Annals of Surgical Oncology 15(3):745–753

DOI: 10.1245/s10434-007-9700-5

Swedish Experience with Peritonectomy and HIPEC. HIPEC in Peritoneal Carcinomatosis B. L. van Leeuwen, MD, PhD, W. Graf, MD, PhD, L. Pahlman, MD, PhD, H. Mahteme, MD, PhD

Department of Surgical Sciences, Akademiska Sjukhuset, Uppsala University Hospital, SE 751 85, Uppsala, Sweden

Background: Peritonectomy with heated intraperitoneal chemotherapy (HIPEC) has shown a survival benefit in selected patients with peritoneal carcinomatosis. This prospective nonrandomized study was designed to identify factors associated with postoperative morbidity and survival after peritonectomy HIPEC in patients with this condition. Method: Data were prospectively collected from all patients with peritoneal carcinomatosis treated by means of peritonectomy and HIPEC at Uppsala University Hospital between October 2003 and September 2006. Depending on the primary tumor, mitomycin C or a platinum compound was used as a chemotherapeutic agent for perfusion. Results: A total of 103 patients were treated. Primary tumors were pseudomyxoma peritonei (47 patients), colorectal cancer (38 patients), gastric cancer (6 patients), ovarian cancer (6 patients) and mesothelioma (5 patients). Postoperative morbidity was 56.3% and was significantly lower in patients treated with mitomycin C for pseudomyxoma peritonei (42%) than in those with another diagnosis treated with platinum compound (71%, P < 0.05). Postoperative mortality was less than 1%. At 2 years, overall survival was estimated to be 72.3%, and disease-free survival was 33.5%. Factors influencing overall and disease-free survival were tumor type and optimal cytoreduction. Conclusion: Postoperative morbidity is dependent mainly on a tumor type; however, the chemotherapeutic agent used might also influence morbidity. Survival is determined by optimal cytoreduction and tumor type. Irrespective of age, patients with good performance status benefit from this treatment. Key Words: Peritonectomy—HIPEC—Peritoneal carcinomatosis.

The diagnosis of peritoneal carcinomatosis is often associated with poor prognosis and a median survival of 3 months, with some variation depending on the primary tumor.1 However, there is increasing evidence that there is an effective treatment for patients in this category. Peritonectomy combined with Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) 2 prolongs survival for several tumor types with

peritoneal spread; and, for pseudomyxoma peritonei (PMP) and carcinomatosis of colorectal origin, it is now the treatment of choice.3–5 The positive effect on survival of peritonectomy and HIPEC in advanced ovarian cancer,6,7 gastric cancer8,9 and the much rarer peritoneal mesothelioma10,11 are increasingly reported. There is, however a need for ongoing evaluation of this treatment modality: costs and postoperative morbidity remain a constant factor; improved results from systemic chemotherapy in advanced cancers12 warrant comparison; and the risks and benefits of peritonectomy and HIPEC for patients over the age of 65 years need clearly defining. The aim of this study was to investigate factors influencing postoperative morbidity and survival.

Received August 16, 2007; accepted October 19, 2007; published online: December 5, 2007. Address correspondence and reprint requests to: H. Mahteme, MD, PhD; E-mail: [email protected] Published by Springer Science+Business Media, LLC Ó 2007 The Society of Surgical Oncology, Inc.

745

746

B. L. VANLEEUWEN ET AL.

The results from peritonectomy and HIPEC treatment of peritoneal carcinomatosis from different causes, in patients who were treated at Uppsala University Hospital, Sweden, between October 2003 and September 2006, are reported.

