Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion

Analysis of morbidity and mortality in 209 peritoneal surface malignancies treated with closed abdomen technique

Authors


Abstract

BACKGROUND

The purpose of this prospective Phase II study was to analyze morbidity and mortality of cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP) in the treatment of peritoneal surface malignancies.

METHODS

A total of 205 patients (50 with peritoneal mesothelioma, 49 with pseudomyxoma peritonei, 41 with ovarian cancer, 32 with abdominal sarcomatosis, 13 with colon cancer, 12 with gastric cancer, and 8 with carcinomatosis from other origins) underwent 209 consecutive procedures. Four patients underwent the intervention twice because of disease relapse. There were 70 men and 135 women. Mean age was 52 years (range, 22–76 yrs). CRS was performed by using peritonectomy procedures. IPHP through the closed abdomen technique was conducted with a preheated (42.5 °C) perfusate containing cisplatin + mitomycin C or cisplatin + doxorubicin.

RESULTS

Major morbidity rate was 12%. The most significant complications were 23 anastomotic leaks or bowel perforations, 4 abdominal bleeds, and 4 sepses. Operative mortality rate was 0.9%. On logistic regression model multivariate analysis, extent of cytoreduction (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.29–6.40) and dose of cisplatin for IPHP ≥ 240 mg (OR, 3.13; 95% CI, 1.24–7.90) were independent risk factors for major morbidity. Ten patients presented with Grade 3 to 4 toxicity.

CONCLUSIONS

CRS + IPHP presented acceptable morbidity, toxicity, and mortality rates, all of which support prospective Phase III clinical trials. Cancer 2006. © 2006 American Cancer Society.

The evolution of locoregional therapy in the last 2 decades has changed the paradigm that has supported management of patients affected by peritoneal surface malignancies (PSM). In fact, results from Phase II studies that tested the efficacy of combination cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP) in the treatment of carcinomatosis of various origins have been somewhat encouraging. In our previous experience with CRS + IPHP, we reported 5-year overall survival rates of 97% and 67%, respectively, for pseudomyxoma peritonei1 and peritoneal mesothelioma.2 Other groups have reported 5-year overall survival rates of 63.4% and 19%, respectively, in ovarian3 and colorectal cancers.4 Moreover, results of a Phase III trial have confirmed the superiority of CRS + IPHP in the treatment of patients with carcinomatosis from rectal cancer over other standard surgical and/or systemic chemotherapy modalities.5 More prospective randomized trials are ongoing to test the efficacy of this treatment in other tumor types.6

Nevertheless, CRS + IPHP still suffers from a broad range of variability, with no consensus on its various technical aspects. Thus, we attempted to make a contribution to this debate by providing results of a Phase II study in which we analyzed morbidity, toxicity, and mortality of CRS followed by IPHP (closed abdomen technique) in the treatment of patients affected by PSM.

MATERIALS AND METHODS

Patient Characteristics

All patients included in this study were treated under an institutionally approved protocol with written informed consent. The eligibility requirements for treatment were as follows: histologically confirmed diagnosis of peritoneal carcinomatosis or sarcomatosis; age ≤ 75 years; no distant metastasis; adequate renal, hematopoietic, and liver functions; and Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

Data on patient characteristics are summarized in Table 1. A total of 205 patients (50 with peritoneal mesothelioma, 49 with pseudomyxoma peritonei, 41 with ovarian cancer, 32 with abdominal sarcomatosis, 13 with adenocarcinoma of the colon, 12 with gastric cancer, and 8 with carcinomatosis from other origins) underwent 209 consecutive procedures from February 1995 to November 2004. Four patients underwent the intervention twice because of disease relapse. There were 70 men and 135 women. The mean age was 52 years (range, 22–76 yrs). The mean body mass index was 25 (range, 15.9–40). A total of 160 (75%) cases presented with an ECOG performance status of 0.

Table 1. Patient Characteristics
CharacteristicNo.
  1. PCI: peritoneal cancer index.

