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Figure 1.
Overall survival by primary site.

Overall survival by primary site.

Figure 2.
Overall survival by resection status. See the "Cytoreductive Surgery" subsection of the "Methods" sectioon for a description of the resection classes.

Overall survival by resection status. See the "Cytoreductive Surgery" subsection of the "Methods" sectioon for a description of the resection classes.

Figure 3.
Overall survival by the presence vs absence of liver metastases.

Overall survival by the presence vs absence of liver metastases.

Figure 4.
Overall survival by histologic features.

Overall survival by histologic features.

Table 1. 
Patient Demographics and Baseline Clinicopathologic Data
Patient Demographics and Baseline Clinicopathologic Data
Table 2. 
Univariate Analysis of Clinicopathologic Variables for Overall Survival
Univariate Analysis of Clinicopathologic Variables for Overall Survival
Table 3. 
Cox Regression Analysis of Overall Survival
Cox Regression Analysis of Overall Survival
Table 4. 
Published Series of Intraperitoneal Hyperthermic Chemotherapy and Cytoreductive Surgery for Peritoneal Carcinomatosis
Published Series of Intraperitoneal Hyperthermic Chemotherapy and Cytoreductive Surgery for Peritoneal Carcinomatosis
1.
Pilati  PRossi  CRMocellin  S  et al.  Multimodal treatment of peritoneal carcinomatosis and sarcomatosis. Eur J Surg Oncol. 2001;27125- 134Article
2.
Sadeghi  BArvieux  CGlehen  O  et al.  Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer. 2000;88358- 363Article
3.
Chu  DZLang  NPThompson  COsteen  PKWestbrook  KC Peritoneal carcinomatosis in nongynecologic malignancy: a prospective study of prognostic factors. Cancer. 1989;63364- 367Article
4.
Wong  CSHarwood  ARCummings  BJKeane  TJThomas  GMRider  WD Total abdominal irradiation for cancer of the colon. Radiother Oncol. 1984;2209- 214Article
5.
Dedrick  RL Theoretical and experimental bases of intraperitoneal chemotherapy. Semin Oncol. 1985;121- 6
6.
Sugarbaker  PHJablonski  KA Prognostic features of 51 colorectal and 130 appendiceal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneal chemotherapy. Ann Surg. 1995;221124- 132Article
7.
Esquivel  JVidal-Jove  JSteves  MASugarbaker  PH Morbidity and mortality of cytoreductive surgery and intraperitoneal chemotherapy. Surgery. 1993;113631- 636
8.
Schneebaum  SArnold  MWStaubus  AYoung  DCDumond  DMartin Jr  EW Intraperitoneal hyperthermic perfusion with mitomycin C for colorectal cancer with peritoneal metastases. Ann Surg Oncol. 1996;344- 50Article
9.
Yonemura  YFujimura  TFushida  S  et al.  Hyperthermo-chemotherapy combined with cytoreductive surgery for the treatment of gastric cancer with peritoneal dissemination. World J Surg. 1991;15530- 535Article
10.
Bartlett  DLBuell  JFLibutti  SK  et al.  A phase I trial of continuous hyperthermic peritoneal perfusion with tumor necrosis factor and cisplatin in the treatment of peritoneal carcinomatosis. Cancer. 1998;831251- 1261Article
11.
Park  BJAlexander  HRLibutti  SK  et al.  Treatment of primary peritoneal mesothelioma by continuous hyperthermic peritoneal perfusion (CHPP). Ann Surg Oncol. 1999;6582- 590Article
12.
Stephens  ADAlderman  RChang  D  et al.  Morbidity and mortality analysis of 200 treatments with cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy using the coliseum technique. Ann Surg Oncol. 1999;6790- 796Article
13.
Cavaliere  FDi Filippo  FBotti  C  et al.  Peritonectomy and hyperthermic antiblastic perfusion in the treatment of peritoneal carcinomatosis. Eur J Surg Oncol. 2000;26486- 491Article
14.
Beaujard  ACGlehen  OCaillot  JL  et al.  Intraperitoneal chemohyperthermia with mitomycin C for digestive tract cancer patients with peritoneal carcinomatosis. Cancer. 2000;882512- 2519Article
15.
Watanabe  MTanaka  RHondo  HKuroki  M Effects of antineoplastic agents and hyperthermia on cytotoxicity toward chronically hypoxic glioma cells. Int J Hyperthermia. 1992;8131- 138Article
16.
Teicher  BAKowal  CDKennedy  KASartorelli  AC Enhancement by hyperthermia of the in vitro cytotoxicity of mitomycin C toward hypoxic tumor cells. Cancer Res. 1981;411096- 1099
17.
Sugarbaker  PHChang  D Results of treatment of 385 patients with peritoneal surface spread of appendiceal malignancy. Ann Surg Oncol. 1999;6727- 731Article
18.
Pestieau  SRSugarbaker  PH Treatment of primary colon cancer with peritoneal carcinomatosis: comparison of concomitant vs delayed management. Dis Colon Rectum. 2000;431341- 1346Article