PATIENTS AND METHODS Between October 2003 and September 2006, data were prospectively collected from 103 consecutive patients with peritoneal carcinomatosis who were treated with combined peritonectomy and HIPEC; these patients became the subjects of this study. The patients were diagnosed with PMP (47 patients), colorectal cancer (38 patients), gastric cancer (6 patients), ovarian cancer (6 patients) or mesothelioma (5 patients). One patient was initially diagnosed with rectal cancer, although this was changed to pancreatic cancer, based on the specimens collected during peritonectomy—this patient was included in the analysis based on the intention to treat principle. In the PMP cases, a histological distinction was made between high- and low-grade tumors. Informed consent was obtained from each patient, and the regional ethics committee approved the study. The presence of several comorbidities was recorded, including: cardiovascular disease, pulmonary disease, hypertension, irritable bowel disease, renal failure, diabetes and coagulopathic/thrombotic disorders. Because our unit was the only HIPEC center in Sweden during the study period, most patients were referred from different parts of the country, and some even from outside Sweden (patientsÕ characteristics are presented in Table 1). During this period, 22 patients underwent a second-look procedure, which included peritonectomy and HIPEC, but these data will be reported elsewhere. Treatment The peritonectomy was performed as described by Sugarbaker,13 and the open abdomen ‘‘coliseum’’ technique was used to administer HIPEC.14 All operations were performed by either one or two senior surgeons specialized in this procedure. Prior to surgery, extra-abdominal metastasis was excluded by means of abdominal ultrasound, CT scan of the abdomen and thorax, and, when necessary, PET CT scan. Patients with a Kanofsky performance score less than 60 were refused surgery. The chemotherapeutic agent administered depended on tumor type, and dosing changed during the study period. All Ann. Surg. Oncol. Vol. 15, No. 3, 2008

TABLE 1. PatientÕs characteristics. ASA American Society of Anaesthesiologists. n = 103 Median age in years (range) Comorbidity ASA

Previous tumor-related surgery Time since last surgery (months) Previous IP* chemotherapy Neo adjuvant chemotherapy

$ # 55 (13–76) Yes No I II III Unknown Yes No 6 (1–70) Yes No Yes No

55 48 30 (29.1%) 73 (70.9%) 50 (48.5%) 44 (42.7%) 6 (5.8%) 3 (2.9%) 91 (88.3%) 12 (11.7%) 13 90 17 86

(12.6%) (87.4%) (16.5%) (83.5%)

* IP = intraperitoneal.

patients with PMP received intraperitoneal mitomycin C (MMC) at a concentration of 10–12 mg/m2 body surface area (BSA) until 22 February 2005; thereafter, the dose changed to 30–35 mg/m2 BSA, based on Van RuthÕs findings.15 The lower dose was used for patients with preoperative comorbidity. Patients with colorectal cancer received oxaliplatin at a dose of 460 mg/m2 BSA, as described by Elias;16,17 these patients also received concomitant i.v. 5-FU (500 mg/m2 BSA) and isovorin (30 mg/m2 BSA). Patients diagnosed with gastric cancer, ovarian cancer or mesothelioma received intraperitoneal cisplatin (50 mg/m2 BSA) combined with doxorubicin (15 mg/ m2 BSA). The duration of perfusion with oxaliplatin was 30 min, for all other drugs the duration was 90 min. The carrier solution used for MMC, cisplatin and doxorubicin was a low calcium peritoneal dialysis solution PD4 [Dianeal 13.6 mg/ml (Baxter, USA)]. For oxaliplatin, the carrier solution was 50 mg/ml glucose. Prior to the start of perfusion, the patients were cooled to 35°C with a cooling blanket (Allon). The intra-abdominal temperature during perfusion ranged from 42°C to 44°C. In all patients, four intra-abdominal drains were left in place after surgery, so early postoperative intraperitoneal chemotherapy (EPIC) could be administered daily during the first 5 postoperative days. Chemotherapeutics used for this purpose were 5-FU (550 mg/m2 BSA) or paclitaxel (20 mg/m2 BSA). Patients with mesothelioma, ovarian cancer or gastric cancer received paclitaxel, and those with PMP or carcinomatosis of colorectal origin received 5-FU. After recovering from the peritonectomy and HIPEC procedure, 12 patients received further systemic therapy—8 with PMP were treated with capecitabine (Xeloda), 2 with

