O. Glehen 1,2, E. Cotte 1,2, J. C. Lifante 1,2, C. Arvieux 2,3, N. Moles 1, C. Brigand 2,4, A. C. Beaujard 1,2, Y. François 1,2, F. N.

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1 Acta chir belg, 2006, 106, Peritoneal Carcinomatosis in Digestive Cancers : Cytoreductive Surgery Combined with Intraperitoneal Chemohyperthermia. The Experience in Centre Hospitalier et Universitaire Lyon Sud (CHLS) O. Glehen 1,2, E. Cotte 1,2, J. C. Lifante 1,2, C. Arvieux 2,3, N. Moles 1, C. Brigand 2,4, A. C. Beaujard 1,2, Y. François 1,2, F. N. Gilly 1,2 1 Department of surgery, Centre Hospitalier et Universitaire Lyon Sud, HCL, 69495, Pierre Bénite cedex, France ; 2 EA 3738, Faculté Médecine Lyon Sud, Université Lyon 1, BP 12, Oullins, France ; 3 Department of surgery, CHU Grenoble, Hopital Michalon, 38000, France ; 4 Department of surgery, CHU Strasbourg, 67000, France. Key words. Peritoneal carcinomatosis ; Cytoreductive surgery ; Hyperthermic Intraperitoneal chemotherapy (HIPEC). Abstract. Intraperitoneal chemohyperthermia (IPCH) with Cytoreductive surgery (CS) has been used in Centre Hospitalier et Universitaire Lyon Sud (CHLS) since Up to 2005, 420 patients were involved in different phase II studies for peritoneal carcinomatosis (PC) from colorectal, gastric or ovarian origin, as well as for pseudomyxoma peritonei and peritoneal mesothelioma. Encouraging results were achieved in case of optimal PC cytoreduction. The CHLS experience, as well as the Dutch randomized trial and the international registration, underline the advantage of such an aggressive combined therapy for selected patients in experienced multidisciplinary centers. Peritoneal carcinomatosis (PC) is a major cause of surgical treatment failure. Despite advances in the early detection of colonic and rectal cancer, carcinomatosis is detected in approximately 10 per cent of patients at the time of primary cancer resection (1, 2). In contrast to metastatic spread to the two other major anatomical sites for colorectal dissemination (lymph nodes and liver), peritoneal carcinomatosis has long been considered incurable. In a recent multicentre prospective study that included 370 patients with carcinomatosis from non-gynaecological malignancies (3), the median overall survival was 5.2 months for patients with colorectal cancer, and all patients with this condition had a lethal outcome. However, over the past decade there has been renewed interest in peritoneal surface malignancy and new therapeutic approaches have been proposed, including intraperitoneal injection of anticancer drugs, early postoperative intraperitoneal chemotherapy, cytoreductive surgery with extended peritonectomy (4) and intraperitoneal chemohyperthermia (IPCH) (5). The effectiveness of these approaches has not been well established. Following an experimental study in dogs (6), IPCH with cytoreductive surgery has been used since 1989 in Centre Hospitalier et Universitaire Lyon-Sud (up to 2005, 420 patients underwent cytoreductive surgery and IPCH for peritoneal carcinomatosis arising from colorectal, gastric or ovarian cancer and from peritoneal pseudomyxoma and mesothelioma) We report here the different phase II studies conducted in our institution and dedicated to colorectal cancer, gastric cancer, peritoneal pseudomyxoma and mesothelioma. 1. Natural history of peritoneal carcinomatosis from digestive origin While PC is a common evolution of digestive cancers with a poor prognosis, the literature available on the natural history of PC is not very extensive (1-3). In 1989, Chu (1) reported low median survival in PC from colorectal origin (6.0 months), from pancreas origin (0.7 month) and from gastric cancer (1 month). To define more precisely the evolution of palliatively treated non gynaecologic PC and the survival of patients with this disease, a multicentric prospective study named EVOCAPE 1 was initiated in 1997 (3). Three hundred seventy patients were entered (206 males, 164 females, mean age 67.7, range years) with the following tumor types : 125 gastric, 118 colorectal, 58 pancreas, 12 pseudomyxoma