Multimodality treatment of peritoneal carcinomatosis from colorectal cancer: first results of a new German centre for peritoneal surface malignancies

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1 DOI /s z ORIGINAL ARTICLE Multimodality treatment of peritoneal carcinomatosis from colorectal cancer: first results of a new German centre for peritoneal surface malignancies P. Piso & M. H. Dahlke & N. Ghali & I. Iesalnieks & M. Loss & F. Popp & P. von Breitenbuch & A. Agha & S. A. Lang & F. Kullmann & H. J. Schlitt Accepted: 28 March 2007 # Springer-Verlag 2007 Abstract Background The presence of peritoneal carcinomatosis arising from colorectal cancer is associated with a poor prognosis. It was the purpose of this study to analyze morbidity, mortality, and survival after major cytoreductive surgery and intraperitoneal chemotherapy. Materials and methods Thirty-two patients with peritoneal carcinomatosis were operated between April 2004 and June 2006 with the aim of complete macroscopical cytoreduction. All had a primary colorectal carcinoma. Surgery in these patients was followed by hyperthermic intraperitoneal chemotherapy (HIPEC) consisting of mitomycin C and doxorubicin. Data were analyzed retrospectively. Results Of all patients, 16 had appendix and 16 nonappendiceal colorectal carcinoma. A macroscopically complete cytoreduction was achieved in 24 patients by parietal and visceral peritonectomy procedures. All resections were combined with HIPEC. Overall morbidity was 34%. Most frequent surgical complications were intestinal obstruction P. Piso : M. H. Dahlke : N. Ghali : I. Iesalnieks : M. Loss : F. Popp : P. von Breitenbuch : A. Agha : S. A. Lang : H. J. Schlitt Department of Surgery, University of Regensburg, Regensburg, Germany F. Kullmann Department of Internal Medicine I, University of Regensburg, Regensburg, Germany P. Piso (*) Klinik und Poliklinik für Chirurgie, Klinikum der Universität Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, Germany pompiliu.piso@klinik.uni-regensburg.de (4/32), enteric fistula (2/32), pancreatitis (2/32), and bile leakage (2/32). One patient presented grade 4 renal toxicity. There was no hospital mortality. The median follow-up was 12 months. The 1-year overall survival rate is 96%. All patients after complete cytoreduction are still alive. Conclusions Cytoreductive surgery combined with HIPEC is associated with an acceptable morbidity and low mortality. Complete cytoreduction may improve survival, particularly in well-selected patients having a low tumor volume and no extra-abdominal metastases. Keywords Peritoneal carcinomatosis Introduction Peritoneal carcinomatosis can be diagnosed in 10 15% of all patients with colorectal cancer at initial presentation. Among patients with recurrent disease, this number rises to 40 70%. However, these patients may have a peritoneal carcinomatosis alone or associated with organ metastases and/or locoregional recurrence [1]. The natural history of patients with peritoneal carcinomatosis from colorectal cancer has been investigated in two studies [2, 3]. The largest series was the Evolution of Peritoneal Carcinomatosis 1 trial. In this prospective French trial, data 118 from patients with colorectal cancer and peritoneal carcinomatosis were analyzed. The mean survival was 6.5 months, the median 5.2 months. Systemic chemotherapy for metastatic colorectal cancer has changed substantially over the recent years. Combined chemotherapy with 5-FU and/or oxaliplatinum/irinotecan has improved the median survival up to 20 months as

2 compared to fluorouracil (5-FU) alone. By adding monoclonal antibodies, e.g., bevacizumab or cetuximab, prognosis can be further improved, and the median survival may be prolonged to up to 30 months [4]. However, in all studies, mainly patients with solid organ metastases were included. The impact of modern systemic chemotherapy in patients with isolated peritoneal carcinomatosis has not been investigated yet. Due to the poor vascularization, it has to be assumed that the effect of systemic chemotherapy is less notable and that survival is poorer than in patients with liver metastases. In the 1980s, Sugarbaker [5] developed a multimodality treatment approach for peritoneal surface malignancies. This consists of parietal and visceral peritonectomy with the aim of complete cytoreduction. After resection, an intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) is performed. In this way, the survival probability of selected patients can be as high as 30 to 40% after 5 years [6]. The impact on prognosis was proven in a prospective randomized trial. As compared to patients treated only by limited surgery and systemic chemotherapy, patients after complete cytoreduction and systemic chemotherapy had a statistically significant improvement of the 2- year survival rate [7]. This aggressive treatment concept has been adopted by several surgical departments worldwide. Many results of Phase II trials have been published over the last decade. A meta-analysis including 506 patients from 28 institutions demonstrated a median survival of 32.4 months after complete cytoreduction compared to 8 months after incomplete cytoreduction [8]. It seems more and more that peritoneal carcinomatosis can be treated as successful