747

HIPEC IN PERITONEAL CARCINOMATOSIS

colorectal cancer received 5-FU combined with oxaliplatin (Folfox), 1 received interferon and 5-FU, and 1 with ovarian cancer received a regimen of carboplatin and paclitaxel (Taxol). Tumor load and completeness of surgical resection were immediately recorded postoperatively using the Peritoneal Cancer Index (PCI) and Completeness of Cytoreduction Score (CC Score), respectively.18 The PCI consists of lesion size scores in 13 different regions of the abdomen: 0 = no visible tumor, 1 = tumor up to 0.5 cm, 2 = tumor up to 5 cm and 3 = tumor > 5cm. The maximum PCI is 39. The cytoreduction score is based on the size of tumor remaining after cytoreduction: 0 = no peritoneal seeding visible, 1 = nodules up to 2.5 mm, 2 = nodules up to 2.5 cm and 3 = nodules > 2.5 cm. To prevent anastomotic leakage, protective or decompressing stomas were used frequently, with the intention of reanastomosing them during a later procedure. Patients stayed in the intensive care unit or postoperative care unit for as long as needed postoperatively and were then discharged to the ward. All intraoperative and 3-month postoperative complications were recorded. For the grading of postoperative morbidity, the common terminology criteria for adverse events (National Cancer Institute19) were used: the five grades increase in severity. Grade 1 is a mild adverse event (usually asymptomatic), grade 2 is moderate, grade 3 is a severe adverse event often requiring an invasive intervention, grade 4 is a lifethreatening or disabling adverse event and grade 5 is death related to an adverse event. All patients were examined at the outpatient unit at Uppsala University Hospital 6–8 weeks postoperatively. Timing of follow-up depended on the patientÕs place of residence and the adjuvant treatment given. Tumor markers (CEA, CA15-3, CA19-9, CA 72-4 and CA 125) were determined every 3 months. Beginning 6 months after surgery, every patient underwent a routine CT scan of the thorax and abdomen every 6 months. Other diagnostic procedures were undertaken when deemed necessary by the treating physician or surgical team. The occurrence of liver and/or lung metastasis and the recurrence of intra-abdominal disease were recorded. Statistical Analysis To test for differences between groups, the MannWhitney U test was used for quantitative variables and v2 or FisherÕs exact test for categorical variables.

Overall and disease-free survival were estimated using the Kaplan-Meier method. The Gehan Wilcoxon method tested the effect of individual variables. The Cox proportional hazard ratio was used to compare the effect of multiple variables on (disease-free) survival. P < 0.05 was considered statistically significant for all tests. Statistical analysis was with Statistica software version 7 (StatSoft, Tulsa, USA).

RESULTS Operative and Postoperative Course Surgery was extensive in most patients. The most common resections were major omentectomy (88), pelvic peritonectomy (72) and stripping of the right diaphragm (68). The majority of patients underwent either partial or total resection of the colon. A total of 13 patients underwent a hysterectomy, 8 a gastrectomy, 5 concomitant liver resection and 4 a partial pancreas resection. There were 23 patients (22.3%) who had a colo-colonic anastomosis, 21 (20.4%) a small bowel anastomosis (with a maximum of 14 in 1 patient) and 15 patients (14.6%) an ileocolonic anastomosis. A total of 21 colostomies and 56 ileostomies were constructed. The median PCI score was 22 (3–39). Intraoperative complications occurred in 12 patients (11.7%: as presented in Table 2). The most frequent complication was accidental perforation of the diaphragm, which occurred in 8 patients. In these cases, the diaphragm was sutured after completing the perfusion. In one patient, there was an accidental bladder perforation and one patient developed an allergic reaction to rocurniumbromide (Esmeron) without any sequelae. Perfusion with MMC was terminated prematurely in two patients receiving high-dose MMC, due to anuria in one patient and an allergic reaction in the other. Complete cytoreduction (CC-0) was achieved in 49 patients (47.6%), CC-1 in 12 (11.7%), CC-2 in 19 (18.4%) and CC-3 in 16 (15.5%): data on completeness of cytoreduction were missing in 7 (6.8%) cases. For further analysis, patients with a CC-0 and CC-1 score were combined and considered as optimal cytoreduction; the other patients were considered to have suboptimal cytoreduction. There was no correlation between total PCI score in regions 7–9 (lower abdomen) and the inability to achieve optimal cytoreduction in the pelvic region. A higher PCI score in regions 1–3 (upper abdomen) increased the risk of suboptimal cytoreduction in the hepatic ligament and Ann. Surg. Oncol. Vol. 15, No. 3, 2008

B. L. VANLEEUWEN ET AL.

Intraoperative complications

Yes: 12 (11.7%) No: 91 (88.3%)

