Protocol

The type of study was an open, prospective, nonrandomized, monocentric phase II study performed at Centre Hospitalo-Universitaire Lyon-Sud. It was initiated in January 1998 and closed in September 2001.

The inclusion criteria were age younger than 65 years, abdominal cancer patients including malignant peritoneal mesothelioma as well as pseudomyxoma peritonei, PC confirmed by pathologic examination, synchronous or metachronous PC, absence of extraabdominal metastases, no liver metastases on preoperative explorations, satisfactory cardiorespiratory and renal status, and signed informed consent.

The exclusion criteria were unresectable primary tumors, renal or myocardial failures, administration of systemic chemotherapy 1 month before inclusion, CNS disease (vascular or neoplastic), and World Health Organization (WHO) index more than 2.

Before inclusion in the protocol, all patients underwent a physical examination, blood cell count, serum electrolytes, hepatic function test, Quick’s test, kaolin-activated partial thromboplastin time test, blinding test, cardiac ultrasound, spirometry, cerebral and thoracic computed tomography (CT) scan, abdominal ultrasonography for liver exploration and abdominal CT scan for PC exploration, and biologic renal and hemostasis exploration.

The protocol required that for synchronous PC, surgical resection of the primary tumor had to be performed before or at the same time as peritonectomy and IPCH with a maximal allowed delay of 5 weeks; peritonectomy had to minimize as much as possible the residual tumor volume exposed to IPCH; and postoperative systemic chemotherapy was recommended, according to the general status of the patient, at least 6 weeks after IPCH and following the rules for palliative systemic chemotherapy.

This protocol was performed in accordance with the precepts established by the Helsinki declaration, and has been approved by the Lyon Human Investigation Committee.

Surgical Procedures

Under general anesthesia and complete hemodynamic monitoring, careful abdominal exploration and cytological as well as pathologic samples were taken through a median laparotomy (from xyphoid to pubis). Surgical resection of the primary tumor was performed according to oncologic surgical rules (lymphadenectomy, acceptable margins). Once the primary tumor had been removed, a peritonectomy was performed, adapted to the location of the malignant granulations as guided by the surgeon, exploration, and extemporaneous biopsies (systematic, extensive peritonectomies were not performed). These peritonectomies were performed according to Sugarbaker’s surgical.¹⁰ Locations of peritonectomy performed were preoperatively recorded on a specific form: right diaphragmatic cupula, left diaphragmatic cupula, greater omentum, lesser omentum, omental bursa, right paracolic gutter, left paracolic gutter, Douglas’pouch, anterior wall peritoneum, posterior wall peritoneum, Glisson capsula, and mesenteric peritoneum (mesenteric peritoneum was not extensively removed, but after acceptable small bowel resections guided by maximal tumor volume locations, remaining malignant granulations were destroyed using electrosurgical fulguration).

Type of IPCH

At the end of each surgical procedure, an IPCH infusion was carried out under general anesthesia and general hypothermia (32°C induced by duration of peritonectomy procedure, cold wraps on the legs, and ice hat). Before closure of the laparotomy, two inflow drains were inserted under the left and right diaphragmatic cupula (30 French silicone drainage, William Harvey, Bard Cardiopulmonary Division, USA), whereas a third drain (outflow drainage) was inserted in the Douglas’pouch (32 French). Thermic probes (Mallinckrodt SA and Cair SA, Lozanne, France) were also inserted within the abdominal cavity (behind the liver pedicula and near the first jejunal loop). Other thermic probes were set up outside the abdominal cavity on the inflow and outflow drains (8 cm from the skin) and inside the bladder with a Foley catheter. Laparotomy was then closed and inflow and outflow drains were connected to a closed sterile circuit in which a 4 to 6 L perfusate (Travenol laboratory, Norfolk, England) was circulated by means of an electromagnetic pump at a flow rate of 500 mL/mn. The closed sterile circuit was heated by means of a thermal exchanger (Dideco, France) connected to a heating circuit. Intra- and extraabdominal temperatures were connected to a thermic reader (Cair SA, Lozanne, France) and monitored every 10 minutes (Fig 1⇓). IPCH was performed for 90 minutes with close monitoring of respiratory and hemodynamic parameters at inflow temperatures ranging between 46°C and 48°C.

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Fig 1.

Intraperitoneal chemohyperthermia device.

Type of Intraperitoneal Chemotherapy (IPC)

For PC from digestive origin, mitomycin C (MMC) was used at the dose of 0.7 mg/kg (maximum dose of 60 mg). For PC from ovarian origin, cisplatin (CDDP) was used at the dose of 1 mg/kg (maximum dose of 80 mg). For PC from peritoneal malignant mesothelioma and pseudomyxoma, MMC and CDDP were combined intraperitonealy at the dose of 0.5 mg/kg and 0.7 mg/kg, respectively. MMC and/or CDDP were inserted in the peritoneal dialysis liquid at the beginning of IPCH.

