mg of MMC was added to keep MMC perfusate concentrations higher than 5 g/mL. In certain patients (elderly individuals, those with extensive previous chemotherapy, those with inanition or poor performance status, and patients having extensive peritoneal stripping during oepration), reductions in the dose of MMC (to 30 mg total) or perfusion time (to 60 to 90 minutes) were made because of concerns about potential toxic effects. Other chemotherapeutic agents were also used based on primary tumor site and previous systemic therapy. Since 2004, we have used cisplatinum 250 mg/m2 with sodium thiosulfate for mesothelioma patients and cisplatinum or carboplatinum for ovarian cancer patients. Sarcoma patients (and gastrointestinal stromal tumor [GIST] patients before the introduction of imatinib) were perfused with MMC with or without mitoxantrone.
Clinical followup

Table 1. Clinicopathologic Data for 460 Patients Undergoing 501 Cytoreductive Surgeries and Intraperitoneal Hyperthermic Chemotherapy for Peritoneal Surface Disease
Characteristic n %

Gender Male Female Race Caucasian African-American Other Performance status (ECOG) 0 1 2 3 4
ECOG, Eastern Cooperative Oncology Group.

232 228 406 39 15 160 213 67 18 2

49.6 50.4 90.2 8.7 1.1 34.8 46.3 14.6 3.9 0.4

tained with each followup visit and when clinically indicated. Patients were typically followed jointly with medical oncologists. Some patients received systemic chemotherapy at the discretion of their medical oncologists.
Statistical analysis

All data were collected prospectively; descriptive statistics were generated for all measures, including means, ranges, and standard deviations for continuous measures and frequencies and proportions for categorical data. Overall survival (OS) was calculated from the date of CS and IPHC to the last known date of followup or date of death. Estimates of survival were calculated using the Kaplan-Meier (product-limit) method; analysis using Cox proportional hazards was performed on all pertinent clinicopathologic variables to determine each ones association with survival. Group comparisons of OS were performed using the approximate chi-square statistic for the log-rank test. Additionally, the Cox proportional hazards regression model was used in a stepwise fashion to perform a multivariate analysis of clinicopathologic factors to determine an overall model of independent predictors of OS. Statistical significance was defined as a p value 0.05.

RESULTS
Patients and clinicopathologic features

Clinical followup occurred at 1 month, and at least every 6 months thereafter for up to 5 years. After 5 years from the last IPHC, followup was annual. Blood counts, liver functions and tumor markers (as appropriate), and abdominal and pelvic CT scans with oral and IV contrast, were ob-

A total of 501 IPHC procedures were performed on 460 patients with peritoneal surface malignancy who underwent the procedures between December 30, 1991 and June 8, 2006. This study was approved by our Institutional Review Board. Patient demographics and baseline data are listed in Tables 1 and 2. The mean age was 53.0 12.7

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Table 2. Operative and Perfusion Data for Patients Undergoing Cytoreductive Surgery and Intraperitoneal Hyperthermic Chemotherapy for Peritoneal Surface Disease
Characteristic n Value

Table 3. Organs Resected as Part of the Cytoreductive Surgery in Addition to Peritoneal Resections
Resected organ n %

Length of operation, min Mean Range Resection status R0-1 R2a R2b R2c Length of hyperthermic chemoperfusion, min Mean Range Median Number of IPHC procedures 1 2 3 Outflow temperature of perfusate, C Mean Range Median

560 175 2501,080 294 115 65 84

111.4 19.4 60120 120 460 37 4

Diaphragm Colon Rectum Small bowel Stomach Spleen Uterus Ovaries Gallbladder Pancreas Appendix Omentum Kidney Lung Liver Bladder

28 215 39 176 60 166 29 73 89 37 45 296 9 1 33 5

5.6 42.9 7.8 35.1 12.0 33.1 5.8 14.6 17.8 7.4 9.0 59.1 1.8 0.2 6.6 1.00

Omentectomy (supracolic) was performed routinely if not previously resected.

