in the past , peritoneal carcinomatosis ( pc ) was considered as a final stage of unresectable cancer with a short duration of survival [ 13 ] . since the mid 1990s , studies on crs combined with perioperative intraperitoneal chemotherapy ( pic ) , hyperthermic intraperitoneal chemotherapy ( hipec ) , and/or early postoperative intraperitoneal chemotherapy ( epic )
are considered a new treatment options for selected patients with pc and peritoneal mesothelioma [ 412 ] . as the surgical technology has improved and the regimens for administering chemotherapy have become safer ,
the complications associated with this treatment approach have decreased [ 1318 ] .   in a systematic review
, chua reviewed all the relevant studies reported before august 2008 and concluded that the morbidity and mortality of crs and hipec were similar to other major gastrointestinal interventions .
an important concept ,  the learning curve ,  has been demonstrated to operate in the expanded application of crs and hipec [ 2022 ] .
reported the results of 323 procedures over a 10-year time period ; they showed a decrease in major morbidity from 71% to 34% .
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 . in recent publications
overall grade iii - iv morbidity rates are shown to be between 7 and 41% [ 2326 ] . for gastrointestinal events , small bowel perforations and anastomotic leaks
are the most common and clinically significant complications after crs and pic [ 2327 ] .
the aim of this study was to report the incidence of gastrointestinal events and identify the associated risk factors .
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 .
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 ) .
the goal of surgery in these patients was to visibly clear the abdomen and pelvis of cancer nodules .  
a mechanical bowel preparation was used in all patients . within one hour prior to the abdominal incision
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 ) and doxorubicin ( 15  mg / m ) .
simultaneously , intravenous 5-fluorouracil ( 400  mg / m ) and leucovorin ( 20  mg / m ) were administered as a rapid infusion over 68 minutes .
a heater circulator ( belmont instruments corporation , billerica , ma ) was used to maintain moderate hyperthermia within the abdomen and pelvis ( 4143c ) .
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 ) .
if the colorectal stapled anastomoses could be well visualized , a second layer of 30 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 .
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 / day for women and 600  mg / m / 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 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 .
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 .
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 .  
the following clinical variables were analyzed to asses factors predictive of gastrointestinal complications : gender , age ( 50 versus > 51 ) , primary cancer location , grade ( grade 1 versus grade 2 - 3 ) , prior surgical score ( 02 versus 35 ) , peritoneal cancer index ( 010 , 1120 , 2130 , 3139 , and 0 - 20 versus 3139 ) , completeness of cytoreduction ( complete versus incomplete ) , peritonectomy procedures ( pelvic , right upper quadrant , left upper quadrant , omental bursa , and anterior abdominal wall ) , number of peritonectomy procedures per patient ( 02 versus 35 ) , visceral resections performed ( omentectomy , splenectomy , rectosigmoid colon resection , right colon resection , hysterectomy , small bowel resection , transverse colon resection , and gastrectomy ) , visceral resections performed per patient ( 02 versus 37 ) , types of anastomoses performed ( esophago - jejunal , small bowel , ileocolic , colocolic , and colorectal ) , number of anastomoses performed per patient ( 02 versus 35 ) , ostomies performed ( none , diverting ileostomy and end ileostomy ) , blood replacement ( none , 13 units , 46 units , > 6 units ) , fresh frozen plasma replacement ( none , 14 units , > 4 units ) , time in the operating room in hours ( 06 , 712 , > 12 ) , and chemotherapy treatment ( hipec only versus hipec plus epic ) .
for univariate methods to assess the association between gastrointestinal complications and pre- and perioperative clinical characteristics , the pearson chi - square was used , or the fisher 's exact test was used if there was sparse distribution .
those clinical characteristics that were significantly correlated to the outcome by univariate analysis ( p - value < 0.05 ) were then fitted into the logistic regression model for multivariate analysis of variances to assess the strength of the risk factors .
all statistical analyses were conducted using sas ( sas institute inc , cary , nc , usa .
between january 1 , 2006 and december 31 , 2009 , a total of 147 patients ( 135 appendiceal cancer , 12 colorectal cancer ) were treated .
data on patient characteristics , quantitative prognosis indicators , peritonectomies , visceral resections , and intraoperative treatments are summarized in table 1 . in these 147 patients ,
424 peritonectomy procedures were performed with a mean of 3 peritonectomies per patient ( range 0 to 5 ) . in 18 patients ( 12% ) ,
no peritonectomy procedures were performed and 32 patients ( 22% ) had all 5 peritonectomy procedures .
greater omentectomy was performed in 144 patients ( 98% ) and 4 ( 3% ) had a total or partial gastrectomy . in two patients ( 1% ) , there were no visceral resections .  
thirty - four ( 23% ) had 2 visceral resections and an additional 34 patients ( 23% ) had 3 visceral resections .
the total number of anastomoses in all patients was 112 with a mean of 0.76 per patient ( range 04 ) .  
the most common anastomosis was a colorectal anastomosis performed in 56 patients ( 38% ) .
thirty ( 20% ) were diverting ileostomies to protect a colorectal anastomosis and , 13 ( 9% ) were permanent - end ileostomies following total abdominal colectomy . in 39 patients ( 27% ) ,
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 ) . 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 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 ,
ten of 69 patients ( 14% ) who had hipec only were observed to have a grade i 
this was not significant by a univariate ( p = 0.2314 ) or by the multivariate analysis .
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 .  
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 .
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 .
iv ) , in that 35 gastrointestinal events occurred in 25 of the 147 patients .
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 ) .
conducted a study of 207 patients treated by crs and hipec with the closed abdominal technique .
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 .
conducted a study of 205 patients treated by crs and hipec with the closed abdominal technique .
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 .
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% ) . 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
youssef et al . conducted a study of 456 patients with pseudomyxoma peritonei syndrome of appendiceal origin ; grade iii - iv morbidity was 7% .
, 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 .
 
                     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 ) . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion