Gastrointestinal Complications in 147 Consecutive Patients with Peritoneal Surface Malignancy Treated by Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy

Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly used in the treatment of peritoneal carcinomatosis from gastrointestinal malignancies. The purpose of this study is to reevaluate the incidence of gastrointestinal events and identify risk factors associated with this treatment approach. Between January 1, 2006 and December 31, 2009, 147 patients with appendiceal and colorectal carcinomatosis were treated. Gastrointestinal events were analyzed. The overall incidence of grade I–IV gastrointestinal events was 17%. There were 4 grade III gastrointestinal events that occurred in 4 patients and 11 grade IV gastrointestinal events that occurred in 8 patients. On univariate analysis of grade I–IV events a statistically significant association was observed with the following variables: histological grade, peritoneal cancer index (PCI), small bowel resection, colorectal anastomosis, and the number of anastomoses performed per patient. By multivariate analysis, PCI was identified as the only independent risk factor for gastrointestinal complications. CRS combined with a uniform HIPEC regimen is associated with a 17% gastrointestinal morbidity rate (grade I–IV). The frequency of gastrointestinal complications was associated with a large extent of disease measured by PCI (>30).

As the surgical technology has improved and the regimens for administering chemotherapy have become safer, the complications associated with this treatment approach have decreased [13][14][15][16][17][18]. In a systematic review, Chua reviewed all the relevant studies reported before August 2008 and con-cluded that the morbidity and mortality of CRS and HIPEC were similar to other major gastrointestinal interventions [19]. An important concept, "the learning curve," has been demonstrated to operate in the expanded application of CRS and HIPEC [20][21][22]. Smeenk et al. reported the results of 323 procedures over a 10-year time period; they showed a decrease in major morbidity from 71% to 34% [22]. Yan et al. demonstrated a reduction in the rate of severe morbidity, transfusion requirement, duration of operation, and length of intensive care unit stay over a similar period of time in 140 patients [21].
In recent publications overall grade III-IV morbidity rates are shown to be between 7 and 41% [23][24][25][26]. For gastrointestinal events, small bowel perforations and anastomotic leaks are the most common and clinically significant complications after CRS and PIC [23][24][25][26][27]. The aim of this study was to report the incidence of gastrointestinal events and identify the associated risk factors.

Patient Characteristics.
All patients with appendiceal and colorectal carcinomatosis treated in a uniform manner at Washington Hospital Center, between January 1, 2006 and December 31, 2009 constituted the basis of the present study. Institutional Review Board approval was obtained to collect and analyze these data. All patients with appendiceal and colorectal malignancy who received CRS combined with a standardized treatment with PIC were included (Table 1). Patients who had an incomplete CRS combined with PIC were included in the study, patients who had an open and close procedure or palliative debulking were not included. The quantitative prognostic indicators were the histological grade, the prior surgical score (PSS), the peritoneal cancer index (PCI), and the completeness of cytoreduction score (CC) [28].

Cytoreductive Surgery and Perioperative
Intraperitoneal and Systemic Chemotherapy. The goal of surgery in these patients was to visibly clear the abdomen and pelvis of cancer nodules. This required a series of peritonectomy procedures and visceral resections (Table 1). Normal peritoneum or normal visceral structures were not resected. A mechanical bowel preparation was used in all patients. Within one hour prior to the abdominal incision, patients received antibiotic prophylaxis. Prophylaxis for venous thrombosis and pulmonary embolus during the cytoreductive surgery was limited to sequential compression devices (SCD Response, Kendall Co., Mansfield, MA).
All patients received HIPEC in the operating room immediately after the CRS but before intestinal anastomoses or repair of seromuscular tears. A combination of two drugs was administered intraperitoneally: mitomycin C (15 mg/m 2 ) and doxorubicin (15 mg/m 2 ). The target temperature for the entire abdomen during HIPEC was 41.5 • C. Simultaneously, intravenous 5-fluorouracil (400 mg/m 2 ) and leucovorin (20 mg/m 2 ) were administered as a rapid infusion over 6-8 minutes. HIPEC was given using the Coliseum technique [29]. A heater circulator (Belmont Instruments Corporation, Billerica, MA) was used to maintain moderate hyperthermia within the abdomen and pelvis (41-43 • C). During the first 45 minutes, only manual distribution of the chemotherapy solution occurred. In the second 45 minutes of the 90-minute treatment, seromuscular tears were repaired, the anterior and posterior rectus sheath were brought together with a running 2-0 Vicryl suture (Ethicon, Cincinnati, OH), and chest tubes were positioned.
Esophago-jejunal and colorectal anastomoses were performed with a 28 mm or 33 mm diameter circular stapler, respectively (Ethicon, Cincinnati, OH). Esophago-jejunal anastomoses were reinforced with a layer of silk sutures. If the colorectal stapled anastomoses could be well visualized, a second layer of 3-0 silk sutures was used to plicate the anastomosis. If this double layer anastomosis was performed,  no diverting ostomy was constructed. If the colorectal anastomosis was too low to place a second layer of silk sutures over the circular stapled anastomosis, a diverting ostomy was constructed. All small bowel, colo-colic and ileocolic anastomoses were double-layer hand sewn with an inner layer of running 3-0 Maxon (Davis and Geck, Danbury, CT) and interrupted outer layer of 3-0 silk.