40.2 .8 3944 40

IPHC, intraperitoneal hyperthermic chemotherapy.

years (range 15 to 87 years of age), with a slight female preponderance. The median intensive care unit and hospital stays were 2 and 9 days, respectively. Second IPHC was performed on 41 selected patients for recurrent or persistent disease,23 with 4 patients undergoing 3 procedures. 20.1% of patients had an ileostomy (11.7%) or colostomy (8.4%) created as part of the CS. The organs resected as part of the CS are listed in Table 3. The median hospital stay was 9 days, with an average of 15.3 ( 17.9) days. Most patients were admitted to the ICU, with an average stay of 2 days. Primary sites of origin for the patients were as follows: adrenal, 1 (0.2%); appendix, 163 (35.4%); colorectal, 133 (28.9%); gall bladder, 3 (0.7%); gastric, 42 (9.1%); gastrointestinal stromal tumor (GIST), 9 (2%); liver, 1 (0.2%); mesothelioma, 27 (5.9%); ovary, 46 (10%); pancreas (cystic neoplasm and intrapancreatic mucinous tumor), 5 (1.1%); sarcoma, 11 (2.4%); small bowel, 6 (1.3%); urachal, 5 (1.1%); and unknown, 8 (1.7%). The median survival (months) was considerably different by site of origin as follows: appendix, 63.5; colorectal, 16.4; gastric, 6.1; mesothelioma, 27.1; ovary, 28.5; and sarcoma, 28.1 (p 0.0001). For other histologic sites of origin, the series had too few patients for meaningful analysis.

Operative and perfusion data are summarized in Table 2. The organs resected are shown in Table 3. The length of the operation (range 250 to 1,080 minutes) was dependent on the extent and location of disease at exploration, but it averaged just under 10 hours. The quantity of residual disease was recorded by the primary surgeon and was scored according to the R status for residual disease.24 The resection status of all patients undergoing IPHC is listed in Table 2. Resection status was a marked predictor of survival (p 0.0001). For the purposes of survival calculations, R0 and R1 were combined because of the difficulties clearly separating them in the setting of PSD.
Mobidity and mortality

The 30-day postoperative morbidity and mortality rates were 43.1% and 43.9%, respectively. Twenty-two patients in this study died within 30 days of IPHC. Wound infection, hematologic toxicity, sepsis, respiratory failure, anastomotic leak, pneumonia, and enterocutaneous fistula accounted for the majority of the postoperative complications in this cohort of patients. Patients who experienced a complication had poorer survival than those who did not (p 0.002). This difference remained pronounced on multivariate analysis. Complications were less common in patients undergoing R0/1 resections when compared with patients with more residual disease (p 0.044).
Experience over time

To evaluate our experience over time, we divided our patient experience into 4 time periods (quartiles) of 115 pa-

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Table 4. Univariate and Multivariate Analyses of Clinicopathologic Variables, Based on Stepwise Regression Analysis
Variables p Value

Figure 1. Overall survival for patients treated with cytoreductive surgery and intraperitoneal hyperthermic chemotherapy.

tients each. The median survival rates in months for the four quartiles were 16.2%, 18.2%, 30.5%, and 30.0 %, respectively, p 0.031 (Fig. 5). But the median length of stay was precisely 9 days in each of the quartiles. The mortality rate ranged from 2.6% to 7.0% over the four quartiles without marked differences.
Survival and followup

Univariate Race Dose of mitomycin C Resection status Gender Complications Length of operation Previous CS and IPHC Age Temperature of perfusate Length of chemotherapy Primary tumor histology (site) Performance status Multivariate Resection status Performance status Primary tumor histology (site) Complications

0.87 0.82 0.0001 0.24 0.002 0.12 0.006 0.19 0.80 0.22 0.0007 0.0001 0.001 0.0012 0.0001 0.0006

CS, cytoreductive surgery; IPHC, intraperitoneal hyperthermic chemotherapy.

For the cohort of 460 patients with a median followup of 55.4 months, the median OS was 22.2 months. One, 3-, and 5-year OS rates were 66.8%, 40.0%, and 27.8%, respectively (Fig. 1). The survival rates included operative mortality. A univariate analysis of clinicopathologic factors was performed to identify singularly pronounced prognostic factors associated with OS after CS and IPHC for PSD. Multivariate analysis of factors affecting survival was performed through a stepwise regression technique. This analysis allowed for all variables regardless of level of importance in the univariate analysis. The Cox proportional hazards regression model found that four clinicopathologic factors were independent predictors of OS: tumor histology, resection status, complications, and performance status (Table 4). Figures 1 to 5 depict the Kaplan-Meier actuarial survival curves for these factors.