Total no. of patients205
Total no. of procedures209
Mean age (range)52 yrs (22–76)
Male/female70/135
Body mass index in kg/m2 (range)25 (15.9–40)
Histologic type distribution
 Peritoneal mesothelioma50
 Pseudomyxoma peritonei49
 Ovarian cancer41
 Abdominal sarcomatosis32
 Adenocarcinoma of the colon13
 Gastric cancer12
 Carcinomatosis from other origins8
Performance status(ECOG)
 0160
 141
 28
Carcinomatosis extension, mean PCI (range)20 (5–39)

Cytoreductive Surgery

The technique of cytoreductive surgery has been described elsewhere.7 Briefly, the surgical procedure was carried out with 1 or more of the following steps, depending on disease extension: 1) greater omentectomy, right parietal peritonectomy ± right colon resection; 2) pelvic peritonectomy ± sigmoid colon resection ± hysteroadnexectomy; 3) lesser omentectomy and dissection of the duodenal–hepatic ligament ± antrectomy ± cholecystectomy; 4) right upper quadrant peritonectomy ± Glisson capsule; 5) left upper quadrant peritonectomy ± splenectomy; 6) other intestinal resection and/or abdominal mass resection. A ball-tip electrosurgical hand piece was used to dissect the tumor on peritoneal surfaces from normal tissue.8 Electrosurgery was used on pure cut at high voltage. The 2 mm ball-tip electrode was used for dissection on visceral surfaces, including stomach, small bowel, and colon. When more rapid tumor destruction is required, the 5 mm ball-tip can be used.

Anastomotic Techniques

Whether a partial or total gastrectomy is performed, we always use a Roux-en-Y reconstruction. In cases of partial gastrectomy, the stomach and proximal duodenum are, respectively, transected using a GIA stapler (GIA™, United States Surgical, a division of Tyco Healthcare Group LP, Pembroke, Bermuda). In case of total gastrectomy, the distal esophagus is divided 2 cm above the cardia with the scalpel. The lower part of the GIA-stapled line of the gastric remnant is then cut with scissors, and the ensuing end-to-end gastrojejunal anastomosis is hand sewn with 1 layer of extramucosal continuous polyglyconate 4-0 sutures. The distal terminolateral jejunojejunal anastomosis is also hand sewn in the same fashion as above. When a total gastrectomy is completed, a terminolateral esophagojejunal anastomosis is performed with a circular stapler usually of size 21–25 mm. A GIA stapler is applied to the remaining proximal end of the jejunal limb. The distal anastomosis is similar to the one described above.

Small bowel and colic anastomoses are always hand sewn in an end-to-end fashion using single-layer extramucosal continuous polyglyconate 4-0 or 3-0 suture. For all anastomoses, we start a running stitch on the antimesenteric border for the anterior layer and then start a second running stitch at the mesenteric side for the posterior layer. This allows completion of the anastomosis on the free antimesenteric border, avoids the mesentery, and allows better observation of the bowel wall.

Most of the time, we, as well as other investigators, have found that the Douglas pouch area is filled with coalescing tumor implants that also include much of the sigmoid colon. A complete pelvic peritonectomy with a low anterior resection is frequently needed to completely remove these tumor implants. In a few selected cases, however, we were able to preserve the rectum and only resect the overlying visceral peritoneum, including the peritoneal reflection. In case of low anterior resection, the lower margin of bowel transection is usually below the level of the peritoneal reflection. The low colorectal anastomosis is performed with an intraluminal stapler of 29–33 mm diameter after a distal washout of the rectal remnant with a proviodine iodine. We then test the integrity of the anastomosis with air insufflation from below.

All patients who underwent intestinal resections received an anastomosis just after completion of CRS and before initiation of IPHP. Our initial policy was to perform diverting ostomies only in high-risk patients. Peritoneal carcinomatosis was quantified according to the Peritoneal Cancer Index (PCI).9 The mean PCI was 20 (range, 6–39). Cytoreduction was classified into 3 levels according to the number of procedures performed: Level I, 1 to 2 procedures; Level II, 3 or 4 procedures; Level III, 5 procedures or more. Residual disease after surgery was classified according to Sugarbaker9 criteria: cc-0, no residual disease; cc-1, minimal residual disease of 0–2.5mm; cc-2, residual disease of 2.5 mm–2.5 cm; cc-3, residual disease of > 2.5 cm.