as liver metastases. However, the multimodality treatment concept is very complex and includes a long learning curve due to major surgery and the HIPEC. Precise definition of selection criteria and standardized techniques make a low morbidity and mortality of the procedure possible. Initiation of a program for peritoneal surface malignancies is a real challenge. Appropriate patients are not only those with peritoneal carcinomatosis arising from colorectal cancer, but also selected patients with ovarian cancer or gastric cancer and peritoneal metastases. The aim of this paper is to analyze our own results in the first 32 patients with peritoneal carcinomatosis from colorectal cancer treated by multimodality treatment. Materials and methods Patients A total of 32 patients with peritoneal carcinomatosis arising from colorectal cancer were treated in the Department of Surgery of the University Regensburg, Germany, between April 2004 and June All patients were operated by the same surgeon. The treatment of peritoneal surface malignancies was established at this institution 6 months before treating the first patient. Standard treatment protocols were formulated according to the recommendations of the German Society for Visceral Surgery. Guidelines for safe administration of the chemotherapy in the operating room and the technique of HIPEC were established. Surgical peritonectomy procedures The aim of surgery was to remove all macroscopically visible tumor nodules from the visceral and parietal peritoneum. Thus, cytoreductive surgery consisted of a variety of peritonectomy procedures, as previously describedbysugarbaker[5]. These included omentectomy and splenectomy, left subdiaphragmatic peritonectomy, right subdiaphragmatic peritonectomy, pelvic peritonectomy and sigmoidectomy (in female patients with hysterectomy), cholecystectomy with lesser omentectomy, and partial gastrectomy (mostly antrectomy). The extent was individual according to the tumor infiltration in different areas of the peritoneal space. Often multivisceral resections were required to achieve complete macrosopical cytoreduction. Hyperthermic intraperitoneal chemotherapy After resection, intestinal anastomoses were performed prior HIPEC; the abdominal wall was closed (skin and fascia) and not reopened at the end of the procedure. One inflow catheter was placed below the epigastrium between small bowel loops, and three outflow catheters were positioned in the cul-de-sac and subphrenical right and left. Temperature probes were placed next to the inflow catheter and in the small pelvis. Up to 3 l of fluid carrier solution were used to fill the abdominal cavity before the circulation of the fluid was started. A roller pump and a heater device allowed a continuous distribution of fluid within the abdominal space at C. The chemotherapeutic agent (mitomycin C 20 mg/m 2 with doxorubicin 15 mg/m 2 ) was then added to the circulating solution when optimal flow and heat parameters were established. After adding the chemotherapeutics, the heated circulation was maintained for one additional hour. During the time of perfusion, the operating table was moved in all possible directions to guarantee optimal distribution of the heated agent within the abdomen. To prevent the establishment of flowroutes, discontinuous clamping of the outflow catheters was used. Intermittent repeated manual pressure of the anterior abdominal wall was applied to support distribution of the intra-abdominal fluid.

3 Early postoperative intraperitoneal chemotherapy Postoperatively, a normothermic intraperitoneal chemotherapy with 5-FU 650 mg/m 2 was performed in patients with complete cytoreduction, provided the postoperative course was uncomplicated. The cytostatic agent was added to 1 l of hetastarch 6% solution and distributed intraperitoneally for 24 h. During this period, all drainage tubes were clamped. The procedure was repeated for up to three postoperative days, starting with day 1. Patient data were compiled into a database (SPSS 12), including epidemiologic, surgical, pathologic, and survival data. All hospital deaths were considered. Results The study population included 13 women and 19 men, with a mean age of 50.6 years (range, 28 77). In 16 patients, the originating tumor site was the appendix, in 16 patients colorectal tumors derived from various sites. Of these, eight had carcinomas of the right hemicolon and six of the transversal colon or descending colon. Two patients had had a sigmoid and a rectal carcinoma, respectively. Eight of the patients had liver metastases (in five cases simultaneous, in three metachroneous). The primary tumor has been operated before cytoreductive surgery in nine patients with appendiceal cancer and eight patients with nonappendiceal colon carcinoma. Patients were selected between 97 cases with peritoneal carcinomatosis referred to our institution, meaning one third being offered surgery with the option of peritonectomy and HIPEC. Of all patients, 23 patients had previously undergone laparotomy (median 1, range 0 3). Most of these patients had one or two abdominal operations in their history (53 and 15%, respectively). One patient had had three laparotomies before cytoreductive surgery. These were appendectomy in nine cases, hemicolectomy in