19.
Loggie  BWFleming  RAMcQuellon  RPRussell  GBGeisinger  KR Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for disseminated peritoneal cancer of gastrointestinal origin. Am Surg. 2000;66561- 568
20.
Schag  CCHeinrich  RLGanz  PA Karnofsky performance status revisited: reliability, validity, and guidelines. J Clin Oncol. 1984;2187- 193
21.
McCarter  MDFong  Y Role for surgical cytoreduction in multimodality treatments for cancer. Ann Surg Oncol. 2001;838- 43Article
22.
Schwartz  PERutherford  TJChambers  JTKohorn  EIThiel  RP Neoadjuvant chemotherapy for advanced ovarian cancer: long-term survival. Gynecol Oncol. 1999;7293- 99Article
23.
Sugarbaker  PH Peritoneal Carcinomatosis: Principles and Management.  Boston, Mass Kluwer Academic Publishers1996;337- 357
24.
Simpson-Herren  LSanford  LHolmquist  JP Effects of surgery on the cell kinetics of residual tumor. Cancer Treat Rep. 1976;601749- 1760
25.
Gunduz  NFisher  BSaffer  EA Effects of surgical removal on the growth and kinetics of residual tumor. Cancer Res. 1979;393861- 3865
26.
Los  G Penetration of carboplatin and cisplatin into rat peritoneal tumor nodules after intraperitoneal chemotherapy. Cancer Chemother Pharmacol. 1991;28159- 165Article
27.
Markman  M Intraperitoneal therapy in ovarian cancer utilizing agents achieving high local but low systemic exposures. Reg Cancer Treat. 1991;3264- 268
28.
Sugarbaker  PHZhu  BWSese  GBShmookler  B Peritoneal carcinomatosis from appendiceal cancer: results in 69 patients treated by cytoreductive surgery and intraperitoneal chemotherapy. Dis Colon Rectum. 1993;36323- 329Article
29.
Jacquet  PSugarbaker  P Abdominal adhesions causing intestinal obstruction following cytoreduction surgery and early postoperative intraperitoneal chemotherapy. Acta Chir Austriaca. 1995;2792- 95Article
30.
Jacquet  PSugarbaker  P Influence of wound healing on gastrointestinal cancer recurrence. Wounds. 1995;71- 8
31.
Spratt  JAdcock  MMuskovin  MSherrill  W Clinical delivery system for intraperitoneal hyperthermic chemotherapy. Cancer Res. 1980;40256- 260
32.
Giovanella  BCStehlin  JSMorgan  AC  et al.  Selective lethal effect of supranormal temperature on human neoplastic cells. Cancer Res. 1976;363944- 3950
33.
Dudar  TEJain  RK Differential response of normal and tumor microcirculation to hyperthermia. Cancer Res. 1984;44605- 612
34.
Joiner  MCSteel  GGStephens  TC Response of two mouse tumors to hyperthermia with CCNU or melphalan. Br J Cancer. 1982;4517- 26Article
35.
Sugarbaker  PH Pseudomyxoma peritonei: a cancer whose biology is characterized by a redistribution phenomenon. Ann Surg. 1994;219109- 111Article
36.
Loggie  BWFleming  RAMcQuellon  RPRussell  GBGeisinger  KRLevine  EA Prospective trial for the treatment of malignant peritoneal mesothelioma. Am Surg. 2001;67999- 1003
37.
Elias  DBlot  FEl Otmany  A  et al.  Curative treatment of peritoneal carcinomatosis arising from colorectal cancer by complete resection and intraperitoneal chemotherapy. Cancer. 2001;9271- 76Article
38.
Piso  PBektas  HWerner  U  et al.  Improved prognosis following peritonectomy procedures and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis from appendiceal carcinoma. Eur J Surg Oncol. 2001;27286- 290Article
39.
Witkamp  AJdeBree  EKaag  MMVanSlooten  GWvanCoevorden  FZoetmulder  FAN Extensive surgical cytoreduction and intraoperative hyperthermic intraperitoneal chemotherapy in patients with pseudomyxoma peritonei. Br J Surg. 2001;88458- 463Article
40.
Witkamp  AJdeBree  EKaag  MM  et al.  Extensive cytoreductive surgery followed by intra-operative hyperthermic intraperitoneal chemotherapy with mitomycin-C in patients with peritoneal carcinomatosis of colorectal origin. Eur J Cancer. 2001;37979- 984Article
41.
McQuellon  RPLoggie  BWFleming  RARussell  GBLehman  ABRambo  TD Quality of life after intraperitoneal hyperthermic chemotherapy (IPHC) for peritoneal carcinomatosis. Eur J Surg Oncol. 2001;2765- 73Article
42.
McQuellon  RPLoggie  BWLehman  AB  et al.  Long-term survivorship and quality of life following intraperitoneal hyperthermic chemotherapy (IPHC) for peritoneal carcinomatosis. Ann Surg Oncol. In press.
43.
Zoetmulder  FANVerwaal  V Hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C significantly improves survival in patients with peritoneal carcinomatosis of colorectal origin [abstract]. ASCO Prog Proc. 2002;21147a
Original Article
January 2003