IPHP Technique

After cytoreduction, 4 silicone catheters are placed in the abdominal cavity; 1 in the right subphrenic cavity, 1 in the deep pelvis, 1 in the left subphrenic cavity, and 1 in the superficial pelvic site cavity. To continuously monitor peritoneal temperature during IPHP, thermocouples are placed in the abdominal cavity. After the closed abdomen technique is performed, the skin is closed with a running suture. The catheters are then connected to the extracorporeal circuit Performer LRT®, (RAND, Medolla, MO, Italy). Intraperitoneal chemotherapy regimens were as follows: cisplatin (CDDP, 25 mg/m2/L) and mitomycin C (MMC, 3.3 mg/m2/L)10 for pseudomyxoma peritonei, colorectal, and gastric carcinomatosis; cisplatin (CDDP, 43 mg/L of perfusate) and doxorubicin (Dx, 15.25 mg/L of perfusate)11 for mesothelioma, ovarian carcinomatosis, and abdominal sarcomatosis. A heat exchanger kept the perfusate at 44 °C as it was being administered, so the intracavitary perfusate temperature was maintained at 42–43 °C. The IPHP lasted 60–90 minutes, depending on the drug schedule. After perfusion, the perfusate was quickly drained, and the abdomen closed after careful intracavitary inspection.

Study Parameters

We defined bowel complications as any of the following categories: 1, Bowel perforation; 2, anastomotic leak. A bowel perforation occurs at a site away from an anastomosis. An anastomotic leak is a breach and/or complete dehiscence at the suture line. We adopted a criteria scale, which was coined by Bozzetti et al.,12 to grade surgical morbidity. This scale has been followed historically by the surgical department of the National Cancer Institute of Milan. It classifies the postoperative complications as G1, no complications; G2, minor self-limiting complications; G3, major complications (requiring reoperation or intensive care unit admission or interventional radiology); and G4, in-hospital mortality.12 Grading of toxicity was performed according to World Health Organization (WHO) criteria. Dependent variables were classified in 2 groups, major or combined Grade 3/4 morbidity and combined Grade 3/4 IPHP-related toxicity. We considered only those unfavorable events (both for morbidity and mortality) occurring within 30 days after the procedure.

Independent variables were taken into consideration for potential association with postoperative major complications as follows: histology of the primary tumor (tumor of gastrointestinal origin vs. non-GI origin), gender, performance status (WHO: 0 vs. 1 or 2), age (< 52 yrs vs. ≥ 52 yrs), body mass index (< 25 vs. ≥ 25), previous chemotherapy, previous radiation therapy, extension of carcinomatosis, number of intestinal anastomoses (< 2 vs. > 2), duration of the procedure (< 530 min vs. ≥ 530 min), extent of cytoreduction (Level 1/2 vs. 3), completeness of cytoreduction (cc 0/1 vs. 2/3), IPHP drug schedule (CDDP + MMC vs. CDDP + Dx), and dose of CDDP in the IPHP (< 240 mg vs. ≥ 240 mg). Continuous variables were categorized in 2 classes using their mean value as cutoff.

Follow-Up and Statistical Analysis

During the postoperative period, patients were admitted to the intensive care unit, where they were evaluated daily with laboratory and instrumental examinations. They were then discharged to the surgical ward for recovery. Long-term follow-up was carried out by physical examination, tumor markers (Ca125, CEA, CA19.9), and thoracic and abdominal computed tomography (CT) scans every 3 months in the first year and every 6 months thereafter. Analysis of treatment-related toxicity was performed according to WHO criteria.13 A univariate analysis of each clinical variable was performed by Fisher exact test or chi-square test to determine a probability of association with each morbidity variable. A logistic regression model was used in a multivariate analysis to determine correlation between clinical variables and morbidity variables. All clinical variables that presented a P ≤ 0.05 were included in the model. The backward elimination method was used to determine which clinical variables best predicted the presence of morbidity. All statistical analyses were conducted using SPSS for Windows Version 8.0.0 (SPSS, Chicago, IL).