DISCUSSION CS and IPHC represent a substantial operative undertaking for both patient and surgeon. Average operative times are approximately 10 hours, with long ICU and hospital stays that consume substantial resources. Morbidity and mortality are severe, and straightforward preoperative discussions with the patient and family are mandatory. But properly selected patients have a real chance at longterm

survival rarely, if ever, realized without such aggressive efforts. We have avoided addressing PSD from hepatic biliary and pancreatic sources principally because of the difficulty in obtaining control of the primary lesion. We currently consider patients with gastric cancer only if R0/1 resection can be anticipated. Systemic chemotherapy for peritoneal surface malignancies is limited in effect by its limited entry into the peritoneum. Any systemic chemotherapy for IP disease must overcome the plasma-peritoneal partition. Pharmacokinetic studies have confirmed the presence of this 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.25-27 The addition of IP chemotherapy can be viewed as a tool to overcome this drug resistance and toxicity associated with systemic administration. Because of this partition, drugs without lipophilic properties and high molecular weights have optimal characteristics for IP application. The pharmacokinetic advantage of IP perfusion can be seen by the area-under-the-curve ratios of peritoneal fluid to plasma that favor retention of drug in the peritoneum.28-34 In addition to the pharmacokinetic advantage that IP chemotherapy infusion after maximal tumor debulking offers, the addition of hyperthermia affects cell membranes, cytoskeletons, synthesis of macromolecules, and DNA repair mechanisms.35,36 Our institution (and others) has used

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Figure 2. Overall survival by primary tumor site. Differences are signicant: p 0.0001.

Figure 3. Overall survival by preoperative performance status. Differences are signicant: p 0.0001.

MMC primarily. The synergy between MMC and hyperthermia occurs independent of the cell cycle, allowing for major tumoricidal activity with brief exposures.37-39 In this study, we evaluated various clinical, treatment, and pathologic characteristics that potentially have an impact on survival for patients undergoing CS and IPHC with MMC for peritoneal surface neoplasms. There is a paucity of data about the utility of systemic therapy for PSD in general and for appendiceal tumors, particularly the more common low grade tumors. So, the foundation of treatment for PSD of appendiceal malignancies remains aggressive surgical cytoreduction followed by

hyperthermic peritoneal perfusion. Removal of bulk disease is imperative because even the most ambitious perfusion strategies penetrate only 5 mm into peritoneal surfaces. So aggressive cytoreduction allows hyperthermic chemoperfusion to treat the microscopic or small volume residual. Pathologic characteristics clearly have an impact on the clinical outcomes of patients with PSD. For appendiceal tumors, surgical series, patients with low grade mucinous carcinoma peritonei (also described as disseminated peritoneal adenomucinosis or pseudomyxoma peritonei [PMP]) experience better clinical outcomes than do those with higher

Figure 4. Overall survival by resection status, p

0.0001.

Figure 5. Overall survival by quartile of experience. Differences are signicant: p 0.031.