Factors Predicting Survival After Intraperitoneal Hyperthermic Chemotherapy With Mitomycin C After Cytoreductive Surgery for Patients With Peritoneal Carcinomatosis

Author Affiliations

From Wake Forest University Baptist Medical Center, Departments of General Surgery (Drs Shen, Levine, and Hall), Oncology (Drs Case and McQuellon and Mr Russell), and Pathology (Dr Geisinger), and Kucera Pharmaceutical Co (Dr Fleming), Winston-Salem, NC; and Creighton University Cancer Center, Omaha, Neb (Dr Loggie).

Arch Surg. 2003;138(1):26-33. doi:10.1001/archsurg.138.1.26
Abstract

Hypothesis  Certain clinicopathologic factors predict improved survival after cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis.

Design  Prospective clinical trial.

Setting  Surgical oncology service at a university academic hospital.

Patients  A population of 109 consecutive patients with peritoneal carcinomatosis treated between December 1991 and November 1997.

Intervention  All patients underwent resection of gross disease followed by 2-hour intraoperative perfusion of mitomycin C (20-40 mg) into the peritoneal cavity at a temperature of 40.5°C.

Main Outcome Measures  Clinicopathologic factors that independently predicted improved overall survival rates.

Results  Overall survival at 1 and 3 years was 61% and 33%, respectively. With median follow-up of 52 months, median overall survival was 16 months. Four factors were significant independent predictors of improved survival by multivariate analysis: nonadenocarcinoma histologic features (P = .001), the appendix as a primary site (P = .003), the absence of hepatic parenchymal metastases (P = .01), and complete resection of all gross disease (R1/0 resection) (P<.001). Patients with an R1/0 resection vs an incomplete resection of gross disease (R2 resection) had 3-year overall survival of 68% vs 21% (P<.001).

