Königsrainer

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Königsrainer

  1. 1. ORIGINAL ARTICLE Cytoreductive surgery and HIPEC in peritoneal recurrent ovarian cancer: experience and lessons learned Ingmar Königsrainer & Stefan Beckert & Sven Becker & Derek Zieker & Tanja Fehm & Eva-Maria Grischke & Olivia Lauk & Jörg Glatzle & Björn Brücher & Diethelm Wallwiener & Alfred Königsrainer Received: 15 April 2011 /Accepted: 3 August 2011 /Published online: 13 August 2011 # Springer-Verlag 2011 Abstract Purpose Peritoneal recurrence of ovarian cancer is frequent after primary surgery and chemotherapy and has poor long- term survival. De novo cytoreductive surgery is crucial with the potential to improve prognosis, especially when combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Methods The sampled data of 40 consecutive patients were retrospectively analyzed. Thirty-one patients were treated with cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. Results No patient was lost in the perioperative period, and the combined procedure was performed with acceptable morbidity. Colon-preserving cytoreductive surgery was associated with reduced morbidity. Conclusions Patients suffering from peritoneal recurrence of ovarian cancer should be considered for radical reoper- ation with HIPEC in a center with expertise in multimodal therapeutic options. Organ-preserving cytoreductive surgery allows complete cytoreduction with the goal of decreasing morbidity. Keywords Peritoneal carcinomatosis . Ovarian cancer. HIPEC Introduction Median survival in stage III and IV ovarian cancer ranges from 12 to 25 months [1]. So far, standard treatment consists of radical cytoreductive surgery (CRS) followed by platinum/paclitaxel-based adjuvant chemo- therapy. Even though most patients initially respond well to this treatment, about 50% develop intraperitoneal recurrent disease within 5 years [1]. Since a regimen of combined intraperitoneal and intravenous administration of chemotherapeutic drugs achieved encouraging results in primary stage III ovarian cancer in randomized trials [2], cytoreductive surgery along with hyperthermic intraperi- toneal chemotherapy (HIPEC) was proposed as new treatment. Two recent reviews prove this strategy to be a valuable option in primary advanced stage III–IV disease, in that it affords complete cytoreduction and has the greatest impact on 5-year survival, reported to range from 12% to 66% [2, 3]. Because the results were so promising, we proposed this concept for recurrent ovarian cancer and peritoneal spread at our center for peritonectomy primarily set up for colorectal cancer and primary peritoneal malignancies. We herein present our first experience with cytoreductive surgery and This manuscript contains original material that has not been previously published. I. Königsrainer (*) :S. Beckert :D. Zieker :O. Lauk : J. Glatzle :B. Brücher :A. Königsrainer Department of General, Visceral and Transplant Surgery, Comprehensive Cancer Center, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany e-mail: ingmar.koenigsrainer@med.uni-tuebingen.de S. Becker :T. Fehm :E.-M. Grischke :D. Wallwiener Department of Gynecology, Comprehensive Cancer Center, University of Tübingen, Calwerstrasse 7, 72076 Tübingen, Germany Langenbecks Arch Surg (2011) 396:1077–1081 DOI 10.1007/s00423-011-0835-2
  2. 2. HIPEC for recurrent ovarian cancer and our first lessons learned from it. Methods Patients Between February 2007 and February 2010, reoperation was indicated in 40 patients with peritoneal recurrence of ovarian cancer. Preoperative workup was done by CT or PET-CT scan and laparoscopy. The selection algorithm for PC is described elsewhere [4]. In nine patients HIPEC was not performed, and thus these patients were excluded from analysis after explorative laparotomy or nonradical tumor debulking either because of an extensively high tumor load with a peritoneal carcinomatosis index (PCI) of more than 35 or because of deep infiltration of the retroperitoneum or the mesenterial axis. In 31 patients, cytoreductive surgery followed by HIPEC was performed. All patients received peridural anesthesia and close temperature monitoring. Data were analyzed retrospectively. The study was conducted in compliance with the regulations