peritonei, seven malignant peritoneal mesothelioma, four small bowel, three liver and 43 unknown primary tumors. Of these 370 patients 212 were found at the time the primary tumors were diagnosed (synchronous PC) and 158 found during the follow-up of known malignancies (metachronous PC). All 370 patients underwent surgery. The staging of peritoneal carcinomatosis, using Gilly staging (Table I) was as follow : stage 0 (n = 13), stage 1 (n = 47), stage 2 (n = 71), stage 3 (n = 84) and stage 4 (n = 155). The procedures performed were resection of primary tumors in 144 patients, by-pass to restablish gastrointestinal continuity in 125 and only laparotomy with biopsies in 101 patients. The overall operative mortality and morbidity rates were 21%

2 286 O. Glehen et al. Table I Peritoneal Carcinomatosis Staging (5) Stage Peritoneal Carcinomatosis Description Stage 0 No macroscopic disease Stage 1 Malignant granulations less than 5 mm in diameter localized in one part of the abdomen Stage 2 Malignant granulations less than 5 mm in diameter diffuse to the whole abdomen Stage 3 Malignant granulations 5 mm to 2 cm in diameter Stage 4 Large malignant cakes (more than 2 cm diameter) (77/370) and 16% (60/370) respectively. Ninety seven patients underwent postoperative palliative systemic chemotherapy (1-8 courses, 5-fluorouracil combined with folinate for 64 patients and 5-fluorouracil combined with oxaliplatinium for 33 patients). The mean and the median overall survival were 6.0 months and 3.1 months respectively.for colorectal cancer patients, overall mean and median survival times were 6.9 months (range ) and 5.2 months respectively. Median survival was 12.5 months in PC stage 1, 8.3 months in PC stage 2, 5.7 months in PC stage 3 and 3.0 months in PC stage 4. For gastric carcinoma patients, overall mean and median survival were 6.5 months (range ) and 3.1 months respectively. Mean survival was 8.0 months for PC stage 1 and 1.9 months for PC stage Cytoreductive surgery and IPCH : the protocol used in Centre Hospitalier et Universitaire Lyon Sud (7) Surgical Procedures Under general anesthesia and complete hemodynamic monitoring, careful abdominal exploration and cytological as well as pathologic samples are taken through a median laparotomy (from xyphoid to pubis). Surgical resection of the primary tumor is performed according to oncologic surgical rules (lymphadenectomy, acceptable margins). Once the primary tumor had been removed, a peritonectomy is performed, adapted to the location of the malignant granulations as guided by the surgeon, exploration, and extemporaneous biopsies. These peritonectomies are performed according to Sugarbaker s surgical description (8). Locations of peritonectomy performed are peroperatively 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 is not extensively removed, but after acceptable small bowel resections guided by maximal tumor volume locations, remaining malignant granulations are destroyed using electrosurgical fulguration). Type of IPCH At the end of each surgical procedure, an IPCH infusion is 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 are inserted under the left and right diaphragmatic cupula (30 French silicone drainage, William Harvey, Bard Cardiopulmonary Division, USA), whereas a third drain (outflow drainage) is inserted in the Douglas pouch. Thermic probes are inserted within the abdominal cavity, on the inflow and outflow drains and inside the bladder. Laparotomy is then closed and inflow and outflow drains are connected to a closed sterile circuit in which a 4 to 6 L perfusate (Travenol laboratory, Norfolk, England) is circulated by means of an electromagnetic pump at a flow rate of 500 ml/min (Fig. 1). Since 1998, we use a dedicated apparatus named Cavitherm (EFS Electronic, Millery, France) which allows a very safe and automatically controlled procedure. IPCH is performed for 90 minutes with close monitoring of respiratory and hemodynamic parameters at inflow temperatures ranging between 46 C and 48 C. Type of Intraperitoneal Chemotherapy For PC from digestive origin, mitomycin C (MMC) is used at the dose of 0.7 mg/kg (maximum dose of 60 mg). For PC from peritoneal malignant mesothelioma and pseudomyxoma, MMC and Cisplatinium (CDDP) are combined intraperitonealy at the dose of 0.5 mg/kg and 0.7 mg/kg, respectively. 