Conclusions  Patients with peritoneal carcinomatosis have a uniformly poor prognosis. However, in select patients, the natural history of this disease condition may be altered by using the multimodality approach of cytoreductive surgery and intraperitoneal hyperthermic chemotherapy. These results require confirmation in prospective randomized studies.

TREATMENT OF patients with peritoneal carcinomatosis (PC) from gastrointestinal and nongastrointestinal malignancies is in evolution. Peritoneal carcinomatosis is the most common cause of death in patients resected for intra-abdominal carcinomas.1 A multicenter study2 prospectively following 370 patients with PC reported mean and median overall survival (OS) of 6.0 and 3.1 months, respectively.

Surgical resection alone has been shown3 to be ineffective for the treatment of PC, with median survival of 1.0, 1.0, 0.7, and 6.0 months for PC from gastric, small-bowel, pancreas, and colorectal cancer treated in this fashion. Attempts at controlling PC with either external beam radiation therapy or brachytherapy have not demonstrated efficacy.4 The use of systemic chemotherapy for PC has not been shown to be efficacious, as many patients present with PC after failing systemic chemotherapy.5 Intraperitoneal administration of chemotherapy has the benefit of higher concentrations of cytotoxic drug delivered locally to the site of the tumor while minimizing systemic toxic effects compared with intravenous administration. Pharmacokinetic studies5 have demonstrated a 107-fold increase in the concentration of mitomycin C (MMC) in the intraperitoneal perfusate vs plasma concentrations when administered systemically. Initial studies from Sugarbaker and colleagues6,7 at the Washington Cancer Institute described the use of cytoreductive surgery (CS) and early postoperative intraperitoneal chemotherapy using fluorouracil and MMC. Three-year OS of 66% for men and 84% for women with PC from appendiceal cancer has been reported with such a multimodality approach.6

Recent studies814 have reported on the combination of CS and intraoperative intraperitoneal chemotherapy administered under hyperthermic conditions (40°C-43°C). The use of intraperitoneal chemotherapy at the time of surgery allows a potentially more even distribution of drug without having to deal with catheter-related complications and postoperative adhesions. Hyperthermia has been shown to potentiate the cytotoxicity of drugs such as MMC and cisplatin.15,16 These interactions are enhanced under hypoxic conditions, which is not true for most agents given after surgical resection.

Data on prognostic factors for this procedure are limited. Factors such as completeness of resection, lymphatic or hematogenous spread, histologic features of the tumor, site of primary tumor, previous surgery, and malignant ascites have been proposed as significant variables determining outcome.14,1719 We examined the results of a prospective phase 2 protocol of CS and intraperitoneal hyperthermic chemotherapy (IPHC) with MMC for PC to determine the clinicopathologic factors that were independent predictors for OS.

METHODS

The study protocol was reviewed and approved by the institutional review board of the Wake Forest University School of Medicine. Eligible patients entered the protocol between December 1991 and November 1997. The protocol was open to patients with PC from gastrointestinal and nongastrointestinal primary sites without evidence of extra-abdominal disease. Eastern Cooperative Oncology Group performance status was recorded in all patients entering the protocol.20

CYTOREDUCTIVE SURGERY

All patients in the study were operated on by the same surgeon (B.W.L.). Cytoreductive surgery consisted of the removal of all gross tumors and involved organs, peritoneum, or tissue deemed technically feasible and safe for the patient. Any tumors adherent or invasive to vital structures that could not be removed were cytoreduced using the cavitational ultrasonic surgical aspirator (CUSA; Valleylab, Boulder, Colo). Peritonectomy was performed as indicated. The resection status of patients was estimated 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 cytologic findings or microscopic margins; R2a, minimal residual tumor, nodule(s) measuring 0.5 cm or less; R2b, gross residual tumor, nodule greater than 0.5 cm but less than or equal to 2 cm; and R2c, extensive disease remaining, nodules greater than 2 cm.

