ANTICANCER RESEARCH 31: 2603-2608 (2011)

First Surgical Experience of Intraperitoneal Treatment with the Trifunctional Antibody Catumaxomab (Anti-EpCam × Anti-CD3) for Epithelial Ovarian Cancer

GEORGIOS PAPANIKOLAOU1, CHRISTINA FOTOPOULOU1, IOANA BRAICU1, RADOSLAV CHEKEROV1, SVEN CHRISTIAN SCHMIDT2, KLAUS PIETZNER1 and JALID SEHOULI1

1Department of Gynecology, Virchow Campus Clinic, Charité University Hospital, Berlin, Germany; 2Department of General, Visceral, and Transplantation Surgery, Virchow Campus Clinic, Charité University Hospital, Berlin, Germany

Abstract. Aim: Intraperitoneal (i.p.) treatment with the (score system 0-3), while 3 patients developed repeated trifunctional antibody catumaxomab is a novel promising abscesses. Four out of the six patients operated due to option in the clinical management of advanced or recurrent recurrent EOC, presented extensive tumor load with severe epithelial ovarian cancer (EOC). As yet, no data exists peritoneal carcinosis. Nevertheless, none of the relapsed sregarding the surgical experience after i.p. catumaxomab patients had at surgery ascites >500 ml. Conclusion: Surgery application. Therefore we analyzed the surgical outcome of after i.p. catumaxomab appears feasible, however, larger EOC patients, previously treated with i.p. catumaxomab, prospective evaluations are warranted to assess its true with special focus on the effect on adhesion formation and impact on adhesion formation and postoperative morbidity. morbidity. Patients and Methods: We conducted a retrospective evaluation of patients with EOC, who were The trifunctional, bispecific antibody catumaxomab (anti- previously treated with catumaxomab, either at time of EpCAM × anti-CD3) is a new therapeutic strategy for primary cytoreduction (n=6) or due to malignant ascites in epithelial cancer patients with symptomatic malignant ascites. the recurrent situation (n=4), and who underwent surgery The trifunctionality has the advantage of binding tumor cells due to various indications between 01/2007 and 03/2010. and, simultaneously, two different immune effector cells (e.g. Surgical outcome, grade of adhesions and operative macrophages and T-lymphocytes) (1). The unique binding morbidity were analyzed based on surgical reports and a specificities of catumaxomab induce an effective destruction validated intraoperative documentation tool ‘Intraoperative of tumor cells, including those resistant to apoptosis, through Mappinf of Ovarian Cancer’. Results: Ten patients with EOC different mechanisms, such as perforin-mediated lysis, (FIGO stage III-IV; median age 68 years; range: 45-77 antibody-mediated phagocytosis, and cytokine release (2-4). years) were evaluated. The mean time between catumaxomab Catumaxomab (Removab®) is the first medication approved treatment and surgery was 187 days (range: 8-481 days). by the EMEA European Medicines Agency for the treatment Mean operation-time was 185 minutes (range:69-32). The of malignant ascites due to EpCAM-positive carcinomas indications for surgery were as follows: 3 patients due to where no standard therapy is available or it is no longer anastomotic insufficiency after primary tumor debulking; 2 feasible with an acceptable safety profile (5). Encouraging patients due to secondary tumor debulking; 4 patients due to experience has been collected so far for intraperitoneal ileus in recurrent EOC; and 2 patients for restoring treatment with catumaxomab plus paracentesis in patients intestinal continuity. At the post-catumaxomab surgery 7 with advanced epithelial cancer including advanced ovarian patients presented massive intraoperative adhesion grade 3 cancer (EOC). Various trials have demonstrated a significant clinical benefit in puncture free survival in patients with malignant ascites due to EOC relapse (6-8). Currents studies evaluate the role of catumaxomab in primary ovarian cancer Correspondence to: Professor Jalid Sehouli, MD, Department of (9) in combination with chemotherapy. Gynecology, Virchow Campus Clinic, Charité University Hospital, No data so far exists regarding the alterations induced Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: [email protected] intraperitoneally by catumaxomab, which would influence operability in this heavily pretreated patient population. To Key Words: Ovarian cancer, relapse, intraperitoneal, catumaxomab, our knowledge, this is the first attempt to describe the surgical tumor debulking, operative morbidity, operative mortality. surgical experience after intraperitoneal catumaxomab