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grade nonmucinous appendiceal malignancies.40-46 In this study, the survival rate in patients with high-grade lesions was substantially lower than for those with low-grade PSD. This is not an unexpected finding based on the biologic and molecular differences between low- and high-grade nonmucinous appendiceal tumors.16,17 PMP does not typically metastasize beyond the abdominal or pelvic cavity. A recent correlative study found that appendiceal tumors associated with PMP have lower proliferative and apoptotic indices than colorectal epithelial neoplasms do. In addition, PMP-producing tumors have decreased cell adhesion molecule expression.42 Such studies are important in determining the biologic underpinnings of PMP. PMP has been considered the classic indication for IPHC. Five-year survivals after IPHC for PMP have ranged between 66% and 97%, and our experience is consistent with those results.43-46 Tumor histology is an independent prognostic factor in the subset of patients with PMP. The outcomes with the low-grade disseminated peritoneal adenomucinosis and intermediate/ hybrid histology were considerably better than those of high-grade peritoneal mucinous carcinomatosis in the original description of the histologic subtypes of PMP.47 Later, data from the Washington Hospital Center suggested that patients with low-grade disseminated peritoneal adenomucinosis had a better prognosis than those with mucinous adenocarcinoma or intermediate histology after exploratory laparotomy and cytoreduction.43 A subsequent study revealed a difference in 5-year survival between patients with low-grade (64%) and those with hybrid/high-grade (54%) treated with CS and IPHC (p 0.05). There were, however, very few peritoneal mucinous carcinomas (3 of 36) in the followup study.45 A criticism of past work evaluating CS and IPHC for PNP is that only benign or low-grade lesions were included in these studies, so confounding factors such as tumor biology and patient selection were not accounted for in these earlier studies. We believe that the behavior of PMP/appendiceal carcinoma is best described simply as low- and high-grade rather than using a more cumbersome three-tier classification.16,17 This clearly demonstrates the differences in tumor biology among these histologic subgroups of PMP. We reported in a earlier study of patients with peritoneal carcinomatosis (from a variety of histologies) that patients with Eastern Cooperative Oncology Group (ECOG) performance scores of 2 to 3 had considerably poorer overall survival (median survival of 9.5 months) than patients with performance scores of 0 or 1 (median survival of 21.7 months, p 0.02).18 This study supports our previous findings in a wide variety of tumor types. It also high-

lights the importance of evaluating candidates for the procedure while they are medically fit to undergo such a largescale intervention. In this study, preoperative performance status notably affected survival after CS and IPHC. Patients with performance scores of 0 had median survival four times that of Eastern Cooperative Oncology Group 2 patients; those with poorer performance status had median survival of 6 months (p 0.001). So we select patients for IPHC with Eastern Cooperative Oncology Group scores of 2 or better. Despite recent improvements in systemic therapy for colorectal cancer, treating patients with second line therapy while their performance status declines may deprive candidates of the opportunity to be salvaged with CS and IPHC. Patients undergoing complete CS before IPHC had superior outcomes compared with those who underwent incomplete CS, regardless of the primary lesion site. The 3-year survival rate for patients with a R0/1 resection was 59.9 3.9%; 3-year survivals for patients with R2a, R2b, and R2c resections were 38.7 5.3%, 15.0 5.3%, 14.0 4.2%, respectively (p 0.0001). This finding confirms data from our institution, and others, that demonstrate an important survival advantage for patients undergoing R0/R1 resection compared with those having R2 resections.18,48,49 In a review of 506 patients, Glehen and coworkers50 analyzed the survival of patients with peritoneal surface malignancies from colorectal primary tumors undergoing incomplete CS followed by IPHC, and found that this treatment paradigm resulted in limited longterm survival. Patients who are unable to undergo major CS (R2a or better) at laparotomy may be spared the potential toxicity of IPHC. Surgical resection remains the primary mode of therapy for colon and rectal cancer. Treatment options for patients with unresectable metastatic disease have improved considerably in the past few years. Patients with stage IV colorectal cancer treated with newer combinations of cytotoxic chemotherapy,51 biologic agents, or both52 have resulted in an unprecedented median survival of approximately 20 months. But such therapeutic combinations are not an optimal treatment strategy for all categories of stage IV disease. We are unaware of patient survival beyond 5 years with medical therapy of any kind alone. Patients undergoing CS and IPHC had a 5-year survival of 17%; those undergoing R0/1 resections had survivals twice that.19 This is consistent with results from other high volume centers.50,53 This experience is supported by a randomized trial from the Netherlands comparing palliative surgery with chemotherapy to CS and IPHC with the same systemic chemotherapy.9 That randomized trial found a doubling of sur-