RESULTS

CRS + IPHP

We submitted 37 (17.7%), 86 (41.1%), and another 86 (41.1%) patients to Levels I, II, and III cytoreduction, respectively. The mean number of peritonectomy procedures for each patient was 4.9. Details of cytoreductive surgery are outlined in Table 2. Accordingly, 182 (87%) cases were optimally cytoreduced (cc, 0/1). The mean duration of the procedure was 532 minutes (range, 240–1320 min). The mean number of blood units received was 2.4 (range, 0–18 units). With respect to the IPHP, 84 (40.2%) and 125 (59.8%) cases received CDDP + MMC and CDDP + Dx regimens, respectively. The mean doses of drugs administered were 218 mg (range, 100–300 mg) for CDDP, 31 mg (range, 15–50 mg) for MMC, and 63 mg (range, 25–90 mg) for Dx. The mean length of intensive care unit stay was 3 days, and the mean hospitalization was 23 days (range, 7–73 days).

Table 2. Surgical Results with Description of Peritonectomy and Resection Procedures
Surgical procedures and resultsNo.
Peritonectomy
 Left diaphragm101
 Right diaphragm106
 Glissonian capsule82
 Lesser omentectomy92
 Pelvic peritonectomy123
 Greater omentectomy148
Other surgical procedures 
Great bowel resection132
Small bowel resection20
Subtotal gastrectomy8
Total gastrectomy18
Marginal gastrectomy3
 Cholecystectomy41
 Splenectomy71
 Diaphragm resection8
 Hysterectomy24
 Bilateral oophorectomy22
 Other resections19
Bowel anastomosis
 Esophagojejunal18
 Jejunoileal26
 Gastrojejunal8
 Ileoileal20
 Ileocolic50
 Colocolic9
 Colorectal58
 Ileorectal2
Protective ostomy2
Mean duration of the procedure (minutes)532 (240–1320)
Mean No. of Blood units transfused2.4 (0–18)
Mean No. of peritonectomy procedures/patient4.9
Level of peritonectomy procedure (%)
 I37 (17.7)
 II86 (41.1)
 III86 (41.1)
No. of optimally cytoreduced cases in cc0/1 (%)182 (87)

Morbidity and Mortality

Major morbidity occurred in 25 (12%) cases. The most significant morbidities were 17 anastomotic leaks, 6 intestinal perforations, 6 with fever, 4 abdominal bleeds, and 4 sepses. Other complications were 1 pulmonary embolism, 2 with pancreatic fistula, and 1 with biliary fistula. One patient presented an acute hypotensive episode, clinically diagnosed as cardiac arrest, on the 8th day after the procedure; he was urgently resuscitated without any short- or long-term sequelae. Examples of postoperative main complications (G1-4), their anatomic location, description, and management are outlined in Table 3.

Table 3. Anatomic Location, Description, and Management of Main Complications
Type of complicationAnatomic locationNo. of complicationsSurgical treatment or ICU recoveryConservative management
  • ICU: intensive care unit.

  • a

    Unrelated to infectious problems.

Anastomotic leakIleocolic anastomoses752
 Small bowel anastomoses312
 Colocolic anastomoses330
 Colorectal anastomoses211
 Not available220
Digestive tract perforationDuodenum110
 Small bowel330
 Colon110
 Stomach110
Other gastrointestinal complicationsBiliary fistula110
 Pancreatic fistula202
 Ileus/gastric stasis404
PulmonaryPneumonia909
 Pleural effusion404
 Pulmonary embolism110
 Respiratory failure110
InfectiousAbdominal infection (abscess)312
 Sepsis404
 Fevera606
BleedingAbdominal440
Other clinical complications 10010

Two patients died in the early postoperative period. The first one on the 21st day after the procedure because of a duodenal perforation associated with abdominal bleeding. The second patient died on the 26th day after the procedure because of a colic perforation, bronchial bleeding, and sepsis. The overall mortality rate was 0.9%.

By univariate analysis, the following variables were proven to have a statistically significant correlation with major morbidity: male gender (P = 0.016), ECOG performance status (P = 0.05), no previous systemic chemotherapy (P = 0.004), carcinomatosis extension (P = 0.027), number of bowel anastomoses > 2 (P = 0.028), duration of procedure (P = 0.014), extent of cytoreduction (P = 0.019), and dose of CDDP for IPHP ≥ 240 mg (P = 0.02). Multivariate analysis was performed with a logistic regression model, and after the backward elimination method, no previous systemic chemotherapy (odds ratio [OR], 2.719; 95% confidence interval [CI], 0.984–7.512; P = 0.054), extent of cytoreduction (OR, 2.877; 95% CI, 1.292–6.404; P = 0.010), and dose of CDDP for IPHP ≥ 240 mg (OR, 3.128; 95% CI, 1.239–7.900; P = 0.016) remained in the model (Table 3).