Blood loss (ml) Operating time (h) Days in ICU Median PCI EPIC

1,200 (0–14,000) 10.5 (4–16.6) 1.4 (0–6.6) 22 (3–39) Yes: 100 (97%) No: 2 (2%) md 1 (1%) 58 (56.3%) 31 (29%) 8 (7.8%) 15 (7–53)

Postoperative morbidity Reintervention Readmittance to ICU Postoperative days in hospital (range) Discharged to:

Metachronous metastasis

Failure site

Home 50 (49%) Other hospital/ward 50 (49%) Hospice 1 (1%) md 2 (2%) None 86 (83.5%) Liver 4.9% Lung (9.7%) Liver and lung 1.9% Small bowel 22 (21.4%) Liver hilus 10 (9.7%) Hepatoduodenal ligament 8 (7.8%) Pelvic 7 (6.8%)

a

PCI score and liver hilus failure site 25

0

1

20

15

N

TABLE 2. Perioperative results. Median values are presented as continuous variables (range in brackets). ICU intensive care unit, PCI peritoneal cancer index, EPIC early postoperative intraperitoneal chemotherapy, md missing data.

10

5

0 0

1

2

3

4

5

6

7

8

9

Total PCI score in region 1-3

b

PCI score and pelvic failure site 25

0

1

20

15

N

748

10

5

0

0

1

2

3

4

5

6

7

8

9

Total PCI score in region 5-7

the liver hilus (P < 0.05), but in the majority of the patients with high PCI scores in these regions, an optimal cytoreduction was achieved (Fig. 1a, b). This means that, even when there was a high tumor load, the surgeons were still able to remove all visible tumor from this location in most cases. Postoperative intraperitoneal chemotherapy was not given to 2 patients: in 1 because of leakage of the intra abdominal drains; in the other, because the patient persistently refused the treatment. Postoperative complications occurred in 58 (56.3%) patients (Table 3). When graded according to the most severe complications, we observed grade-I complications in 6 patients (5.8%), grade II in 13 (6.8%), grade III in 32 (31.1%), grade IV in 12 (11.7%) and grade V (death) in 1; this patient, aged 64 years, died 25 days postoperatively from the sequelae of cerebral infarction. There were no other treatment-related deaths. Reintervention was necessary in 31 patients (30.1%). This included one or more surgical procedures in 19 patients and other invasive procedures (such as percutaneous drainage of an abscess) in 16. Readmittance to the intensive care unit was indicated in 8 patients (7.8%). Ann. Surg. Oncol. Vol. 15, No. 3, 2008

FIG. 1. a Combined Peritoneal Cancer Index (PCI) scores in regions 1–3 related to radicality of resection in liver hilus. Light = patients in whom the liver hilus was completely cleared of tumor load; dark = patients in whom the liver hilus was a failure site. b Combined PCI score in regions 5–7 related to radicality of resection in pelvis. Light = patients in whom the pelvis was completely cleared of tumor load, dark = patients in whom the pelvis was a failure site.

Risk Factors for Postoperative Complications Age, sex, previous intraperitoneal chemotherapy, comorbidity, PCI score, CC score, duration of surgery, number of organs removed, preoperative blood loss, chemotherapeutic agent given during HIPEC and diagnosis were analyzed for influence on the risk of postoperative complications. Postoperative complications occurred in 47 of the 85 patients younger than 65 years and in 11 of the 18 older patients (P = 0.651). There was no difference in the number of surgical reinterventions needed between the younger patient group (<65 years: (17 of 85) and the older group (2 of 18: P = 0.902), or the number of readmittances to the intensive care unit (younger patient group 6 of 85; older group 2 of 18; P = 0.560). Comorbidity was present in 22 of the 85 younger patients and 8 of the 18 older

749

HIPEC IN PERITONEAL CARCINOMATOSIS

TABLE 3. Postoperative complications per chemotherapeutic agent given during HIPEC. Postoperative complication Total Platinum MMC Significance Respiratory Abscess Systemic sepsis Neutropenia Urinary tract infection Small bowel fistula Wound problems Anastomotic leakage Bile leakage Oral/esophageal Candida Bowel/gastric perforation Impaired gastric emptying Rectal/duodenal stump leakage Bleeding Thromboembolic Pancreatitis Urinary bladder leakage Hypokalemia Cerebral infarction Pericardial fluid