INTRAPERITONEAL HYPERTHERMIC CHEMOTHERAPY

Patients were cooled to a core temperature of approximately 34°C to 35°C by passive measures (ie, not warming airway gases or intravenous 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 catheter tips. The abdominal skin incision was closed temporarily with a running suture to prevent leakage of peritoneal perfusate. A perfusion circuit was established with approximately 3 L of Ringer lactate. Flow rates of approximately 600 to 800 mL/min were maintained using a roller pump managed by the pump technician. The circuit continued through a single roller pump, through a heat exchanger (SCI-MED, No. A-714; Gish Biomedical, Irvine, Calif), and then to the patient.

Constant temperature monitoring was performed at all temperature probes. Once inflow temperatures exceeded 38.5°C, 30 mg of MMC was added to the perfusate, and at 60 minutes an additional 10 mg of MMC was added to keep MMC perfusate concentrations higher than 5 µg/mL. A maximum inflow temperature of 40.5°C was realized during perfusion, with an outflow temperature at the pelvis of 39.5°C. The abdomen was gently massaged throughout perfusion to improve drug distribution to all peritoneal surfaces. Total perfusion time after the initial addition of MMC was 120 minutes. In certain patients (elderly individuals, those with extensive previous chemotherapy, those with inanition or poor performance status, and patients having extensive peritoneal stripping during surgery), reductions in the dose of MMC (to 30 mg total) or perfusion time (to 60-90 minutes) were made owing to concerns about potential toxic effects.

CLINICAL FOLLOW-UP

Clinical follow-up occurred at 1 and 3 months, and then every 3 months thereafter for up to 1 year. After 1 year, follow-up was at 3-month intervals or less frequently if the patient continued to remain without evidence of disease. Abdominal and pelvic computed tomographic scans were obtained 3, 6, and 12 months after surgery or when clinically indicated. Some patients received systemic chemotherapy after referral back to their medical oncologists.

STATISTICAL ANALYSIS

The rate of OS was calculated from the date of CS and IPHC to the last recorded date of follow-up or recorded date of death. All data were collected prospectively. Kaplan-Meier analysis was performed on all pertinent clinicopathologic variables to determine estimates of survival over time. Group comparisons of OS rates were performed using the log-rank test. The Cox proportional hazards regression model was used to perform multivariate analysis of clinicopathologic factors to determine independent predictors of OS.

RESULTS
PATIENTS

A total of 109 patients with PC from gastrointestinal and nongastrointestinal origins were entered into the protocol. Table 1 lists patient demographics and baseline data. The site of primary tumor categorized as "other" includes 1 patient each with pancreas, small intestine, periampullary, and bladder tumors.

SURVIVAL AND FOLLOW-UP

For the cohort of 109 patients, 1- and 3-year OS was 61% and 33%, respectively. Median OS was 16 months (95% confidence interval, 12-24 months), with median follow-up of 52 months. Table 2 gives the results of a log-rank analysis of the multiple clinicopathologic variables listed in Table 1.

Multivariate analysis demonstrated 4 clinicopathologic factors that were independent predictors of OS (Table 3): the appendix as a primary site, complete resection of all gross tumor, absence of liver metastases, and nonadenocarcinoma histologic features. Figure 1, Figure 2, Figure 3, and Figure 4 depict the survival curves for these factors. When the appendix was the primary site, the histologic findings consisted of adenocarcinoma (n = 13), pseudomyxoma peritonei (n = 9), and carcinoid (n = 1).