0250-7005/2011 $2.00+.40 2603 ANTICANCER RESEARCH 31: 2603-2608 (2011) treatment in patients with primary and relapsed EOC. The All surgeries were scored for overall adhesion formation primary aim of our study was to evaluate the surgical according to a 4-point (0-3) adhesion scoring system based on a outcome and morbidity, intraperitoneal adhesions, and ascites system developed for use in gynecological surgery (15), variations of which had been used previously in general surgery (16): grade in all consecutive patients operated on in our department due 0=no adhesion; 1=firm avascular adhesion separated easily with to EOC who had been previously treated with catumaxomab, blunt dissection; 2=firm limited vascular adhesion separated with either in the primary or recurrent situation of the disease. sharp dissection; and 3=fibrotic, dense, vascular adhesion separated with sharp dissection. Adhesion formation was assessed according Patients and Methods to whether the adhesions were filmy or fibrous and whether they would have required a blunt or sharp dissection to become separated. Patient’s informed consent was always given prior to Patient selection and follow-up. The present retrospective evaluation surgery, sample collection and documentation. included all women with advanced primary or relapsed EOC who All data regarding the intraoperative tumor dissemination pattern, underwent surgical treatment at the Department of Gynecology at 30-day operative morbidity, surgical outcome, operability and the Charité, Campus Virchow Clinic between January 2007 and intraperitoneal adhesions were collected as based on the IMO, on March 2010, and who had been treated previously with the operation protocols, and on patients’ charts. intraperitoneal infusions of the trifunctional antibody catumaxomab. All patients underwent regular follow-up examinations. They The catumaxomab treatment was conducted within the multicenter were regularly evaluated at the end of their initial treatment for phase-II trial IP-CAT-OC-02 (ClinicalTrials.gov Identifier: evidence of disease recurrence. Clinical examinations, transvaginal NCT00563836) or the multicenter (still recruiting) phase-IIIb trial and transabdominal ultrasound and CA-125 (if the preoperative CASIMAS (ClinicalTrials.gov Identifier: NCT00822809). value was elevated) assays were performed every 3 months for the Information about these two studies has been described in detail first 3 years, and thereafter every 6 months. elsewhere (9, 10). The indication for surgery after administration of catumaxomab was either curative or palliative, as indicated by the Statistics. Analyses were conducted in an exploratory and physicians, due to postoperative complications after primary tumor descriptive fashion. All results are presented in raw numbers, rates, debulking, secondary cytoreduction due to EOC relapse, or or means and ranges according to the underlying distribution. The palliation due to tumor-related symptoms such ileus. GraphPad Prism® 5 statistical software was applied. Primary tumor debulking was performed according to the International Federation of Obstreticians and Gynaecologists (FIGO) criteria, aiming at maximal tumor reduction. Standard Results procedures included midline laparotomy, peritoneal cytology, hysterectomy, adenectomy, infragastric omentectomy and systematic Patient data. A total of 10 patients, 6 with primary and 4 pelvic and paraaortic lymph node dissection (11). In cases of with recurrent EOC were included in the present analysis. advanced tumor disease with multivisceral involvement, additional procedures such as peritonectomy, intestinal resection, splenectomy All patients had an advanced initial FIGO stage IIIc (n=5) or and diaphragmatic resection were performed in order to achieve IV (n=5) (15). The median age of patients was 68 years maximal cytoreduction. (range: 45-77 years). The vast majority of the tumors were In recurrent situations, patients were selected for secondary poorly differentiated (8/10). All but one patient, who had an tumor debulking mainly based on the DESKTOP criteria (12), also endometrioid histology, presented a serous-papillary aiming at maximal tumor reduction. Emergency indications for re- carcinoma. In 6 patients the previous i.p. catumaxomab laparotomy included anastomotic insufficiency with peritonitis or treatment was performed at primary tumor debulking for obstructive ileus. Intraoperative tumor dissemination pattern, surgical outcome, EOC and in 4 patients due to malignant ascites in the morbidity and mortality were recorded as based on a systematic and recurrent situation of the disease. Half of the patients (n=5) validated surgical and histopathological documentation system initially operated on had optimal tumor residuals (0-0.5 cm), (Intraoperative Mapping of Ovarian Cancer, IMO) especially while for 2 patients only suboptimal tumor debulking with conducted for the objective and systematic description of ovarian tumor residuals <2 cm was achieved. The localization of tumor spread within the abdominal cavity, both in primary and tumor residuals was diffuse in mesentery and/or small recurrent situations (13, 14). Three IMO levels divide the abdomen intestine. All patients at their initial presentation of the into three spaces: the lower (level 1), middle (level 2) and upper (level 3) abdomen. Nine IMO fields, three at each level, provide a disease had diffuse peritoneal carcinomatosis and 6 of them sub classification of the peritoneal cavity, this aiming at a more had ascites with >500 ml. Detailed patient data and data precise documentation of the tumor dissemination pattern. The regarding initial surgery are shown in Table I. pattern of tumor spread was intraoperatively and prospectively assessed by an independent person based on the surgical procedures Intraoperative tumor dissemination, surgical outcome and performed and postoperative interview of the surgeon. Based on morbidity. The mean time between catumaxomab application IMO (13, 14), the surgeon had to describe the intraoperative tumor and surgery was 175 days (range: 8-481 days). The mean dissemination pattern, the maximal tumor load and the localization of tumor residuals and would also list the various procedures time between last chemotherapy administration and surgery performed in detail. All patients were operated on by one of the two was 132 days (range: 6-358 days). Half of the patients (n=5) gynecological oncological surgeons (JS, CF). were finally treated using a combination of paclitaxel and