Laboratory Data

Samples of blood, urine, and perfusate were collected during IPCH at 45 and 90 minutes, and MMC and CDDP concentrations were measured by high-performance liquid chromatography.¹⁴ After the end of IPCH, MMC concentrations were measured at 24 hours and CDDP concentrations at 12, 24, and 72 hours, in blood, urine, and abdominal drainages.

Patients

From January 1998 to September 2001, 56 patients were included in the present study. A great number of selection factors (according to the inclusion and exclusion criteria of the protocol) were used before and after referral and strongly influenced the composition of this patient population: during the 45-month period of the study, 240 patients with PC were referred to our department for treatment, whereas only 56 met the selection criteria and gave their informed consent. Unfortunately, no data in regard to the follow-up of the 184 excluded patients was obtained. Exclusions were mainly decided according to age, WHO index less than 2, unsatisfactory cardiac or renal functions, clear evidence of massive and total abdominal cavity involvement on clinical examination, and presence of extraabdominal metastasis. The 184 excluded patients were then followed by the referring hospital.

The 56 selected patients were 35 females and 21 males, mean age 49.3 years (SD = 10.7 years, range, 25 to 65). Locations of primary tumor were right colon adenocarcinoma (n = 15), left colon adenocarcinoma (n = 11), gastric adenocarcinoma (n = 6), peritoneal malignant mesothelioma (n = 5), pseudomyxoma peritonei (n = 7), ovarian carcinoma (n = 7), and miscellaneous malignancies (n = 5: three small bowel adenocarcinoma and two adenocarcinoma from unknown primary origin). Details on age and sex according to tumor type, differentiation, pTNM (using 1988 American Joint Committee on Cancer and International Union Against Cancer TNM staging criteria), PC staging according to the PC staging described in Table 1⇑, and clinical presentation are detailed in Table 2⇓.

For 36 patients, PC were synchronous ones and for 20 PC were metachronous ones (diagnosed during the follow-up of a previously resected primary abdominal cancer). Four patients had liver metastases that were removed at the time of treatment. These patients had a normal preoperative liver CT scan and normal liver ultrasonography. They were not excluded from the study. Seven patients presented with abundant ascitis (> 1 L).

Fifteen patients underwent peritonectomy and IPCH 15 to 30 days after surgical resection of their primary tumors (these patients underwent surgery at a different hospital and postoperatively were referred to our center for peritonectomy and IPCH treatments), whereas 21 underwent peritonectomy and IPCH immediately at the end of the surgical removal of their primary tumor. The remaining 20 patients presented metachronous PC and were treated 4 to 46 months (mean 18.0 months, SD = 14.6) after the resection of their primary tumor. All surgical anastomoses were fashioned before the perfusion.

Three patients were included twice in the present study: one 61-year-old female underwent a peritonectomy first and IPCH in March of 1998 for a pseudomyxoma peritonei (PC 4 surgically reduced to PC 3), and a second course treatment in February 1999 (PC 3 surgically reduced to PC 0), one 57-year-old female underwent a first course in July 1998 for a pT3N1 left colon adenocarcinoma (PC 1 surgically reduced to PC 0) and a second course in November 1999 (PC 4 surgically reduced to PC 1), and a third patient, a 31-year-old female underwent a first course in January 1998 for a right colon adenocarcinoma (PC 2 surgically reduced to PC 0) and a second course in June 2000 (PC1 surgically reduced to PC 0). The decision to perform a second peritonectomy and IPCH course was based on the persistence of an excellent performance status and evidence of recurrent peritoneal disease (increase in tumor markers, abdominal CT scan findings, abdominal pain episodes, vomiting, and partial bowel obstruction). Details of peritonectomies and digestive organ resections performed are outlined in Tables 3⇓ and 4⇓.

Patient Follow-up

All the patients included in this study were postoperatively transferred to an intensive care unit for 24 hours and then to the surgical department. Mean duration of hospital stay was 15.7 days (SD = 6.4; range, 8 to 41). Clinical, biologic, and radiologic follow-up of the patients was repeated on a monthly basis after discharge from the hospital. Thirty-two of the included patients received postoperative palliative systemic chemotherapy during their follow-up, as indicated in Table 5⇓.

Statistical Analysis

Data were collected and analyzed on a commercially available compute program (Statview 4.5, Abacus Inc., Berkeley, CA) and are expressed as mean, SD, median, and range. The two-tailed Student’s t-test was used to take into account differences in the mean survival of the different groups. The log-rank and Kaplan and Meier tests were used for analysis of the censored survival rates.