MORBIDITY AND MORTALITY

Postoperative morbidity and mortality were 36% and 8%, respectively. Mortality was calculated as postoperative deaths directly attributable to the procedure, regardless of time since the operation. Causes of death included bowel perforation (n = 3), bone marrow suppression (n = 2), respiratory failure (n = 2), methicillin-resistant Staphylococcus aureus infection (n = 1), and pulmonary embolus (n = 1). Twenty-three patients (21%) developed hematologic toxic effects requiring growth factor support or platelet transfusion. The median number of units of single donor platelets transfused was 2 (range, 1-104 U). Sixty-nine patients (63%) required a blood transfusion, with a median of 3 U (range, 1-38 U) transfused. The median operative time and length of hospital stay for CS and IPHC was 9 hours (range, 4-18 hours) and 9 days (range, 5-105 days), respectively.

DELIVERY OF IPHC

Of 103 patients whose IPHC dosages and perfusion times were available, 67 (65%) received the standard intraperitoneal perfusion of 2 hours and 40 mg of MMC. Another 14 patients (14%) underwent 2 hours of perfusion but received only 30 mg of MMC. The other 22 patients underwent 1 hour of perfusion with the following amounts of MMC administered: 40 mg in 2 patients (2%), 30 mg in 19 (18%), and 20 mg in 1 (1%). When the clinical outcome of patients was stratified by those who received a standard protocol perfusion vs those who did not, there was no significant difference (P = .60).

COMMENT

As surgical techniques and perioperative care have improved, there has been a greater trend toward more aggressive surgical treatment of solid tumors. The role of cytoreduction, which implies treatment that incompletely eradicates tumor, has traditionally been reserved for chemotherapy or radiation therapy because it was believed that using surgery for this purpose was associated with excessive morbidity and mortality.21 However, there is a theoretic and a clinical basis to suggest that the role of CS should be reexamined.

The benefit of CS has been demonstrated in the treatment algorithm for peritoneally disseminated ovarian cancer. The combination of aggressive surgical debulking of disease with systemic chemotherapy and radiation therapy resulted in the best survival advantage.22 The experience in ovarian cancer illustrates the treatment of a disease for which chemotherapeutic options exist and in which surgery is performed only to reduce the bulk of disease to a level at which the chemotherapy could be expected to be most effective.

The benefit of intraperitoneal chemotherapy in the setting of PC can be explained by gompertzian cellular kinetics: in the initial stages, tumoral cell growth is exponential, but as the tumor enlarges, its blood supply and growth slow down, and a gradually larger percentage of tumor cells enters a nonproliferative phase of the cellular cycle.23 In theory, debulking should rid the body of more cells, thereby stimulating the remaining cells to enter the proliferating phase of the cell cycle, potentially becoming more responsive to administration of antineoplastic agents.24,25 Studies26 of intraperitoneal delivery of cytotoxic agents have shown that direct tumor absorption of drugs occurs to a level of 5 mm beneath the tumor surface. Low transperitoneal absorption, owing to the plasma-peritoneal barrier,23 allows systemic drug concentrations 18- to 620-fold lower than intraperitoneal concentrations.27

Such historic and theoretic considerations gave credence to the concept of intraperitoneal chemotherapy as an adjunct to CS. Initial studies7,28 reported the use of early postoperative intraperitoneal chemotherapy given through Tenckhoff catheters placed at the time of surgery. Although there have been no controlled studies, to our knowledge, comparing postoperative and intraoperative intraperitoneal therapy, a potential criticism of postoperative therapy is inhomogeneous drug distribution caused by early postoperative adhesions. The resultant tumor entrapment by fibrin in dissected areas decreases its exposure to chemotherapeutic agents.29,30

Spratt et al31 were the first researchers to associate hyperthermia with intraperitoneal chemotherapy after CS. Experimental evidence32 suggests that tumor tissue is more sensitive to heat than normal tissue because of intrinsic thermosensitivity and lower efficacy in heat exchange through vasodilation. The effects of hyperthermia on malignant tissue seem to be mediated by direct cytotoxicity and the microcirculation peculiar to neoplasms.33 Moreover, hyperthermia synergistically enhances the chemosensitivity of tumor cells to MMC.15 Mechanisms of action include increased cellular accumulation and activation of MMC and altered repair of DNA damage caused by MMC.16