2604 Papanikolaou et al: Surgery after Intraperitoneal Catumaxomab in Ovarian Cancer

Figure 1. Intraoperative tumor dissemination pattern in patients with advanced EOC who had been previously treated with catumaxomab (n=10).

carboplatin, while pegylated liposomal doxorubicin was later Table I. Clinical and tumor-related characteristics of the 10 patients administered in 2 further patients, 1 patient received with advanced ovarian cancer, previously treated with intraperitoneal carboplatin monotherapy and 2 patients received no infusions of catumaxomab, who underwent surgical treatment. chemotherapy prior to surgery. Indications for relaparotomy All patients after i.p. catumaxomab were as follows: 3 patients due to (n=10) anastomotic insufficiency after primary tumor debulking (on the 6-8th day), 2 patients due to secondary tumor debulking, Median age, years 68 (range: 45-77) 4 patients due to ileus in recurrent EOC and 2 patients for FIGO stage IIIc 5 restoration of intestinal continuity. One patient was re- IV 5 operated on twice due to abscess formation by anastomotic Grading insufficiency 10 days after the primary operation. The mean G2 2 operation time was 185 minutes (range: 69-325 min). The G3 8 performed operative procedures are shown in Table III. In 2 Histology patients (20%) tumor residuals <0.5 cm could be achieved, Serous-papillary 9 Endometrioid 1 while in 3 (30%) of the patients, tumor residuals were <1 cm Initial postoperative residuals and in other 3 patients (30%) this was <2 cm. Two patients None 3 did not have any tumor manifestation. <0.5 cm 2 The vast majority of the patients operated on (7/10) <1 cm presented with massive adhesions (score 3) according to the <2 cm 3 scoring system developed for use in gynecologic surgery (15). 2 Localization of initial tumor residuals Eight patients presented diffuse peritoneal carcinomatosis. Mesentery 5 Nevertheless, at the time of surgery, none of the patients Small intestine 5 presented with amounts of ascites >500 ml; most patients Initial ascites (7/10) had small amounts of ascites (<500 ml). None 0 Due to the advanced stage of the disease most patients (n=7) <500 ml 4 had a diffuse tumor involvement of the mesentery; 8/10 of >500 ml 6 Initial diffuse peritoneal carcinomatosis 10 the parietal peritoneum; 2 patients had bulky lymph nodes

2605 ANTICANCER RESEARCH 31: 2603-2608 (2011)

Table II. Data regarding surgical outcome and intraoperative findings in patients with EOC after the intraperitoneal treatment with catumaxomab.

All patients (n=10)

Aim of surgery Curative 2 Palliative 8 Indication for surgery Relapse- secondary tumor debulking 2 Anastomotic insufficiency 3 Ileus 4 Intestinal-continuity restoration 2 Mean operation time, min 185 (range: 69-325) Postoperative residuals None 2 <0.5 cm 2 <1 cm 3 <2 cm 3 Adhesions Massive (score 3) 7 Moderate (score 2) 2 None (score 0) 1 Ascites None 3 <500 ml 7 >500 ml 0 Diffuse peritoneal carcinomatosis Yes 8 No 2 Mean time between catumaxomab application and surgery, days 175 (range: 8-481) Mean time between last chemotherapy and surgery, days 132 (range: 6-358) Mean duration of hospital stay, days 29 (9-59) Mean units of blood transfusion (250 ml) 2.8 (range 0-10)