of the local ethics committee. Surgical procedure After laparotomy and complete adhesiolysis, PCI was determined following the criteria described by Sugarbaker et al. [5], in particular with meticulous exploration of small bowel, exclusion of retroperitoneal infiltration, or liver metastases. Then, after meticulous exploration of predilec- tion areas like ligamentum teres, sulcus rex, sulcus arancii, bursa omentalis, space between the vena cava and liver segment 1, and retrosplenic sulcus, where most likely tumor spread is found, cytoreductive surgery was performed according to the Sugarbaker technique [6, 7]. In the majority of cases, a multivisceral resection was necessary to achieve the aim of complete cytoreduction (CC0, CC1; CC0 meaning no visible disease, CC1 meaning nodules smaller than 0.25 cm). After complete cytoreduction and fashioning of intestinal anastomoses, if necessary, HIPEC using cis- platin 50 mg/m2 for 90 min at 42°C was administered to the open abdomen. To optimally maintain 42°C, intraper- itoneal temperature was controlled with a probe placed directly in the abdominal fluid. A rubber drain was then routinely placed in the pelvis and an additional drain in the left upper abdominal quadrant if splenectomy was per- formed. Finally, the abdomen was closed with interrupted sutures. Statistics Data are presented as median (min–max) or n (percent), unless otherwise stated. Qualitative differences were com- pared using the chi-square test and quantitative differences using the Mann–Whitney U test. Survival analysis was performed with the Kaplan–Meier method. For overall survival (OS), time to event was calculated as time from cytoreductive surgery until death or time to last contact if the patient was alive. A p value less than 0.05 was considered significant. SPSS version 13.0 software (SPSS, Chicago, Illinois, USA) was used for all statistical analyses. Results Demographic data are given in Table 1. Time from primary diagnosis of ovarian cancer to peritoneal recurrence was 762 (101–3,160) days. Initially, most patients were classi- fied as FIGO IIIc and tumor grading was G2 or G3 (Table 2). In three patients, in whom it was originally deemed possible to eradicate the whole tumor, a radical resection was not possible and therefore a CC2 status was achieved. In 74% of the patients, a colonic or rectal resection was necessary for eradication of all visible tumors. Two patients required diverting loop ileostomy, while three patients Table 1 Clinical characteristics Patients, n 31 Age, years 60 (28–68) BMI, cm/kg2 24 (17–39) ASA, n (%) 1 2 (6) 2 16 (52) 3 13 (42) Time to primary recurrence, days 762 (101–3,160) Data are presented as median (min, max) BMI body mass index FIGO, n (%) IIIb 2 (7) IIIc 28 (90) IV 1 (3) Grading, n (%) 0 1 (3) 1 2 (7) 2 15 (48) 3 13 (42) Table 2 FIGO classification, grading status Initial FIGO classification 1078 Langenbecks Arch Surg (2011) 396:1077–1081
  3. 3. received a terminal colostomy. More than 50% of the patients underwent splenectomy. The types of operation and organ resection are shown in Table 3. Patients who underwent colonic resection had a signifi- cantly longer median hospital stay than did those with no colonic resection [18 vs. 14 days (p=0.026)] and also showed a greater trend to wound infection [(4 vs. 0; p=0.281)] and a higher incidence of reoperation [6 vs. 0 (p=0.137)]. Full details are given in Table 4. No patient was lost in the immediate postoperative period (Table 5), 19% had to be reoperated due to postoperative complications, and an anastomotic leak was observed in three patients. Full details are given in Table 5. Median follow-up was 798 (188–1,297) days (Table 6). Of the 28 patients who underwent complete cytoreduction (CC0 and CC1), 25% experienced tumor recurrence within the follow-up period. Ten (32%) patients died during the follow-up from tumor progression. Tumor recurrence after redo of cytoreductive surgery followed by HIPEC was mainly located in the parietal abdominal wall, where peritonectomy was performed (10.7%). Full details are reported in Table 6. OS is shown in Fig. 1a, and time of recurrence is described in Fig. 1b following CRS and HIPEC. Discussion We here present our first experience with cytoreductive surgery and HIPEC for peritoneal