The most significant predictor of outcome in our series, which is consistent with previous studies,14,1719 is the completeness of the cytoreduction. The ability of hyperthermia and intraperitoneal administration of chemotherapy to work synergistically directly depends on the residual tumor volume.34 Patients who underwent complete CS usually had disease limited to the parietal peritoneum or structures that could be completely removed, such as the colon, omentum, spleen, or gallbladder. When there was extensive involvement of the small intestine or its mesentery, an R0/1 resection was not possible. In fact, one relative contraindication to CS and IPHC is radiologic evidence of substantial tumor infiltration of the small-bowel mesentery.

An appendiceal primary site is known to be an important factor in predicting a favorable outcome.7,19 The appendix as a primary cancer site for the seeding on peritoneal surfaces is unique in that the tumor is often of low biological aggressiveness.35 Disseminated tumors from this primary site have a low incidence of lymphatic and hematogenous spread and tend to spare the small bowel, which makes complete cytoreduction more feasible.

Although nonadenocarcinoma histologic findings were found to be an independent predictor for improved survival, only approximately 20% of patients in the study cohort fit this category. The favorable prognosis of patients with pseudomyxoma peritonei has been well described.6 We36 recently described our experience using CS and IPHC with MMC for patients with malignant peritoneal mesothelioma and reported median survival of 34 months. Owing to the rarity of presentation, no mature outcome data are available for patients with PC from sarcoma and carcinoid, except as part of a larger series such as this.

Frequently, patients will be found to have metastatic implants on the liver surface during abdominal exploration. These are thought to occur from the same process of intraperitoneal dissemination that leads to PC, and their subsequent removal is part of the process of CS. However, when hematogenous spread of tumor leads to hepatic parenchymal metastases, patient outcome is uniformly poor.7,37 This indicates spread of tumor beyond the peritoneal cavity, which makes it a systemic problem. Based on the present analysis, we generally do not perform CS and IPHC in this subset of patients.

Nearly a third of the patients in this series did not receive the full application of heat and chemotherapy as described in the protocol. Log-rank analysis did not find any significant difference in outcome between patients who underwent 2 hours of heated application of 40 mg total of MMC and those who were subjected to less hyperthermia, less chemotherapy, or both. It is not clear whether administering a shorter period of hyperthermia with or without a decreased dosage of MMC would have had the same cytotoxic effect with less hematologic toxic effects. In addition, the literature1 reports that achieving an intraperitoneal temperature of at least 41°C is desirable for optimizing drug diffusion into tissues and for maximizing the synergistic effect with chemotherapy. In our protocol, the maximum inflow temperature achieved was 40.5°C, with an outflow temperature of 39.5°C. At the time of this study, the perfusion machines being used were primarily designed for cardiopulmonary bypass and had safety cutoff temperatures that limited the maximum inflow temperature that could have been achieved. The final plateau temperature was ultimately determined by equipment limitations and any heat losses from the perfusion catheters. Currently, our perfusions are performed using a machine (ViaCirQ, Pittsburgh, Pa) that does not have temperature limitations, and increased intraperitoneal temperatures are being studied.

Table 4 lists previously published series of CS and IPHC for PC, including the present study. Most studies used an intra-abdominal perfusion temperature greater than or equal to 41°C. However, despite using a lower intraperitoneal temperature, our clinical results compare favorably with those from these other studies. In addition, our postoperative morbidity and mortality rates are consistent with those from the other series as well.