Early Postoperative Intraperitoneal Chemotherapy (EPIC).
The EPIC 5-fluorouracil (5-FU) was withheld in patients, who had a full course of oxaliplatin-based FOLFOX chemotherapy prior to CRS. The dose of EPIC 5-FU was 400 mg/m 2 /day for women and 600 mg/m 2 /day for men. It was infused via a Tenckhoff catheter over approximately 15 minutes with a 23-hour dwell time. After one hour of drainage, another administration of 5-FU occurred for 4 days after surgery.

Postoperative Management.
Patients were transferred directly to a surgical intensive care unit for monitoring and extubation. An 18 French nasogastric tube (Silicone Salem Sump Tube, Kendall Co., Mansfield, MA) was placed intraoperatively in all patients and remained until the drainage of bile from the stomach has ceased and some enteric function per rectum or per ostomy had occurred. All patients received postoperative intravenous feeding through the intrajugular vein for the five postoperative days and then through a percutaneous central catheter (Vaxcel, Glen Falls, NY) until gastrointestinal function returned. Closed suction drains remained in place after surgery in all patients until drainage was below 50 mL per 24 hours from a single drain.

Database for Morbidity Assessment.
The database was specially constructed to evaluate gastrointestinal complications in patients with peritoneal surface malignancy. The morbidity variables were prospectively recorded according to the Common Toxicity Criteria (version 3.0) of the National Cancer Institute [30]. It consisted of 11 gastrointestinal adverse events (anastomotic failure, fistula, pancreatic fistula, pancreatitis, bile leak, chyle leak, prolonged ileus, small bowel obstruction, nausea/vomiting, diarrhea and ascites). Types of gastrointestinal adverse events observed and the grade are listed in Table 2.

Preoperative and Intraoperative
In 39 patients (27%), no blood replacement in the operating room occurred. Only 5 patients had more than six units transfused. Sixty-seven patients (46%) received fresh frozen plasma and, 16 (11%) patients had more than four units. All 147 patients were treated with HIPEC and intravenous 5-FU in the operating room. In 65 patients (44%), EPIC was used in the postoperative period (Table 1).

Adverse Events.
In these 147 patients, there was a single postoperative death (0.7%). This patient developed   a profound neutropenia followed by systemic inflammatory response syndrome and multiorgan failure. The overall incidence of gastrointestinal adverse events was 17%. Thirtyfive gastrointestinal events occurred in 25 patients. Nine patients had more than one gastrointestinal event. All the gastrointestinal events observed grade I through IV are summarized in Table 2. The incidence of grade III and IV events was 8% with 15 events observed in 12 patients. There were 5 grade I gastrointestinal events (4 pancreatitis and 1 chyle leak) that occurred in 5 patients. There were 15 grade II gastrointestinal events (4 pancreatitis, 1 prolonged ileus, 7 nausea/vomiting, and 1 diarrhea) that occurred in 11 patients. Four grade III gastrointestinal events (4 nausea/vomiting) occurred in 4 patients. Eleven grade IV gastrointestinal events (3 anastomotic failures, 3 fistulas, 1 pancreatic fistula, 1 pancreatitis, 1 bile leak, 1 small bowel obstruction, and 1 nausea/vomiting) occurred in 8 patients and all but two required a return to the operating room.
By univariate analysis, the following variables were proven to have a statistically significant correlation with gastrointestinal morbidity (Table 3): histological grade (P = 0.0166), PCI (P = 0.0049), small bowel resection (P = 0.0493), performance of a colorectal anastomosis (P = 0.0430) and the number of anastomoses performed per patient (P = 0.0288).
On multivariate analysis using the logistic regression model, the PCI was shown to be the only independent risk factor for gastrointestinal complications (P = 0.0586).
In patients who had HIPEC plus EPIC, an additional four treatments with intraperitoneal 5-fluorouracil were given on postoperative days 1-4. Thirteen of 52 patients (25%) had a grade I-IV complication. Ten of 69 patients (14%) who had HIPEC only were observed to have a grade I-IV complication. As shown in Table 3, this was not significant by a univariate (P = 0.2314) or by the multivariate analysis.