and 4 patients diffuse tumor involvement of the intestinal Postoperative intra-abdominal adhesion formation mucosa. The mean number of blood units per patient was 2.8 remains a significant cause of morbidity in surgical units (range: 0-10). patients. Preliminary evidence revealed that intra-abdominal The mean duration of hospital stay was 29 days (range: 9- adhesion formation is also angiogenesis-dependent (20, 21). 59). Three out of ten patients developed a major Anti-vascular endothelial growth factor (VEGF) therapy postoperative complication in terms of infection or abscess with a specific VEGF monoclonal antibody was shown to in the operated area. None of the patients developed a prevent peritoneal adhesion formation without adversely thromboembolic episode or an intestinal fistula. Data affecting wound strength or anastomotic integrity (20). regarding surgical outcome and morbidity as well as tumor Targeted therapies such as bevacizumab (Avastin®) have dissemination pattern are presented in Tables II and III. been known to influence intraabdominal adhesion formation. A single dose of i.p. bevacizumab was Discussion demonstrated to significantly reduce the grade and severity of abdominal adhesions (21). Nevertheless, operative The present evaluation constitutes the first description of experience after intraperitoneal or intravenous bevacizumab surgical experience in advanced EOC after intraperitoneal is very limited (22, 23); this should be investigated in treatment with catumaxomab, as based on a systematic further studies. documentation tool for ovarian neoplasms (13, 14, 17-19). Surgery is being frequently performed for relapsed ovarian We were able to show that surgery after i.p. catumaxomab cancer. Furthermore, increasingly more novel targeted appears to be feasible and is associated with reduced therapies are currently being applied and investigated, but amounts of ascites in the recurrent situation of the disease, only little is known about their impact on surgical morbidity despite severe peritoneal carcinomatosis. and long-term clinical outcome.

2606 Papanikolaou et al: Surgery after Intraperitoneal Catumaxomab in Ovarian Cancer

Table III. Operative procedures and morbidity in patients with EOC who In the new era of increasing implementation of targeted were operated on after intraperitoneal treatment with catumaxomab. therapies for epithelial tumors, further larger trials are warranted to assess the impact of such therapies on Operative procedure Patients (n=10) intraoperative conditions, operability and operative morbidity.