The morbidity and mortality of this procedure, as demonstrated in this study and others in the literature, are not insignificant. As this is essentially a palliative procedure, with most patients eventually succumbing to their disease process, an important factor to consider besides OS is the effect of this procedure on the individual's quality of life (QOL). Two recent studies from our institution (Wake Forest University Health Sciences, Winston-Salem) examined short- and long-term QOL outcomes after CS and IPHC. Sixty-four patients in the short-term study41 reported decreased overall QOL after surgery compared with baseline but then returned to baseline or better within 3 to 6 months of surgery. A follow-up study42 of 17 patients surviving more than 3 years after CS and IPHC reported that more than 90% had minimal to no limitations of activity, with functional assessments that compared favorably to national reference values for their respective age groups. Currently, all patients undergoing CS and IPHC are entered preoperatively into an ongoing QOL study.

Probably the most difficult aspect of this study to interpret is the heterogeneity of the patient population. Patients in this phase 2 trial presented with PC from various primary tumor types, including appendiceal primaries with good prognosis and gastric cancers with poorer prognosis. Yet, despite the variety of solid malignancies represented in this study, they all presented at a similar stage of disease. As the number of patients undergoing this procedure increases, more emphasis will need to be placed on studying the outcome of patients with PC from specific primary tumor sites with uniform histologic features.

Findings from this trial and available data indicate that applying a multimodality approach to patients with PC can significantly alter the natural history of the disease, palliate symptoms, and even produce long-term survival. A recent prospective trial43 randomized 104 patients with PC from colorectal adenocarcinoma to receive CS and IPHC with MMC followed by systemic fluorouracil and leucovorin calcium therapy or CS and systemic fluorouracil and leucovorin calcium therapy alone. With mean follow-up of 24 months, 2-year OS was 43% in the IPHC arm and 16% in the standard therapy arm (P = .01).43

Cytoreductive surgery and IPHC with MMC is an aggressive multidisciplinary approach to a difficult oncologic situation with few meaningful therapeutic options. Although it is clearly not a treatment for all patients with PC, we believe that selected patients may benefit from improved QOL and extended OS.

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Article Information

Corresponding author and reprints: Perry Shen, MD, Surgical Oncology Service, Wake Forest University Baptist Medical Center, Medical Center Blvd, Winston-Salem, NC 27157 (e-mail: pshen@wfubmc.edu).

Accepted for publication September 7, 2002.

This study was presented in part at the American Society of Clinical Oncology annual meeting, San Francisco, Calif, May 12, 2001.

References
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Pilati  PRossi  CRMocellin  S  et al.  Multimodal treatment of peritoneal carcinomatosis and sarcomatosis. Eur J Surg Oncol. 2001;27125- 134Article
2.
Sadeghi  BArvieux  CGlehen  O  et al.  Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer. 2000;88358- 363Article
3.
Chu  DZLang  NPThompson  COsteen  PKWestbrook  KC Peritoneal carcinomatosis in nongynecologic malignancy: a prospective study of prognostic factors. Cancer. 1989;63364- 367Article
4.
Wong  CSHarwood  ARCummings  BJKeane  TJThomas  GMRider  WD Total abdominal irradiation for cancer of the colon. Radiother Oncol. 1984;2209- 214Article
5.
Dedrick  RL Theoretical and experimental bases of intraperitoneal chemotherapy. Semin Oncol. 1985;121- 6
6.
Sugarbaker  PHJablonski  KA Prognostic features of 51 colorectal and 130 appendiceal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneal chemotherapy. Ann Surg. 1995;221124- 132Article
7.
Esquivel  JVidal-Jove  JSteves  MASugarbaker  PH Morbidity and mortality of cytoreductive surgery and intraperitoneal chemotherapy. Surgery. 1993;113631- 636
8.
Schneebaum  SArnold  MWStaubus  AYoung  DCDumond  DMartin Jr  EW Intraperitoneal hyperthermic perfusion with mitomycin C for colorectal cancer with peritoneal metastases. Ann Surg Oncol. 1996;344- 50Article
9.
Yonemura  YFujimura  TFushida  S  et al.  Hyperthermo-chemotherapy combined with cytoreductive surgery for the treatment of gastric cancer with peritoneal dissemination. World J Surg. 1991;15530- 535Article
10.
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