3. The experience with PC from colorectal cancer in CHLS From 1995 to 2002, a phase II study dedicated to PC from colorectal origin was conducted in our institution. Inclusion criteria were synchronous or metachronous PC, age before 65, OMS < 2, no systemic chemotherapy one month prior to inclusion, normal cerebral and thoracic CT scan, liver metastases only if resectable during the same surgical procedure, normal cardiac ultrasonography, normal renal function, and informed consent of the patient (9, 10). Ninety six patients (55 females and 41 males) were involved in this phase II study and underwent 103 therapeutic procedures. Mean age was 49 years (range 19-65). Primary locations were right colon (n = 39), left colon (n = 39) and appendiceal (n = 18). All were adenocarcinoma and 28% were poorly differenciated. PC

3 Peritoneal Carcinomatosis in Digestive Cancers 287 Fig. 1 Closed IPCH device used in CHLS Time Fig. 2 Survival curves in colorectal cancer with PC according to completeness of cytoreduction were synchronous in 42 patients. Eight patients were included with resectable liver metastases. PC stage were 0 (n = 7), 1 (n = 10), 2 (n = 16), 3 (n = 22) and 4 (n = 41). Seven patients underwent a second cytoreductive surgery and IPCH procedure during their follow up. Results To achieve these 96 cytoreductive surgical procedures, 163 digestive anastomoses were performed (42 right colectomies, 24 left colectomies, 12 subtotal colectomies, 3 low anterior resections, 4 left pancreatectomies, 10 splenectomies, 33 small bowel resections, 18 cholecystectomies, 10 partial gastrectomies, 3 nephrectomies, 8 liver metastasectomies). Duration of surgery ranged from 5.0 to 13.5 hours. Complete macroscopic resection (R0/R1) was achieved in 36 patients while 60 patients underwent a R2 resection. One patient died postoperatively (a 49 years old man with a left colon adenocarcinoma pt3n1m1 and a PC stage 4 treated by subtotal colectomy, small bowel resec-

4 288 O. Glehen et al. Table II Details on 7 re-treated patients 1st session Disease free 2nd session Status Overall survival pt3n1 rectal PC 0 29 mths PC 1 small bowel resection AWR 6 mths 35 mths pt3n2 right colon PC 2DS0 38 mths PC1DS0 AWR 24 mths 62 mths pt3n2 left colon PC 1DS0 50 mths PC 4DS2 DFR 13 mths 63 mths pt3n2 left colon PC 2DS0 26 mths PC 2DS0 DFR 23 mths 49 mths PT3N1 app. PC 4DS1 11 mths PC 2DS0 AWR 46 mths 57 mths pt3n3 right colon PC 2DS0 25 mths PC 4DS0 AWR 3 mths 28 mths pt3n2 left colon PC 3DS2 6 mths PC 4DS2 AWR 12 mths 18 mths PC = Peritoneal carcinomatosis, app = appendiceal cancer, DS = downstaging, mths = months, AWR = Alive with recurrence, DFR = Died from recurrence. tion, left pancreatectomy, liver metastasectomy and IPCH died on the 27 th postoperative day from major septic shock). Postoperative morbidity occurred in 28 patients (30%) : they were 5 anastomotic leakages, 1 biliary fistula, 2 pancreatic fistula, 6 right pleural effusions, 7 wound abcesses, 1 partial bladder necrosis, 1 postoperative hemorrage, 1 prolongated ileus, 3 grade III neutropenia and 1 prolongated intubation. Predictive factors for postoperative morbidity were duration of surgery (p = 0.05) and number of anastomoses performed (p = ). Survival curves are presented in Figure 2. Four year actuarial survival was 45% in R0/R1 patients and major predictive factors for survival were postoperative PC staging (p = 0.023) and completeness of cytoreduction (p = 0.016). Surgical data of the seven re-treated patients are given in Table II. 4. The experience with PC from gastric cancer in CHLS (9, 11) From 1989 to 2002, a prospective phase II study dedicated to gastric cancer was conducted in our institution. Inclusion criteria were gastric adenocarcinoma with synchronous or metachronous PC, age before 65, OMS < 2, resectable or unresectable primary tumor, normal cerebral