six cases, one sigmoid resection and one rectal resection. In addition, nine patients had received systemic chemotherapy or immunotherapy before admission. After laparotomy, the initial peritoneal cancer index was determined (Fig. 1). Of all patients, 21 had an index less than 20 and 11 above. During operation, various peritonectomy procedures were performed (Table 1). Most of the patients had at least one digestive anastomosis (13 patients of 55, range 0 4 anastomoses). Five patients had four digestive anastomoses each. Median operating time (without HIPEC) was 5 h (range, 2 10 h). Macroscopically complete cytoreduction was achieved in 24 patients (75%). During HIPEC, the median intra-abdominal inflow temperature was 41.4 C. The median perfusate volume Fig. 1 Omental cake in a patient with mucinous adenocarcinoma of the cecum and peritoneal carcinomatosis. The small bowel is not affected, indicating a high probability of complete cytoreduction was 3 l. Perfusion flow was l/min. Of all patients, 23 had also an early postoperative intraperitoneal chemotherapy (normothermic). Overall morbidity was 34%. Most frequent surgical complications were intestinal obstruction (4/32 patients), enteric fistula (2/32 patients), pancreatitis (2/32 patients), and bile leakage (2/32 patients). Two patients had a pulmonary embolism. One patient presented grade 4 renal toxicity, and another patient developed pneumonia. To treat postoperative complications, reoperations were necessary in three patients due to anastomotic leakage, small bowel perforation, or intra-abdominal abscess. The median hospital stay was 14 days (range, 6 124). Only two patients had a hospital stay longer than 30 days (124 and 78 days, respectively). Table 1 Peritonectomy procedures in 32 patients with peritoneal carcinomatosis arising from colorectal cancer, operated with the aim of complete cytoreduction Peritonectomy procedure Number of patients Right subdiaphragmatic peritonectomy 25 Pelvic peritonectomy with resection of 21 rectosigmoid Omentectomy and splenectomy 20 Cholecystectomy and lesser omentectomy 18 Left subdiaphragmatic peritonectomy 16 Gastrectomy (partial/total) 7 Peritoneal Cancer Index PCI<20 21 PCI>20 11 Completeness of cytoreduction Complete (CC 0/1) 24 Incomplete (CC 2/3) 8

4 Table 2 Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: results of phase II and III trials published over the last 5 years Author There was no 30- nor 60-day mortality. Median followupwas12months(3 28). The 1-year overall survival rate was 96%. All patients after complete cytoreduction are still alive. No patient with appendiceal cancer and peritoneal carcinomatosis died during follow-up. Among patients with non-appendiceal colorectal cancer, one patient with rectal cancer died 8 months postoperatively from progressive disease with intestinal obstruction. He also had had liver metastases and had undergone an incomplete cytoreduction. Discussion Number of patients Mortality Median survival (months) Appendiceal carcinoma Witkamp et al. [22] Elias et al. [23] Verwaal et al. [7] Non-appendiceal colorectal carcinoma Pilati et al. [24] Glehen et al. [25] Shen et al. [26] Kecmanovic et al. [27] Colorectal cancer shows an increasing incidence in the Western world. In Germany, 66,000 new cases are diagnosed every year. Up to 25% of those patients develop a peritoneal carcinomatosis. The natural course of this disease extent is associated with a median survival of patients of about 6 months. Sugarbaker [9] has pioneered the therapy for peritoneal surface malignancies introducing cytoreductive surgery in combination with HIPEC. Single-institution data for 400 patients with appendiceal malignancies operated by him have been reported [10]. The indication was extended to other colorectal malignancies as well. A multicenter analysis counting 506 patients with peritoneal carcinomatosis and colorectal cancer operated in 28 institutions worldwide demonstrated a better prognosis after complete surgical cytoreduction and intraperitoneal chemotherapy compared to incomplete resection alone (median survival 32.4 vs 8.4 months) [8]. A 5-year survival rate as high as 31% was achieved for selected patients after complete cytoreduction and perioperative intraperitoneal chemotherapy. There has been one Phase III trial performed, and the results were published in 2003 by the group of Zoetmulder in Amsterdam [7]. This prospective randomized study compared cytoreductive surgery combined with hyperthermic intraperitoneal and systemic chemotherapy (experimental arm) vs limited surgery and systemic chemotherapy in 105 patients. The systemic chemotherapy used consisted of 5-FU and leukovorin. The prognosis of patients treated in the experimental arm was significantly better than in control arm (median survival 22.3 vs 12.6 months, p=0.03). This group demonstrated that complete cytoreduction and a limited extent of peritoneal carcinomatosis are the most relevant independent prognostic factors. The same group analyzed the results after cytoreductive surgery and HIPEC in 117 patients [11]. After complete cytoreduction, median survival was 42.9 months, and a 5-year survival of 43% could be achieved. At our institution, parietal and visceral peritonectomy procedures aiming of complete cytoreduction followed by Fig. 2 Proposed therapeutic algorithm for patients with peritoneal carcinomatosis arising from colorectal cancer based on our own selection criteria during assessment of referred patients at our institution Peritoneal carcinomatosis No extraabdominal metastases Karnovsky Index > 75% No/limited small bowel involvement Complete cytoreduction probable (CT scan, laparoscopy) Explorative Laparotomy Complete surgical cytoreduction impossible Complete surgical cytoreduction Debulking resection e. g. relief of symptoms Systemic chemotherapy, targeted therapy Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