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vival for patients treated with CS and IPHC.9 So we concur with the consensus statement in that systemic therapy alone is no longer appropriate for patients with limited peritoneal dissemination from a primary or recurrent colon cancer.54 The surgical management of peritoneal surface malignancies of colorectal origin with CS and IPHC has been clearly defined and continues to improve. This aggressive strategy has resulted in longterm, disease-free survival rates that are unprecedented in the literature. Although at the cost of severe morbidity, properly selected patients have a real opportunity for survival in a situation previously approached with purely palliative intent. Primary peritoneal mesothelioma is a much less common entity than pleural malignancy.48 Although the molecular characteristics of peritoneal disease differ only slightly from the pleural disease, the clinical courses are disparate.55,56 Peritoneal disease typically presents with ascites, abdominal pain, and eventually, bowel obstruction. The disease tends to remain within the abdominal cavity until late in the course, and distant metastasis is distinctly uncommon, making this an excellent candidate for CS and IPHC. We and others have previously reported our experience with this modality,22,57-59 which represents a great improvement over the best systemic therapy.22,55,57-59 In our initial report, we used MMC as the agent,22 but have changed to cisplatinum after the reports from the surgery branch of the National Cancer Institute.57,58 We believe that mesothelioma represents one of the strongest cases for combining IPHC with CS. It is estimated that only a handful of patients who are potential candidates for this therapy actually receive it, which is underscored by the relatively small number of patients accrued to the phase II studies for peritoneal carcinomatosis at large perfusion centers. It is clear that expanding the number of centers should be done by surgical oncologists who have more than a passing knowledge of systemic chemotherapy and are comfortable with the rigors of aggressive operative procedures in the abdomen.23 This has led to a consensus statement by a group of surgeons with an interest in CS and IPHC that outlines an evaluation strategy for PSD from colorectal carcinoma.52,54 Although reported results from perfusion centers represent a substantial improvement in duration and likely quality of life,60-62 the majority of patients undergoing these procedures will experience tumor recurrence. Evaluating patients for second cytoreduction and additional chemoperfusion will become an ever more common problem because patients with PMP often require multiple procedures.23,63 We, and others, believe that in selected patients, a second cytoreductive procedure and chemoperfusion may be of value. In evaluating patients for second cytore-

duction, the same criteria 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 extraabdominal 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 PSD should not be considered candidates for second cytoreductive procedures.23,63 In this study, 41 patients underwent a second (or third) IPHC. Although these patients had good outcomes, this clearly represents a selection bias in choosing patients for repeat procedures. Several issues surround the future of CS and IPHC for PSD. 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 US and only 6 have experience with more than 100 patients. The operations required for aggressive cytoreduction are lengthy, challenging, morbid, and use a great deal of hospital, blood bank, and surgical house officer resources. Resource 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. Our experience has evolved and improved over the years of this study. This implies a learning curve, which may be lengthy. Although we would like to think our surgical techniques have improved substantially over time, we believe that it is primarily better patient selection that accounts for the improved outcomes. In addition, for most primary site tumors, the optimal time, dose, temperature, and chemotherapeutic agent for perfusion are not based on class I data. Fundamental questions about IPHC for PSD need to be addressed. Foremost among these is whether the addition of IPHC after CS is of value. It seems obvious that the value of IPHC should depend on the tumor being treated. The only completed randomized trial for CS and IPHC evaluated patients with PSD from colorectal primary lesions. That trial compared CS and IPHC with standard systemic chemotherapy to standard systemic therapy (fluorouracil and leucovorin) and found the CS and IPHC doubled the survival.9 But to date, no study has compared CS with or without IPHC.53 Clearly, it would be desirable to evaluate the value of IPHC versus CS alone, in a multicenter, prospective randomized trial. But such a randomized controlled trial has proved difficult to complete and efforts have previously failed.53,64 Specifically, many patients presenting themselves for evaluation to specialized centers

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refuse to consider such a randomization.64 Efforts to bring CS and IPHC to multicenter trials have not been embraced by the cooperative oncology groups to date. Such difficulties in performing randomized trials do not mean they should not be pursued. The advancement of centers of excellence and the initiation of cooperative group trials will help define the optimal treatment approach for peritoneal spread for PSD. The future of CS and IPHC for PSD lies in multicenter and randomized trials that not only investigate response and survival, but also standardization of techniques, quality of life, and integration with ever improving systemic therapy.
Author Contributions

Study conception and design: Levine, Loggie Acquisition of data: Levine, Stewart, Geisinger, Loggie, Shen Analysis and interpretation of data: Levine, Russell, Stewart, Loggie, Shen Drafting of manuscript: Levine, Russell Critical revision: Levine, Geisinger, Shen, Russell, Stewart
Acknowledgment: We wish to acknowledge the substantial contributions of house officers, perfusionists, nurses, enterostomal therapists, psychosocial oncologists, urologists, and radiologists who contributed to the care of these patients. We would also like to thank Joan Feder for her editorial support and Mary Cromer for her ongoing database maintenance.