TOXICITY

Ten (4.8%) patients presented Grade 3/4 toxicity. There were 3 cases of G3 hematologic toxicity, 1 case with G3 gastrointestinal toxicity, 2 cases of Grade 3 nephrotoxicity, 2 cases of Grade 4 nephrotoxicity, 1 case of G4 pulmonary toxicity, and 1 case of G3 alopecia. The 2 cases of G4 nephrotoxicity were peritoneal mesothelioma patients who required hemodialysis in the postoperative period and developed chronic renal failure.

DISCUSSION

The locoregional treatment for PSM is attracting an increased interest from the scientific community. However, the procedure of CRS + IPHP is both time- and labor-intensive. The institution of a program in PSM requires not only highly specialized human resources but also complex technological facilities14 to perform the CRS + IPHP safely, to minimize treatment-related morbidity and mortality, and to maximize their results in terms of survival and quality of life. In this context, the identification of risk factors for postoperative complications is one major concern. As outlined in Table 4, we found that only no previous systemic chemotherapy, extent of cytoreduction, and dose of CDDP for IPHP remained in the model after multivariate analysis. However, no previous systemic chemotherapy presented a borderline significance (P = 0.054), and, thus, only the extent of cytoreduction and dose of CDDP for IPHP could be considered the best predictors of major morbidity after CRS and IPHP.

Table 4. Univariate and Multivariate Analysis of Clinical Risk Factors for Major Morbidity
 Independent variablesUnivariateaMultivariateb
ORcrudePORadj 95% CIP
  • OR: odds ratio; GI: gastrointestinal; BMI: body mass index; CHT: chemotherapy; RT: radiotherapy; CDDP: cisplatin; IPHP: intraperitoneal hyperthermic perfusion.

  • a

    Chi square test or Fisher's exact test.

  • b

    logistic regression model with backward elimination method.

  • c

    Cytoreduction was classified into 3 levels according to the number of procedures performed: Level I: 1–2 procedures; Level II: 3 or 4 procedures; Level III: more than 5 procedures.

1Tumor histology of GI origin1.540.213  
2Male gender2.760.016  
3Performance status (ECOG) ≥ 10.430.050  
4Age ≥ 52 yrs1.020.571  
5BMI ≥ 25 kg/m20.760.343  
6No previous CHT3.690.0042.720.054
    0.98–7.51 
7Previous RT1.490.539  
8Carcinomatosis extension (PCI ≥ 20)2.880.027  
9No. of anastomoses ≥22.650.028  
10Procedure duration ≥ 530 minutes3.350.014  
11Extent of cytoreduction: Levels 1/2 vs. Level 3c2.680.0192.880.010
    1.29–6.40 
12Completeness of cytoreduction: cc0/1 vs. cc2/31.270.439  
13CDDP IPHP dose ≥240 mg2.700.0203.120.016
    1.24–7.90 

The most significant complication in our series was digestive fistula due to anastomotic leak and/or digestive perforation. This morbidity constituted about 70% of all cases with major morbidity, and the rate of fistula in the whole series was 11%. There were 17 (9%) dehiscences occurring in 191 fashioned anastomoses. This figure is somewhat higher than the 5% postoperative fistula rate reported for common elective surgeries with bowel anastomoses.15, 16 Several factors could be responsible for this difference, including the effects of locoregional chemotherapy and of hyperthermia on suture healing, the biologic aggressiveness of the neoplastic diseases being treated in our series, and the magnitude of surgical trauma with fairly longer procedures. The influence of chemotherapy on the suture-line healing depends on the type of drug. In animal studies, anastomotic healing can be impaired by intraperitoneal MMC17 and cisplatin18 but not by 5-fluorouracil19 or paclitaxel.20 Local hyperthermia in itself has no adverse effect on anastomotic healing in animal models.21 Our rate of anastomotic fistula, however, is not significantly different from data reported by other authors who performed CRS + IPHP. Data from the literature report rates ranging from 7.2% to 17.4%.22–25