and thoracic CT scan, no distant metastases, normal cardiac ultrasonography and renal function, informed consent of the patients. Fourty nine patients (25 females, 24 males, mean age 53.7 years) were included in the phase II study. PC stages were 1 (n = 13), 2 (n = 5), 3 (n = 12) and 4 (n = 19). Fifty procedures were performed for these 49 patients (one patient underwent a second cytoreductive surgery with IPCH 18 months after the first one). Twenty one IPCH procedures were delayed (1 month) after the cytoreductive surgery. Ten patients had unresectable primary tumor, 14 patients underwent a total gastrectomy, 9 underwent a total gastrectomy extended to the spleen, 3 patients underwent a total gastrectomy combined with left splenopancreatectomy and 13 patients underwent a subtotal gastrectomy. Twenty patients received postoperative systemic chemotherapy and 9 patients underwent external postoperative radiotherapy (44 grays). Results Median follow up for these 49 patients was 99 months. Complete cytoreductive surgery (CCR-0) was achieved in five patients while 20 underwent a CCR-1 resection (no residual nodule greater than 5 mm in diameter) and 24 a CCR-2 resection (at least one residual nodule greater than 5 mm in diameter). Mortality was 2/49 (one pulmonary embolism and one multiple organ failure both occurring on the 4 th postoperative day). Major complications occurred in 13 patients (27%) : 3 pleural effusions, 3 small bowel obstructions, 1 parietal collection, 2 ileocolic fistula, 1 pancreatic fistula, 1 biliary peritonitis, 1 peritonitis and 1 intraperitoneal abcess). Overall median survival was 10 months and six patients presented with unexpected long term survival (two patients alive at 3 years and four patients alive at 5 years). The only major predictive factor for survival was completeness of cytoreduction : median survival was 6 months in CCR-2 patients while it was 21 months in CCR-0 or 1 patients (Fig. 3). 5. The experience with peritoneal pseudomyxoma in CHLS (12) Up to 2005, 48 patients with peritoneal pseudomyxoma have been treated in our institution : we report here the results of a prospective phase II study conducted in CHLS in which 27 patients (11 males and 16 females ; mean age 58.0 years) were involved. Twenty two patients were operated on before their inclusion in the phase II study (16 were operated on once, 3 were operated on twice, 1 was operated on 4 times and 2 were operated on 5 times). Pathologic staging were grade 1 (disseminated peritoneal adenomucinosis, n = 8), grade 2 (intermediate type, n = 10) and grade 3 (mucinous ade-

5 Peritoneal Carcinomatosis in Digestive Cancers 289 to have a CCR-0 or 1 resection). No postoperative death occurred. Six postoperative complications were recorded. The median follow up was 46.7 months (range ). Median survival was 37.8 months and one, two, three and five year survival rate were 69.3, 57.7, 43.3 and 28.9% respectively. The patient presenting with multicystic peritoneal mesothelioma is alive without recurrence at 67 months. One patient underwent a second procedure for recurrence 36 months after the first one and is alive with evidence of peritoneal recurrence 88 months after the first IPCH procedure. Discussion Fig. 3 Survival curves of gastric cancer patients with PC according to completeness of cytoreduction. nocarcinoma, n = 9). The extent of PC was assessed through Gilly staging (PC 1 = 4, PC 2 = 2, PC 3 = 5 and PC 4 = 16). No perioperative death occurred. A total of 17 complications were recorded in 12 patients (44.4%) : 3 anastomotic leakages, 3 wound infections, 2 urinary infections, 2 pleural effusions, 2 pancreatitis, 1 small bowel obstruction, 1 intra abdominal abcess, 1 acute renal failure, 1 pneumonia and 1 bacteriemia). Eleven patients underwent a CCR-0/1 resection while 16 underwent a CCR-2 resection. Eleven patients received postoperative systemic chemotherapy (5FU and leucovorine, Folfox or Folfiri). Median follow up achieved was 23 months (range 3-82). The overall median survival was not reached. The actuarial one, two, three and five year survival rates were 100, 88, 78 and 52 respectively. The major prognostic factor (p = 0.03) was the pathologic grade of pseudomyxoma. The actuarial five year survival rate was 100% for grade 1 disease whereas actuarial one, two, three and five year survival rates for patients with grade 2 and 3 disease were 100, 80, 64 and 32% respectively. Concerning the completeness of cytoreduction, median survival of patients treated with CCR 0 resection was not reached whereas it was 51 months for patients treated with CCR 2 resection (but this difference was not significant, p = 0.11). 