13 9 8 7 6 5 4 4 4 4 3 2 2

8 8 6 4 5 4 3 3 3 1 0 0 2

5 1 2 3 1 1 1 1 1 3 3 2 0

2 2 1 1 1 1 1

1 2 0 1 0 1 1

1 0 1 0 1 0 0

P<0.05

patients. Postoperative complications occurred in 38 of the 73 patients without comorbidity and 20 of the 30 in those with comorbidity. Although not statistically significant, there was a trend of more postoperative complications in patients with comorbidity (P = 0.05906). Karnofsky performance scores (KPS) were 70 in 11 patients, 80 in 23 patients and 90–100 in 69 patients. In the patients over 65 years of age, 4 scored a KPS of 70, 6 had a KPS of 80 and 8 a KPS of 90–100. Except for the chemotherapeutic agent given during HIPEC, the risk factors analyzed did not influence the occurrence of postoperative complications; however, there were more postoperative complications in patients receiving IP oxaliplatin or cisplatin than in those receiving MMC (P < 0.01), which was given exclusively to patients with PMP. Postoperative complications occurred less in patients with PMP (21 of 47) than in those with all other diagnoses combined (37 of 55; P < 0.05); thus, it is difficult to distinguish between the effect of the tumor type and chemotherapeutic agent used. Because the dose of MMC was increased during the study period, a comparison of postoperative complications was made during the different dosing schedules. The overall rate of postoperative complications was 41.2% in patients receiving low dose MMC and 42.9% in those receiving high dose MMC (P = 0.09084). No difference was observed among grades of toxicity between the two groups, but three cases of neutropenia occurred in the high-dose group versus none in the low-dose group.

Overall and Disease-free Survival Median follow-up was 13 months (range 2–37 months). Overall survival for all diagnoses was estimated to be 72.3% at 2 years. With Cox proportional hazard analysis, diagnosis [HR 1.98 (1.21–3.26), P = 0.007] and optimal cytoreduction [HR 3.27 (1.02–10.46), P = 0.046] were found to influence overall survival, but age, sex, comorbidity, chemotherapeutic agent used and PCI score had no influence. Two-year survival was estimated to be 87.3% in patients diagnosed with PMP and 63.7% in those with colorectal cancer (Fig. 2). Although follow-up for the group receiving highdose MMC is too short to draw definite conclusions on the effect of this dose on survival, all but 1 of the 35 patients were still alive at the time of closure of this study. Similarly, all 12 patients who were treated with adjuvant systemic chemotherapy were still alive at the end of follow-up, but the overall follow-up period was too short to allow any firm conclusions on the impact of these schemes. Disease-free survival was estimated to be 33.5% at 2 years. In univariate analysis, there was no difference in disease-free survival between those diagnosed with PMP and those with colorectal cancer. However, when analyzing factors influencing specific survival with the Cox proportional hazard analysis, diagnosis [HR 1.57 (1.17–2.11), P = 0.003] and optimal cytoreduction [HR 3.1 (1.58–6.14), P < 0.005] were found to be statistically significant (Fig. 3).

DISCUSSION A mortality rate of less than 1% in this study was low and comparable to that found in previous studies. The morbidity rate of 56.3%, although high, falls into the range—from 28.6% to a maximum of 65%—reported by others.20–22 Numerous explanations for this high morbidity rate have been presented. First, peritonectomy entails extensive surgery and, as with all difficult procedures, this comes with a learning curve.23 Although the HIPEC procedure was introduced in our unit in October 2003, a learning curve is not the likely reason for the morbidity rate. Surgeons dedicated to this procedure had performed cytoreductive surgery in 111 patients between May 1991 and October 2003 with good results.24,25 One of the factors attributing to the high morbidity rate may be that 88% of all patients had been previously operated on due to the primary tumor: adhesions and scar formation make resection more difficult and give Ann. Surg. Oncol. Vol. 15, No. 3, 2008

750

B. L. VANLEEUWEN ET AL.

Overall survival per group Complete

Censored

1,0

Cumulative Proportion Surviving

0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2

PMP CRC

0,1 0,0 0

5

10

20

15

Time in months No. at risk PMP CRC

47 38

45 35

29 24

23 15

15 8

6 6

FIG. 2. Overall survival in pseudomyxoma peritonei (PMP) and colorectal cancer (CRC) patients.