The higher incidence of anastomotic leak or of intrabdominal abscess in locoregional treatment of PSM with respect to common elective surgical procedures has guided several surgeons to perform protective proximal ostomies more liberally. Indications are not uniform, suffering a range of variation. Verwaal et al. recommend colostomy for all rectal resections.26 Moran et al. and Sugarbaker et al. advocate a proximal diverting stoma in cases of low anterior resections in which the preservation of the rectum is not possible.27, 28 Conversely, Shen et al., despite having found an unacceptably high rate of sepsis correlated with bowel anastomoses, adopted a more flexible policy that suggested the surgical performance of protective stoma is an alternative.29 In our series, we performed only 2 diverting ostomies in the 58 low colorectal anastomoses and found only 2 (3.4%) anastomotic fistulae. Therefore, to primarily perform unprotected colorectal anastomoses can be considered a feasible option.

Digestive tract perforations occurred in 6 cases in our series, and they could be attributed to partial-thickness mechanical and/or thermal damage to intestinal surfaces. This, in turn, could have been aggravated by subsequently administered heated chemotherapy. Other possible explanations for digestive perforation are 1) the focal heat injury at the tip of the inflow catheter, 2) the mechanical trauma elicited by the suctioning effect of the outflow catheter, 3) postoperative shrinking of infiltrating metastatic nodules on the intestinal wall because of the antiblastic effect of heated chemotherapy. The risk for such complications should be minimized by a careful lysis of adhesions and dissection, with a judicious use of the ball-tip electrocautery on the serosal surfaces of the intestine in case the cytoreduction requires an extensive fulguration of metastatic disseminated implants. Another important surgical step is the final inspection of the abdominal cavity after the drainage of perfusate at the end of IPHP. This phase should be performed as accurately as possible to identify and treat all the risky damaged areas on the organs and intestinal tract.

One noteworthy finding in our study was the dose of CDDP used for IPHP as an independent risk factor for major procedure-related morbidity. As already outlined in the Materials and Methods section of this article, 2 IPHP drug schedules were used, according to the tumor type, namely, CDDP (25 mg/m2/L of perfusate) + MMC (3.3 mg/m2//L of perfusate), and CDDP (43 mg/L of perfusate) + Dx (15.25 mg/L of perfusate). The second combination was established formally by a Phase I dose-finding study conducted by Rossi et al.,11 although this does not hold true for the first combination. The dose of CDDP for IPHP in each of the combinations is calculated in different ways and, in our study, ranged from 100 to 300 mg. We chose 240 mg as the cutoff value CDDP dose for IPHP, as it represents the theoretical maximum for a tolerable dose, in our series, according to the schedule proposed by Rossi et al. It is the approximate result of the product of 43 mg by 6 liters (maximal volume of perfusate used in our series). Patients receiving CDDP ≥ 240 mg presented a significantly higher rate of combined major morbidity. However, they presented 3 times higher risk of developing a GIII–IV postoperative complication compared with those who were submitted to IPHP with a lower CDDP dose, when adjusted for the other variables. This finding, at first glance, should not be surprising as it can be supported by an experimental study, which demonstrated the negative influence of CDDP on healing of bowel anastomosis after IPHP.18 In addition, the digestive complications due to anastomotic leaks and/or bowel perforations were the most frequent type of major morbidity in the present series, as already discussed. However, the correlation between CDDP dose during IPHP and the occurrence of procedure-related bowel complications did not present a statistical significance, not even by univariate analysis in a parallel study.30 Whether the experimental evidence of adverse effect of CDDP on bowel anastomotic healing could have a clinical significance on postoperative evolution of patients submitted to CRS + IPHP is still to be evaluated by a formal controlled trial.