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Discussion
KIRBY I BLAND, MD (Birmingham, AL): Dr Levine, it is very commendable, your survival of 27%, which at least in my hands doing this operation has been zero. My results would be in the 380 who had a zero 5-year survival rate. This is a very difficult procedure, and in your own terms was a 10-hour procedure that has been unachieved by other surgeons/clinics. You discussed differentiated histology types and broke out adenocarcinoma, specifically of the GI tract versus other sites, such as carcinoma of the appendix, having different survival outcomes. Knowing that data now, would you reconsider patients who would not be inclusive for the extensive, protracted (and expensive) procedure you describe? In other words, would you exclude those patients with adenocarcinoma of the GI tract even if they did have negative parameters outside the abdomen? And have you considered submitting this technique in a prospective randomized analysis, such as the American College of Surgeons Oncology Trials Group, such that this could truly be studied objectively? KELLY M MCMASTERS, MD (Louisville, KY): The authors report their experience with over 500 cases of cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for a variety of malignancies over the past 15 years. The procedure was associated with a 43% complication rate and a 30-day mortality rate of 4.8%or 4.3% in the updated analysis. Clearly, this is a serious operation with morbidity and mortality rates as high as or higher than any elective operation we perform in surgical oncology. Median survival was about 22 months, with 5-year survival rate of 28%. My questions are, first, does this operation really work? And second, if so, who really benefits from it? I would like to ask a couple of questions related to number two first, and then get to question number one. Some patients may have disease that is very indolent and may not require this procedure at the time of diagnosis. Others may have bulky or more aggressive tumors with a poor performance status, and their chance of benefit from the procedure is small, with a concomitant high likelihood of bad surgical outcomes. Clearly, performance

status, type of primary tumor, disease burden, and development of complications all had a major impact on survival. So my question is: How have you used the data from this study to modify your selection criteria? Will you only perfuse patients with ECOG performance status of zero to one? Did you perform analyses to predict which patients are likely to have major complications and early postoperative death? Finally, concerning question number one: Does this operation really work? I am afraid this paper does little to answer that question. A single randomized study suggests it is effective for patients with carcinomatosis from colorectal cancer. Because randomized trials have been so elusive for this procedure, my final question for the authors is: Are you prepared to restrict your practice of intraperitoneal hypothermic chemotherapy to properly conducted phase III studies? That is the only way we will ever answer this question. If even a modest fraction of the patients in this analysis had been enrolled in a prospective randomized study, we would now have convincing evidence to support its use. Therefore, I challenge the authors and those relatively few other centers in the US that perform this procedure to join together and answer this question once and for all. JOHN M DALY, MD (Philadelphia, PA): This particular report is of great personal interest to me. Your results, Dr Levine, and those of Paul Sugarbaker, David Bartlett, and a number of others, are really quite similar. It is curious that among our gynecologic oncology colleagues this treatment method, that is, hyperthermic intraperitoneal chemotherapy, is not uniformly accepted, and yet they are treating a more favorable disease, ovarian primary cancer. I have a couple of questions for you. One is the anastomosis that is performed at the time of the treatment. Other centers have reported a very large breakdown rate of the anastomosis and subsequent fistula, infection, and mortality. Could you tell us a little bit more about how you manage patients with bowel resection at the time of intraperitoneal treatment? Second, you mentioned some patients undergo a second-look procedure. Could you describe a little bit about that, the adhesions that are found at the time of second-look operation? Some have suggested that the type of chemotherapy, whether it be mitomycin or cisplatin, might be different in terms of subsequent adhesion formation. Finally, I couldnt agree more with the issue of a prospective trial to evaluate this form of treatment, although there are only a few centers throughout the country that are doing this. Without such a trial we will never know the answers to some of the questions you posed. Perhaps you could tell us how you would design the trial that would be used to answer the question. EMMANUEL ZERVOS, MD (Tampa, FL): I would like to congratulate Dr Levine and colleagues. We are kind of a renegade shop in Tampa doing this, and many times we utilize your data to justify the operations that we undertake. I just have a couple questions for you. There has been recent data from Europe and Dr Elias using oxaliplatium and the coliseum technique rather than the closed technique, which has really quite remarkable results. And I wonder if you