Tumour specific survival per group Cumulative Proportion Surviving

Complete

Censored

1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 Optimal cytoreduction (CC0+1) Suboptimal cytoreduction

0,2 0,1 0,0 0

5

10

15

20

25

Time in months No. at risk Optimal

61

56

36

31

19

11

Suboptimal. 35

31

21

10

5

2

FIG. 3. Disease-free survival by optimal or suboptimal cytoreduction.

rise to a greater chance of postoperative morbidity. In addition, the combination of a relatively high dose of chemotherapeutic agents used in the HIPEC setting and in combination with intraperitoneal postoperative chemotherapy might explain the high morbidity rate; others have only used HIPEC.16,17,21 It must be noted that almost 50% of our patients were discharged to another ward or hospital during the first 30 postoperative days. Although these discharges occurred only after patients had recovered Ann. Surg. Oncol. Vol. 15, No. 3, 2008

sufficiently from their surgery to be released to a small rural hospital, this of course affects the duration of hospital stay reported in this study. All postoperative complications that occurred in other wards or hospitals were reported back to us and used in analysis. When compared with MMC treatment only, the use of platinum compounds as a chemotherapeutic agent during HIPEC resulted in an increase in postoperative morbidity of 42–71%: this effect has been described by others.26 In this study, all grades of morbidity were reported, not just grade III–V toxicity, as presented in some studies. This may account for the relatively high number of morbidities found, but does not account for the differences among different chemotherapeutic agents. An important factor influencing this result is that MMC was only used for the PMP cases. Although these patients generally have a higher tumor burden and have often undergone several laparotomies, PMP is sometimes a less invasive tumor, in which optimal cytoreduction can be achieved with less damage to healthy organs. Often finger fracture or blunt dissection may remove the tumor adequately. The more invasive nature of carcinomas requires sharp dissection, especially from tumors adherent to intestinal serosa. Micro leaks from intestinal organs causing bacteremia and fistulas may account for the higher complication rate in platinum-treated patients; however, without a randomized trial comparing the effect of the two drugs, this is only speculation. Although follow-up for the patients receiving high dose MMC is too short to draw definitive conclusions on its effect on long-term survival, it is encouraging to see that the occurrence of postoperative complications was not increased after utilization of the high dose. Neutropenia was determined in patients treated with both high-dose MMC and cisplatin and usually appeared 7–10 days after HIPEC. Although blood cell count always returned to normal after conservative treatment, or administration of granulocyte colony stimulating growth factor (Neupogen), this is a potentially dangerous consequence of HIPEC treatment and may go unnoticed if it is not checked. Patients should be treated in isolation to prevent lethal infections, and blood cell count checked daily. Caution should be exercised to prevent hyperglycemia and hyponatremia after perfusion with oxaliplatin. This agent can only be administered into the intraperitoneal space in dextrose 5% solution, and severe hyperglycemia and hyponatremia was recorded during and shortly after chemoperfusion. It is essential that patients treated with oxaliplatin receive an