Following the gastrointestinal tract, the respiratory tract was the second most affected system by postoperative complications. In fact, according to Table 3, pulmonary morbidity was found in 15 cases. Fortunately, most of them were of Grade 1 or 2, with the exception of 1 case of pulmonary embolism and 1 case of respiratory failure. This finding is in line with reports in the literature.31, 32 Several factors can account for this fact. The stripping of the diaphragmatic peritoneum elicits a mechanical and thermal injury on the muscle, with the formation of clinically nonevident communications between the abdominal and pleural cavities that allow passage of perfusate inside the thorax during IPHP. Moreover, inflammatory reaction secondary to tissue injury could be responsible for continuous production of exudates by the pleura during the postoperative period. The possibly impaired contractive function of the diaphragmatic muscle due to surgical trauma, formation of pleural effusion, along with general causes related to any major surgery (prolonged anesthesia time, inappropriate postoperative analgesia) should all be considered as potential factors for the emergence of pulmonary morbidities. The prevention and management of such complications include careful inspection of the integrity of diaphragmatic muscle after the stripping of its peritoneum and the prompt repair of eventual macroscopic holes, the prophylactic insertion of thoracic drains after the cytoreduction,33 an aggressive control of postoperative pain, a judicious management of respiratory rehabilitation, and administration of antibiotics.

Jacquet et al. conducted a study on 60 patients with peritoneal carcinomatosis from adenocarcinoma of the colon or appendix treated with CRS, IPHP with MMC followed by 1 cycle of early postoperative intraperitoneal 5-fluorouracil.24 They used the closed abdomen technique for IPHP, and after a multivariate analysis including 11 clinical variables, gender, intrabdominal temperature, and duration of surgery were identified as the best predictors of major morbidity. Stephens et al.34 reported on 200 cases of peritoneal carcinomatosis treated with CRS + IPHP using the coliseum technique. After performing multivariate analysis, they found that the number of peritonectomy procedures and resections was the only variable significantly associated with presence of major morbidity (OR = 1.32; P = 0.0002). Glehen et al.35 conducted a study on 216 consecutive treatments of peritoneal carcinomatosis by IPHP by using a closed abdomen procedure combined with cytoreductive surgery when needed. The postoperative mortality and morbidity rates were 3.2% and 24.5%, respectively. The most frequent complications were digestive fistula (6.5%) and hematologic toxicity (4.6%). After univariate analysis, morbidity was proven to be linked with the carcinomatosis stage (P = 0.016), the duration of surgery (P = 0.005), and the number of resections and peritonectomy procedures (P =.042). Verwaal et al.26 conducted a study of complications and toxicity in 102 patients treated by CRS + IPHP. Grade 3, 4, or 5 toxicity (National Cancer Institute, Cancer Therapy Evaluation Program) rate was 65%. Eight patients died of treatment-related causes. Surgical complications (defined as any postoperative event that needed reintervention) rate was 35%. Fistulae were observed in 18 patients. The risk of a complicated recovery was higher in the following situations, 1) carcinomatosis with recurrent colorectal cancer (P = 0.009), 2) more than 5 regions affected (P = 0.044), 3) Simplified Peritoneal Cancer (the Netherlands Cancer Institute) score = 13 (P = 0.012), 4) incomplete initial cytoreduction (P = 0.035), 5) blood loss exceeding 6 L (P = 0.028), and 6) 3 or more anastomoses (P = 0.018). Table 5 presents an overview of the main studies that addressed the issue of operative complications associated with CRS + IPHP.

Table 5. Overview of Operative Complications Associated with CRS+IPHP (Series with More Than 50 Patients)
AuthorYrNo. of procedures% of malesPredominant. histologyProtective ostomy (%)IPHP modalityTiming of anastomosisaDuration of procedure (hrs)Morbidity (%)Mortality (%)Main complicationsRisk factorsStatistical analysis
  • NA: not available; IPHP: intraperitoneal hyperthermic perfusion; PM: peritoneal mesothelioma; PMP: pseudomyxoma peritonei; CC: completeness of cytoreduction.

  • a

    Whether the anastomoses were performed before or after the IPHP.

  • b

    Mean.

  • c

    Median.