Peritonectomy Results

At the end of the surgical procedures, 27 patients were considered as R0 or R1 resection, whereas 29 underwent an R2 resection.

Pre- and Postoperative Course

No preoperative death occurred. Mean duration of surgery was 6.11 hours (SD = 1.73; range, 4 to 13.5) excluding the duration of IPCH.

Postoperative mortality was 1 of 56 (a 49-year-old man with left colon adenocarcinoma and PC stage 4, treated by left colectomy, cholecystectomy, omentectomy, R2 resection and IPCH with 60 mg total dose of MMC) died from peritonitis and septicemia on the twenty-seventh postoperative day (massive leakage of colorectal anastomosis).

Postoperative morbidity was 16 of 56 (28.6%), mainly represented by seven of 56 digestive fistulas. There were two colocutaneous fistula medically treated, one ileocolic fistula, and three ileal fistula surgically treated, and one biliary fistula after Glisson’s exeresis surgically treated. Other complications were two postoperative prolonged ileus (up to the eleventh and fourteenth days), two right pleurisy (treated by external drainage), one pelvic abscess on the twenty-first postoperative day (treated by external drainage), one patient with severe and prolonged respiratory distress syndrome requiring ventilation up to the twenty-fifth postoperative day, two grade 3 leucopenia (day 5 to day 15), and one temporary renal insufficiency (day 4 to day 12).

Delayed Complications

Two patients complained of sexual troubles 6 months after the treatment: one 54-year-old male with mesothelioma complained of impotence after small bowel resection, left colectomy, posterior wall peritonectomy, and IPCH with MMC and CDDP; one 38-year-old male with gastric adenocarcinoma complained of retrograde ejaculation after total gastrectomy, small bowel resection, Douglas pouch, and anterior wall peritonectomy, and IPCH with MMC.

Thermic and Pharmacokinetics Results

No thermal intolerance occurred, and the mean maximal temperature in the pulmonary artery was 38.5°C (SD = 0.7; range, 37.0 to 39.5). In all patients, the temperature in the pulmonary artery dropped to normal values within 2 to 5 hours after the end of IPCH. Mean maximal inflow, outflow and peritoneal temperatures were 45.0°C (SD = 2.2; range, 41.0 to 49.0), 42°C (SD = 0.9; range, 39.5 to 43.0) and 42.1°C (SD = 0.5; range, 41.0 to 43.0), respectively (Fig 2⇓). Mean maximum values of liver, first jejunal loop, and bladder temperatures were 38.5°C (SD = 0.5; range, 37.0 to 39.0), 42.1°C (SD = 2.1; range, 39.5 to 44.0), and 37.5°C (SD = 0.4; range, 36.0 to 38.1), respectively.

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Fig 2.

Mean temperatures during intraperitoneal chemohyperthermia.

Kinetic studies concerning MMC showed a maximum serum concentration 45 minutes after the beginning of IPCH (mean value 0.251 mg, SD = 0.146 mg; range, 0.200 to 0.577), whereas MMC concentration in the perfusate showed a 60% decrease during the time of IPCH. In all patients, MMC disappeared from the blood and urine within 2 hours at the conclusion of IPCH, and MMC was not detectable in the postoperative abdominal fluids.

Kinetic studies concerning CDDP showed a maximum serum concentration 90 minutes after the beginning of IPCH (mean value 0.555 mg; SD = 0.216; range, 0.364 to 0.913), whereas CDDP concentration in the perfusate showed a 65% decrease during the time of IPCH. In all patients, CDDP was detectable in blood and urine up to 3 days after the end of IPCH, whereas CDDP was detectable in postoperative abdominal fluids up to the fifth day.

Survival Results

Up to the end of August 2002, 14 patients had died (one from myocardial necrosis, 13 from peritoneal recurrences). Mean follow-up was 544.4 days (range, 133 to 1,680). Using the Kaplan and Meier method, the overall 30 month actuarial survival rate was 54.2%. R0 patients mean survival was 558.3 days, whereas it was 360.1 days for R2 patients (P = .006). The 2-year actuarial survival rate was 79% for R0 patients (Fig 3⇓) and 44.7% for R2 patients (P = .03).

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Fig 3.

Actuarial survival of R0 and R2 patients with the Kaplan and Meier method.

Survival in the Different Subgroups is Detailed in Table 6⇓

Six of the seven patients with preoperative abundant ascitis were free of ascitis up to their death or up to the end of the follow-up (as judged by clinical examination and abdominal ultrasonography). The three patients included twice (two with colon adenocarcinoma and one with pseudomyxoma peritonei) had their second inclusion 16, 29, and 11 months after the first procedure, respectively. They were alive 20, 22, and 36 months after the second procedure. One is alive with disease recurrence and two with no evidence of recurrence.