5 HIPEC were introduced in The implementation was performed within few months and included clear treatment protocols, courses for doctors and nurses to teach HIPEC, establishing a prospective patient database, environmental safety measurements, morbidity, and mortality conferences. Complete cytoreduction was achieved in 75% of our patients. Analogous results regarding the achievement of a complete cytoreduction were reported by Glehen et al. [12] from Lyon (27/56 patients). These patients were also been treated by closed hyperthermic chemotherapy. Elias et al. [13, 14] investigated different techniques of chemohyperthermia after complete cytoreduction in prospective fashion. Among all techniques, the coliseum open abdomen technique allowed optimal temperatures and diffusion of chemotherapy to all areas. If the open technique is used, air conditioning with efficient high efficiency particulate air filters, smoke evacuators, high power filtration mask, and eye protection is recommended [15]. However, the handling of the chemotherapeutics is much easier, and the risk of contamination is lower for the operating staff with the closed abdomen technique. There is no prospective trial showing higher recurrence rate of close compared to the open abdomen technique. In our opinion, both HIPEC techniques are feasible and have a comparable long-term effect after cytoreductive surgery for peritoneal carcinomatosis. Similar to Sugarbaker [16, 17], we used in all patients the combination of mitomycin C and doxorubicin for the HIPEC. In this combination, the dosage of mitomycin C was moderate (20 mg/m 2 ), particularly if normothermic postoperative intraperitoneal was planed. However, if only mitomycin C is used, the dosage can be increased to of 35 mg/m 2. Doxorubicin did not exceed 15 mg/m 2. Higher dosage may lead to an extensive peritoneal fibrosis [16, 17]. In our experience, the combination of the mentioned drugs for HIPEC is feasible and safe, as we had no case of high-grade bone marrow toxicity. Over the last year, in particular, supported by French data, oxaliplatin and irinotecan also seem to be suitable for HIPEC after complete cytoreduction in patients with peritoneal carcinomatosis from colorectal cancer. Long-term results of large series, however, are at present not available [14]. Cytoreductive surgery and HIPEC are associated with an acceptable morbidity and low mortality in experienced centers, comparable to other major multivisceral resections [18 20]. The mortality rate in our patients confirms this observation. Enteric fistula is the most frequent surgical complication, as in our series, too. This is more frequent after prior abdominal surgery with multiple bowel adhesion formation [18, 20]. Best survival data can be achieved in patients with complete cytoreduction and low tumor volume [7, 10, 21 26]. Among our series of appendix cancer and peritoneal carcinomatosis, no patient died after complete cytoreduction. Among patients with non-appendiceal colorectal cancer, 1 of 16 died during follow-up. These results are in line with other published data, as described in Table 2. However, this is only preliminary survival data with a relative short follow-up period. Quality of life has been analyzed just in few series and was not subject of the present study [20, 28]. Nevertheless, McQuellon et al. [28] found that 87% of long-term survivors after major surgery and HIPEC rated their general health as good to excellent. An optimal patient selection is crucial for short- and long-term results after major cytoreduction and HIPEC [29 31]. Figure 2 shows a therapeutic algorithm that we propose based on our own selection criteria during assessment of referred patients. The documentation of the tumor site and volume should be done. Most data suggest that a scoring system using the peritoneal cancer index is appropriate [32]. The probability of a complete macroscopical cytoreduction can be partially evaluated by computed tomography scan. The selection criteria we use are in line with those adopted by the Peritoneal Surface Oncology Group in 2006 [33]. In conclusion, our data suggest that cytoreductive surgery and HIPEC for peritoneal carcinomatosis from colorectal cancer are associated with an acceptable mortality and low morbidity. Survival may be improved after complete surgical cytoreduction and HIPEC if patients are selected appropriately. One Phase III and many Phase II trials demonstrated that 5-year survival rates of 30 40% can be achieved in patients with peritoneal carcinomatosis from colorectal cancer after complete surgical cytoreduction and HIPEC. 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