Restoration of intestinal continuity 1 Conflict of Interest Statement Partial resection of small bowel 5 Adhesiolysis 10 The Authors declare that there are no conflicts of interest. Total colectomy 4 Ileostomy 2 Jejunostomy 3 References Colostomy Extensive peritonectomy 1 1 Heiss MM, Strohlein MA, Jager M, Kimmig R, Burges A, Pelvic lymphadenectomy 1 Schoberth A, Jauch KW, Schildberg FW and Lindhofer H: Immunotherapy of malignant ascites with trifunctional Major operative complications 3 antibodies. Int J Cancer 117(3): 435-443, 2005. 2 Zeidler R, Reisbach G, Wollenberg B, Lang S, Chaubal S, Schmitt Thromboembolism 0 B and Lindhofer H: Simultaneous activation of T cells and Infection/abscess 3 accessory cells by a new class of intact bispecific antibody results Fistula formation 0 in efficient tumour cell killing. J Immunol 163: 1246-1252, 1999. 3 Zeidler R, Mysliwietz J, Csanady M, Walz A, Ziegler I, Schmitt B, Wollenberg B and Lindhofer H: The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells. Br J Cancer 83: 261-266, 2000. Interestingly, despite the substantial number of patients with 4 Riesenberg R, Buchner A, Pohla H and Lindhofer H: Lysis of recurrent ovarian cancer experiencing gastrointestinal obstruction prostate carcinoma cells by trifunctional bispecific antibodies due to peritoneal carcinosis and adhesions, the rate of (αEpCAM × αCD3). J Histochem Cytochem 49: 1-7, 2001. gastrointestinal perforation and fistula has been shown to be 5 Assessment report for Removab. International Nonproprietary relatively low. The additional combination of bevacizumab with Name: catumaxomab. Procedure No. EMEA/H/C/000972, various first-line chemotherapeutics was associated with a bowel Doc.Ref.: EMEA/CHMP/100434/2009, European Medicines Agency, Evaluation of Medicines for Human Use. perforation rate as high as 1.5%-1.6% (24, 25), while in a large 6 Parsons SL, Kutarska E, Koralewski P, Gore M, Wimberger P, meta-analysis of 5 clinical trials, the risk of arterial Burges A, Stroehlein MA, Lahr A, Jaeger M and Heiss MM: thromboembolic events in patients treated with bevacizumab was Treatment of ovarian cancer patients with malignant ascites significantly elevated compared to that treated with conventional using the trifunctional antibody catumaxomab: Results of a chemotherapy (3.8% vs. 1.7%), as well as the hereby associated phase II/III study. J Clin Oncol 25: 5520, 2007. mortality (0.8% vs. 0.4%) (26). On the contrary, cetuximab, 7 Parsons SL, Murawa PX, Kolesnik OO, Ivanchenko VV, another targeted agent that has shown activity alone or in Koralewski P, Razbadauskas A, Stroehlein MA, Friccius-Quecke H, Jaeger M and Heiss MM: Treatment of epithelial cancer combination with other agents in metastatic colorectal cancer, patients with malignant ascites using catumaxomab: results of does not appear to increase the complication rate of surgery (27). the nonovarian stratum of a phase II/III study. Proc Gastrointest A study by Krueger et al., which compared the Cancer Symp 106, 2008. intraoperative intraperitoneal treatment of gastric cancer 8 Heiss MM, Murawa P, Koralewski P, Kutarska E, Kolesnik OO, with the trifunctional antibody catumaxomab compared to Ivanchenko VV, Dudnichenko AS, Aleknaviciene B, surgery alone, revealed no occurrence of severe adverse Razbadauskas A, Gore M, Ganea-Motan E, Ciuleanu T, reactions or other complications, such as impaired wound Wimberger P, Schmittel A, Schmalfeldt B, Burges A, Bokemeyer C,Lindhofer H, Lahr A and Parsons SL: The trifunctional healing in the catumaxomab group compared to the surgery antibody catumaxomab for the treatment of malignant ascites only group. The most frequently treatment-emergent adverse due to epithelial cancer: Results of a prospective randomized events in the catumaxomab group were anemia, pyrexia, phase II/III trial. Int J Cancer 127(9): 2209-2221, 2010. systemic inflammatory response syndrome (SIRS) and 9 Chekerov R, Reinthaller A, Reimer D, Reimer T, Angleitner- abdominal pain (28). Boubenizek L, Halfen M, Lindhofer H, Braicu I, Oskay-Özcelik G We conclude that surgery after i.p. catumaxomab appears and Sehouli J: Intraoperative immunotherapy with the trifunctional to be feasible, without significantly higher rates of antibody catumaxomab in patients with ovarian cancer: Results from a phase II study. J Clin Oncol 28(7): 5039, 2010. anastomotic insufficiency or postoperative thromboembolic 10 Pietzner K, Linke RG, Jäger M, Lindhofer H, Friccius-Quecke events. Despite distinctive adhesion formations, which could H, Chen F, Braicu EI, Oskay-Özcelik G and Sehouli J: Phase II also be attributed to the peritoneal carcinosis itself, clinical trial to evaluate the safety of repeated cycle of operability does not seem to be influenced negatively. intraperitoneal catumaxomab for treatment of malignant ascites