6. The experience with peritoneal mesothelioma in CHLS (13) From 1990 to 2004, 15 patients (5 females and 10 males, mean age 53.6 years) were involved in cytoreductive surgery program for peritoneal mesothelioma. All patients but one (multicystic) had malignant disease of the following types : 12 epithelial and 2 biphasic. After surgical resection, 11 patients were considered All phase II studies on PC from colorectal origin reported median survival of longer than 2 years for patients treated with complete macroscopic resection (4, 14-16). The results of the randomised Dutch trial (17) comparing cytoreductive surgery and IPCH to intravenous chemotherapy alone showed that 2 year survival was 43% in the IPCH group versus 16% in the control group (p = 0.014). This randomized study has been criticized because of the use of 5-fluorouracile and folinate in the control group. Undoubtly oxaliplatinium or irinotecan would now be used for the control group as well as new targeted drugs. However, since 3 years, many patients involved in cytoreductive surgery and IPCH new phase II studies already received these drugs prior to their inclusion : again, encouraging results were reported. The international registration including 506 patients from 28 institutions reported a median survival of 32.4 months for patients in whom complete cytoreduction was possible (18). In 2006, cytoreductive surgery combined with IPCH appears to be the new gold standard treatment when performed in experienced teams on strictly selected patients (19). However, a lot of questions remain unsolved : is it necessary to add IPCH to complete cytoreductive surgery? Is it necessary to add hyperthermia to intraperitoneal chemotherapy? How can we improve the selection of the patients? New controlled studies would be necessary to answer these questions but will be rather difficult to conduct. For PC arising from gastric cancer, no randomised trials are available in the literature. Only a few experienced teams are dealing with PC from gastric origin (11, 20-22). From our own experience, we will underline that PC stage 1 and 2 in young selected patients could probably be the correct indications for cytoreductive surgery and IPCH. In this field, the great question unsolved is the prophylactic use of IPCH in pt3 gastric cancer and in gastric cancer with free malignant cells in the peritoneum at the first operation (23-25). For PC in pseudomyxoma and mesothelioma, no randomised trials are available in the literature. However,

6 290 O. Glehen et al. the large experience of Sugarbaker (26) as well as some phase II studies (27, 28), clearly indicate the advantage of cytoreductive surgery combined with IPCH in these rare diseases. In conclusion, numerous questions are still unsolved in the PC field. However, encouraging results have been achieved in experienced teams in phase II studies and in a randomised one for selected patients. One has to compare the proposed and admitted surgical treatments in liver metastases arising from colorectal cancer and the new combined treatments proposed in PC. Every one agree that resectable liver metastases from colorectal cancer must be operated on : in fact, advantage for surgical resection was only reported in phase II studies and in a large but retrospective international registration (29). At least, peritoneum could be regarded as an organ, just as liver or lung are regarded. References 1. CHU D. Z., LANG N. P., THOMPSON C. et al. 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