Discussion
At our institution the management of peritoneal surface malignancy requires an integration of extensive surgery combined with intraperitoneal chemotherapy administered as a planed part of the surgical procedures [31]. The aim of this combined treatment modality is to remove all macroscopic tumor nodules and any adhesions between the bowel loops, in order to allow chemotherapeutic agents to be uniformly distributed within the peritoneal cavity to eradicate any microscopic tumor deposits. The potential advantages of using HIPEC compared to standard intravenous chemotherapy include an increased exposure to chemotherapeutic drugs at the peritoneal surface, an increase of drug penetration into the tissues, a synergistic effect of hyperthermia with systemic chemotherapy, and an independent cytotoxic effect of hyperthermia [32].
It is clear, however, that the effects of this regional chemotherapy are not limited to the peritoneal space. The profound effect that these treatments have on wound healing is shown by the increased incidence of gastrointestinal events. This paper represents the effort of our group to identify gastrointestinal events in patients with peritoneal surface malignancy and begin to understand their causes.
We found that our overall incidence of gastrointestinal events was 17% (grade I-IV), in that 35 gastrointestinal events occurred in 25 of the 147 patients. There was often more than one gastrointestinal event per patient. The incidence of grade III and IV gastrointestinal events was 8%.
Our data is compared to those reported by other authors in Table 4. We have calculated the incidence of gastrointestinal events (grades III-IV) in Glehen, Kusamura, and Hansson's manuscripts by dividing the total number of events by the total number of patients. In Youssef manuscript and in our data, we were able to calculate the incidence of events per patient (Table 4). Glehen et al. conducted a study of 207 patients treated by CRS and HIPEC with the closed abdominal technique [23]. The overall postoperative morbidity rate including all grades III-IV was 24.5%. They had 14 digestive fistulas, 11 cases of prolonged ileus, and 5 intraperitoneal abscesses. The presence of digestive fistula was significantly associated with the duration of surgery and the number of anastomoses in the univariate analysis. Kusamura [24]. The overall postoperative morbidity rate including all grade III-IV was 12%. They had 17 anastomotic leaks, 6 digestive perforations, 1 biliary fistula, 2 pancreatic fistulas, and 4 ileus/gastric stasis. The most severe complications in their series were intestinal leakage due to anastomotic insufficiency and/or intestinal perforation. This morbidity constituted approximately 70% of all cases with major morbidity. The rate of fistula in the series was 11%. They found in the multivariate analysis that the extent of cytoreduction (levels 1 and 2 versus 3) and CDDP for IPHP dose ≥ 240 mg were independent risk factors for major morbidity. Hansson et al. conducted a study of 123 patients treated by CRS and HIPEC and observed grade III-IV adverse events in 51 patients (41%) [25]. In multivariate analyses, grade III-IV adverse events were associated with stoma formation, duration of surgery, perioperative blood loss, and peritoneal cancer index. Among the gastrointestinal events, 7 anastomotic leaks, 11 digestive tract perforations, 1 pancreatitis, 1 bile leak, and 3 prolonged ileus occurred.
Youssef et al. conducted a study of 456 patients with pseudomyxoma peritonei syndrome of appendiceal origin [26]; grade III-IV morbidity was 7%. Seven anastomotic leaks, 5 pancreatic complications, and 8 intestinal fistulas were reported. An analysis of prognosis risk factors was not provided.
In our study, we found that the histological grade, PCI, small bowel resection, colorectal anastomoses performed, and the number of anastomoses performed per patient had a statistically significant correlation with gastrointestinal morbidity; by multivariate analysis only, the PCI was an independent risk factor for gastrointestinal complications. These data suggest that CRS combined with a standardized treatment with perioperative chemotherapy is a reasonable safe treatment for selected patients with peritoneal surface malignancy. There is an acceptable gastrointestinal morbidity as compared with modern series of pancreatic-duodenectomy, gastrectomy for cancer, or other multiorgan resections.