2607 ANTICANCER RESEARCH 31: 2603-2608 (2011)

(SECIMAS). J Clin Oncol, 2010 ASCO Annual Meeting 21 Ignjatovic D, Aasland K, Pettersen M, Sund S, Chen Y, Proceedings (Post-Meeting Edition). Vol 28, No 15_suppl (May Spasojevic M and Nesgaard JM: Intra-abdominal administration 20 Supplement), TPS155, 2010. of bevacizumab diminishes intra-peritoneal adhesions. Am J 11 International Federation of Gynecology and Obstetrics. Surg 200(2): 270-275, 2010. Changing in definitions of clinical staging for carcinoma of the 22 Sfakianos GP, Numnum TM, Halverson CB, Panjeti D, Kendrick cervix and ovary. Am J Obstet Gynecol 156: 263-264, 1987. JE 4th and Straughn JM Jr.: The risk of gastrointestinal perforation 12 Harter P, Hahmann M, Lueck HJ, Poelcher M, Wimberger P, and/or fistula in patients with recurrent ovarian cancer receiving Ortmann O, Canzler U, Richter B, Wagner U, Hasenburg A, bevacizumab compared to standard chemotherapy: a retrospective Burges A, Loibl S, Meier W, Huober J, Fink D, Schroeder W, cohort study. Gynecol Oncol 114(3): 424-426, 2009. Muenstedt K, Schmalfeldt B, Emons G and du Bois A: Surgery 23 Scappaticci FA Fehrenbacher L, Cartwright T, Hainsworth JD, for recurrent ovarian cancer: role of peritoneal carcinomatosis: Heim W, Berlin J, Kabbinavar F, Novotny W, Sarkar S and exploratory analysis of the DESKTOP I Trial about risk factors, Hurwitz H: Surgical wound healing complications in metastatic surgical implications, and prognostic value of peritoneal colorectal cancer patients treated with bevacizumab. J Surg carcinomatosis. Ann Surg Oncol 16(5): 1324-1330, 2009. Oncol 91(3): 173-180, 2005. 13 Sehouli J, Senyuva F, Fotopoulou C, Neumann U, Denkert C, 24 Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Werner L and Gülten OO: Intra-abdominal tumor dissemination Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren pattern and surgical outcome in 214 patients with primary E, Ferrara N, Fyfe G, Rogers B, Ross R and Kabbinavar F: ovarian cancer. J Surg Oncol 99(7): 424-427, 2009. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for 14 Sehouli J, Könsgen D, Mustea A, Oskay-Ozcelik G, Katsares I, metastatic colorectal cancer. N Engl J Med 350: 2335-2342, Weidemann H and Lichtenegger W: ‘IMO’- intraoperative 2004. mapping of ovarian cancer. Zentralbl Gynakol 125(3-4): 129- 25 Kozloff M, Cohn A, Christiansen N, Flynn P, Kabbinavar F, 135, 2003. Robles R and Ulcickas-Yood M: Safety of bevacizumab (BV) 15 Adhesion Scoring Group, Improvement of interobserver among patients (pts) receiving first-line chemotherapy (CT) for reproducibility of adhesion scoring systems, Fertil Steril 62: metastatic colorectal cancer (mCRC): preliminary results from a 984-988, 1994. larger registry in the U.S, J Clin Oncol 23: 3566, 2005. 16 Cohen Z, Senagore AJ, Dayton MT, Koruda MJ, Beck DE, Wolff 26 Skillings JR, Johnson DH, Miller K, Kabbinavar E, Bergsland BG, Fleshner PR, Thirlby RC, Ludwig KA, Larach SW, Weiss E, Holmgren SN, Holden SN, Hurwitz H and Scappaticci F: EG, Bauer JJ and Holmdahl L: Prevention of postoperative Arterial thromboembolic events (ATEs) in a pooled analysis of 5 abdominal adhesions by a novel, glycerol/sodium hyaluronate/ randomized, controlled trials (RCTs) of bevacizumab (BV) with carboxymethylcellulose–based bioresorbable membrane: a chemotherapy, J Clin Oncol 23: 3019, 2005. prospective, randomized, evaluator-blinded multicenter study. 27 Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Dis Colon Rectum 48: 1130-1139, 2005. Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I 17 Woopen H and Sehouli J: Current and future options in the and Van Cutsem E: Cetuximab monotherapy and cetuximab plus treatment of malignant ascites in ovarian cancer. Anticancer Res. irinotecan in irinotecan-refractory metastatic colorectal cancer. 29(8): 3353-3359, 2009. N Engl J Med 351: 337-345, 2004. 18 Makey JR and Venner P: Malignant ascites: demographics, 28 Krueger CM, Berdov BA, Roman LA, Luft AV, Lampe P, therapeutic efficacy and predictors of survival. Can J Oncol 6(2): Lindhofer H, Bartelheim K, Klein A and Heiss MM: 474-480, 1996. Intraoperative, adjuvant treatment of gastric cancer with the 19 Wimberger P, Heubner M and Kimmig R: Catumaxomab in the trifunctional antibody catumaxomab compared to surgery alone: Treatment of Malignant Ascites: the Evidence of its Therapeutic A phase II study J Clin Oncol 26(15S): 15529, 2008. Value. Clin Med Insights Ther 2: 481-489, 2010. 20 Sookhai S, Wang J, Austin K, Maguire D, Blankson S, Kirwan WO and Redmond HP: Antivascular endothelial growth factor therapy prevents peritoneal adhesion formation without Received March 16, 2011 adversely affecting wound strength or anastomotic integrity, Revised June 23, 2011 British Journal of Surgery 87(7): 950-951, 2000. Accepted June 24, 2011

2608