Jacquet et al.2419966062Appendix, colonNoneClosedAfter10.9b355Bowel, bleedingSex, intrabdominal temperature, duration of surgeryMultivariate
Stephens et al.34199920053PMP, colonNAOpenAfterNA271.5Peripancreatitis, bowel, bleedingNo. of peritonectomy proceduresMultivariate
Glehen et al.35200321637Colon, PMP, ovarianNAClosedBefore6.1b24.53.2Digestive fistula; hematologic, toxicityCarcinomatosis extension, duration of surgery, No. of peritonectomy proceduresUnivariate
Verwaal et al.26200410256Colon42OpenAfter7.5c358Bowel, intraabdominal abscessRecurrent form, carcinomatosis extension, CC, blood loss, No. of suture linesUnivariate
Shen et al.2920047758Colon13ClosedAfter9c3012Bowel infection, respiratory failure, sepsisBowel anastomoses (with sepsis)Univariate
Present series200520933MP, PMP, ovarian0.5ClosedBefore8.2c120.9BowelExtent of cytoreduction; CDDP IPHP doseMultivariate

All studies agree on the predictive value for postoperative complications of the variables directly or indirectly correlated with extent of cytoreductive procedure (such as number of anastomoses, number of peritonectomy procedures, and duration of the surgery). However, no consensus has been reached on other variables related to clinical data and surgical techniques. Several factors could account for this contrast, such as differences between cohorts concerning gender distribution, tumor type distribution, and IPHP techniques, thus rendering comparison of results somewhat problematic. In addition, different criteria defining postoperative morbidity and mortality were used in different series, and not all authors performed multivariate analysis to assess risk factors for procedure-related complications. The analysis performed in the present study comprised only clinical and surgical variables related to preoperative and intraoperative phases of the procedure. The search for risk factors for complications should be continued, analyzing other aspects of locoregional therapy. If other perioperative parameters are included in multivariate analysis, new independent risk factors for morbidity could emerge. The possible perioperative parameters to be studied are those related to nutritional status and hemodynamic and respiratory variables during and after the procedure.

Investigators have not achieved agreement on open or closed abdomen techniques of IPHP. Proponents of the coliseum technique (open abdomen)34, 36 claim better drug and heat distribution by continuous manipulation of the abdominal organs. Deficiencies were noted in the distribution of methylene blue dye with the closed abdomen technique, which, in turn, was blamed for a higher rate of complications.37 Conversely, the closed technique permits an increase in the intrabdominal pressure that may lead to increased convection-driven drug penetration of macromolecular agents such as TNF-α inside the tumor.38–40 Moreover, Jacquet et al. reported that, in animal models, an intraabdominal pressure of 20 and 30 mm Hg increased tissue uptake of doxorubicin in bladder, diaphragm, and abdominal wall during the first 10 minutes of intraperitoneal administration.41 Furthermore, a recent study carried out by Glehen et al. reported morbidity and mortality results on 216 procedures of intraperitoneal chemohyperthermia using the closed abdomen technique.35 They observed a postoperative mortality rate of 3.2% and morbidity of 24.5%, comparable to other reports. Since, up to now, no prospective controlled clinical trial has been conducted that specifically addresses the superiority of 1 technique over the other, the issue remains unclear with no striking differences between the 2 techniques in terms of operative morbidity.

Another technical variation of CRS + IPHP is the optimal timing for performing bowel anastomoses. They can be performed during the CRS just before IPHP or after completion of IPHP. Proponents of the second alternative argue that delaying the anastomosis permits a better distribution of heat and drugs inside the peritoneal cavity during IPHP and treatment of eventually implanted neoplastic cells on the intestinal end-surfaces that are to be sutured. In addition, they state that risk of postoperative bowel complications can be diminished because of avoidance of potential adverse effects of heat and chemotherapy on suture-line healing. Conversely, others have proposed the first alternative by reporting data of no increased morbidity due to postoperative bowel fistula and/or anastomotic leak when anastomoses are performed before IPHP.44–46

Thus, our low and acceptable morbidity, toxicity, and mortality rates suggest that CRS + IPHP performed by an experienced surgical team with primary intestinal anastomosis, closed abdomen technique, and no liberal indication of ostomies is safe. Although the present study was conducted in a large cohort of patients, it suffers from the methodologic limitation of the absence of a control group. In this sense, it is premature to defend categorically 1 technique over other(s), as any attempt to establish a technical guideline for CRS + IPHP on the basis of experimental and uncontrolled clinical evidence is condemned to fail. A definitive clarification of technical variations will be possible only by adequately designed prospective randomized trials.

Ancillary