carcinomatosis in recurrent ovarian cancer. The indication for a “re-tumor debulking” was prompted by the few available alternatives for those patients and current data on HIPEC in advanced ovarian cancer with a potential chance for cure. The morbidity rates from our data are acceptable and comparable with those reported in the current literature. In a large review conducted by Chua et al., mortality ranged from 0% to 10%. Grade IV morbidity with the need for reoperation ranged from 0% to 15%, and median length of hospital stay was comparable with our results, varying from 8 to 25 days [3]. Median overall survival ranged from 22 to 64 months, which is also comparable with our experience. The decision whether or not complete cytoreduction can be achieved is the most challenging issue here. Broad infiltration of the retroperitoneum, the mesenterial axis, or diffuse tumor spread on the small bowel are generally Table 4 Comparison of data with and without colonic resections Data comparing patients with and patients without colonic resection; p<0.05 is considered significant Colonic resection No colonic resection p value Complications, n (%) 10 (44) 3 (38) 0.552 Hospital stay, days 18 (11–93) 14 (3–21) 0.026 Wound infection, n (%) 4 (17) 0 0.281 Reoperation, n (%) 6 (26) 0 0.137 Operation time, min 664 (178–1,070) 527 (441–582) 0.016 PCI 19 (3–34) 13 (6–32) 0.386 Table 3 Type of operation during cytoreduction Operating time, min 593 (178–1,076) CC status, n (%) 0 20 (65) 1 8 (25) 2 3 (10) Colon or rectum resection, n (%) 23 (74) Small bowel resection, n (%) 9 (29) Protective enterostomy, n (%) 2 (6.5) Colostomy terminal, n (%) 3 (10) Resection of diaphragm, n (%) 10 (32) Pancreatic resection, n (%) 2 (6.5) Splenectomy, n (%) 18 (58) Cholecystectomy, n (%) 9 (29) Time and type of operation during cytoreduction are reported; data are presented as median (min, max) or n (%) Table 5 Complications and mortality, n Cumulative complications 23 30-day mortality, n 0 90-day mortality, n 0 Cardiac 1 (3%) Pneumonia 1 (3%) Sepsis 1 (3%) Thromobembolic 4 (13%) Postoperative bleeding 1 (3%) Ureter injury 1 (3%) Resuscitation during HIPEC 1 (3%) Wound infection 4 (13%) Leukopenia 4 (13%) Anastomotic leakage 3 of 23 (13%) Compartment syndrome 1 (3%) Transient paresthesia in the legs 1 (3%) Reoperation due to complication 6 (19%) Complications and perioperative mortality, n (%) Langenbecks Arch Surg (2011) 396:1077–1081 1079
  4. 4. accepted as limitations for complete cytoreductive surgery. This is also true for liver metastasis. Our median PCI score was 18 (3–34). We were able to achieve radical cytor- eduction in 90% of patients (CC0/CC1) who completed the multimodal concept with HIPEC. In three patients tumor nodules left behind were between 0.25 and 2.5 cm, classified as CC2 status. HIPEC in these particular patients was also performed to treat tumor-related ascites. Since peritoneal carcinomatosis is a disease that rarely involves the organs itself, tumor masses can be removed without resection. The small bowel itself can mostly be meticulously cleaned of tumor nodules with subsequent oversewing of partially removed serosal layers. Cleaning of the mesenterium is much easier, and the nodules can be removed with electrocautery. In patients with colonic spread, partial or even complete colectomy was consid- ered necessary in the past because of the risk of secondary perforation after local resection. With increasing experi- ence we learned to also meticulously clean the colon and rectum of tumor nodules, similar to the small bowel, with no higher complication rate and with equal radicality. In fact, in most cases, this can be achieved without necessitating a colorectal resection. Similarly, serosal defects are oversewn with vicryl 4-0 single sutures. In the case of a full-thickness resection, the colon is oversewn with double-layer sutures. Interestingly, we observed a trend to a higher rate of complications and a significantly longer hospital stay in those patients who underwent colorectal resection. Retro- spectively, we are convinced that in some patients, colon resection might have been an overtreatment, and we therefore changed our policy so as to preserve the large bowel whenever possible. Furthermore, tumor recurrence astonishingly was found most often in the parietal abdominal wall and not on the bowel. Normally, after peritonectomy of the parietal abdominal wall, a large wound area is left behind, which poses a risk for tumor adhesion [8, 9]. However, our patient number is low and it is too early to make conclusions about risk factors for recurrence. We therefore immediately oversew all serosal defects on the small or large bowel to avoid any exposure of the wound surfaces to potential free tumor cells. The management of recurrent ovarian cancer should to be reconsidered from a standpoint that focuses on radical reoperation in combination with HIPEC. No mortality and acceptable morbidity with good overall survival are promising criteria for further promoting this concept. Using organ-sparing cytoreduction, complications and hospital stay were reduced without compromising completeness of cytoreduction. Concerning the effectiveness of CRS and HIPEC, no conclusions can be drawn from this study. A comparison of the “HIPEC group” to a “surgery alone group” is not possible retrospectively because the exact exploration of the whole abdomen is mandatory to obtain the PCI which is crucial for prognosis. To address this question, a randomized controlled trial is needed to prove the benefit of CRS and HIPEC on outcome and survival in patients suffering from recurrent ovarian cancer. Fig. 1 Kaplan–Meier curves for overall survival (a) and recurrence (b) Table 6 Recurrence and mortalities during follow-up Recurrence, n (%) 7/28 (25) Mortality during follow-up, n (%) 10 (32) Follow-up time, days 798 (188–1,297) Overall, n (%) 7 (25) Retroperitoneal, n (%) 1 (3.6) Liver surface/right upper quadrant, n (%) 2 (7.1) Parietal abdominal wall, n (%) 3 (10.7) Spleen, n (%) 1 (3.6) Recurrence data and follow-up time; data are presented as median (min, max) or n (%) 1080 Langenbecks Arch Surg (2011) 396:1077–1081
  5. 5. Conflicts of interest None. References 1. Di Giorgio A, Naticchioni E, Biacchi D, Sibio S, Accarpio F, Rocco M, Tarquini S, Di Seri M, Ciardi A, Montruccoli D, Sammartino P (2008) Cytoreductive surgery (peritonectomy procedures) com- bined with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of diffuse peritoneal carcinomatosis from ovarian cancer. Cancer 113:315–325 2. Bijelic L, Jonson A, Sugarbaker PH (2007) Systematic review of cytoreductive surgery and heated intraoperative intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis in primary and recurrent ovarian cancer. Ann Oncol 18:1943–1950 3. Chua TC, Robertson G, Liauw W, Farrell R, Yan TD, Morris DL (2009) Intraoperative hyperthermic intraperitoneal chemotherapy after cytoreductive surgery in ovarian cancer peritoneal carcinoma- tosis: systematic review of current results. J Cancer Res Clin Oncol 135:1637–1645 4. Königsrainer I, Aschoff P, Zieker D, Beckert S, Glatzle J, Pfannenberg C, Miller S, Hartmann JT, Schroeder TH, Brücher BL, Königsrainer A (2008) Selection criteria for peritonectomy with hyperthermic intraoperative chemotherapy (HIPEC) in peritoneal carcinomatosis. Zentralbl Chir 133:468–472 5. Jacquet P, Sugarbaker PH (1996) Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. Cancer Treat Res 82:359–374 6. Stephens AD, Alderman R, Chang D, Edwards GD, Esquivel J, Sebbag G, Steves MA, Sugarbaker PH (1999) Morbidity and mortality analysis of 200 treatments with cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy using the coliseum technique. Ann Surg Oncol 6:790–796 7. Sugarbaker PH (1996) Complete parietal and visceral peritonec- tomy of the pelvis for advanced primary and recurrent ovarian cancer. Cancer Treat Res 81:75–87 8. Königsrainer I, Zieker D, Beckert S, von Weyhern C, Löb S, Falch C, Brücher BL, Königsrainer A, Glatzle J (2009) Local peri- tonectomy highly attracts free floating intraperitoneal colorectal tumour cells in a rat model. Cell Physiol Biochem 23(4–6):371– 378 9. Jacquet P, Elias D, Sugarbaker PH (1996) Tumor implantation in cicatrization sites following surgery for digestive cancers. J Chir (Paris) 133:175–182 Langenbecks Arch Surg (2011) 396:1077–1081 1081
  6. 6. Copyright of Langenbeck's Archives of Surgery is the property of Springer Science & Business Media B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.

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