HIPEC IN PERITONEAL CARCINOMATOSIS

insulin infusion as well as adequate sodium supplementation. The treatment of older patients with peritoneal carcinomatosis was promising. Although the number of patients over 65 years old was low, those in this age group with a good performance status appeared to benefit from peritonectomy and HIPEC as much as younger patients did. In contrast to recent reports by Liberale,27 Gilly,28 and Gomez,29 gender or age over 65 years did not influence outcome, nor were postoperative morbidity and survival influenced by these factors. Elderly patients benefitted just as much as younger ones from adjuvant treatment in advanced colon cancer;30 the same could hold true for HIPEC treatment. As Uppsala University Hospital is a referral center, there is a selection bias in the whole population, including those over the age of 65 years. Moreover, during the study period, 29 patients referred for treatment were rejected on the basis of a KPS <60. Preoperative comorbidity was low in this study, and the majority of the older patients had excellent performance status. Surgeons frequently have to decide whether major surgery is justified in older patients: the importance of adequate and appropriate treatment of malignant disease does not diminish with age, as inadequate treatment of peritoneal carcinomatosis is associated with poor survival in any age group. The benefit of peritonectomy and HIPEC depends on these procedures being carried out safely in selected patients. The relationship between age and outcome after any major surgery is complex and may be confounded by pre-existing comorbidity and the type of primary tumor. However, this study highlighted that patient selection based on performance status and comorbidity leads to good outcome, regardless of their age. Age as a single predictor of outcome is invalid and should not be used as a reason to deny patients treatment that they could certainly benefit from. The most favorable results for systemic chemotherapeutic treatment of advanced colon cancer have a median survival of 20.3 months.12 After cytoreduction and HIPEC treatment with MMC, a 3-year survival rate of 25–28% has been observed.31,32 In this study, survival appeared higher after perfusion with platinum compound, also described by Elias.33 Platinum compounds may be more appropriate for treating carcinomatosis from a colorectal origin. In metastatic gastric cancer, the 2-year survival is 4% after complete cytoreduction without HIPEC.34 Survival in patients with advanced-stage ovarian cancer

751

who are treated with a combination of systemic platinum-based chemotherapy and cytoreductive surgery is 22.7–33.9 months, depending on the extent of cytoreduction achieved.35 Patients with mesothelioma have a median survival of 12 months when treated with systemic chemotherapy.36 Although our data are not mature enough to accurately predict median survival for different tumor types, overall survival was estimated at 72.3% at 2 years, which is comparable to other findings.37,18 This is an improvement in survival when compared with the patients treated with only the best systemic chemotherapeutic agents available and without HIPEC. However, it is very likely that the patients treated with systemic chemotherapeutic regimens only were too frail to undergo surgical procedures and thus may have been refused a HIPEC procedure at our center. An important factor that influenced disease-free survival was optimal cytoreduction. This confirmed previous findings 34,38,39 and again demonstrated the importance of a thorough surgical resection of all visible tumor deposits. Based on therapeutic levels of MMC found in the muscular layers of the bladder after intravesical instillation of the drug,40 tumors up to 2 mm are penetrable for a chemotherapeutic agent and every lesion over that size has to be removed. Although there are no data on the exact penetration depth of chemotherapeutic agents in the abdomen, suboptimal cytoreduction is followed by inferior outcome, suggesting that residual tumor above a certain size is not penetrated by the chemotherapeutic agent and will inevitably grow again and cause problems. Achieving optimal cytoreduction does entail certain technical difficulties and limitations. The small bowel, liver hilus and hepatoduodenal ligament are the most prominent sites at which it is not possible to achieve optimal cytoreduction. In the pelvic area, technical difficulties in achieving optimal cytoreduction are also presented; in this study no complete urinary bladder resections were performed. Although a higher PCI score in the upper abdominal regions increases the chance of failure to achieve optimal cytoreduction, it is by no means impossible. In 60% of patients, it was possible to resect even the largest tumor loads. The frequent creation of a stoma in this study is in line with previous reports.3,21 However, most centers treat patients only with HIPEC and, in this series, patients were treated with HIPEC as well as EPIC. An anastomotic leak in these patients can be fatal; but, because we found a low rate of such leaks, we feel that the combination of protective stomas with EPIC is a safe one. Ann. Surg. Oncol. Vol. 15, No. 3, 2008

752

B. L. VANLEEUWEN ET AL.

The interpretation of the results of peritonectomy and HIPEC treatment in this study does present some flaws. Patients were treated for a number of different diagnoses and with a diversity of (neo-) adjuvant treatments. The inclusion of small patient groups with gastric and ovarian cancer may be problematic. Therefore, conclusions must be made with some care. The best way to evaluate the effect of this treatment would be a controlled randomized trial. To our knowledge, this has only been done once in patients with peritoneal carcinomatosis from colorectal origin, and peritonectomy combined with HIPEC increased survival compared with standard treatment.41 Patients with peritoneal carcinomatosis are well informed and use the internet and scientific publications to investigate the best treatment for them. This makes patient inclusion in randomized trials more difficult. In future, more attention needs to be paid to the quality of life of patients after HIPEC, and already a few authors report an acceptable-to-good quality of life following this treatment modality,42,43 but the numbers studied are low and warrant further investigation. In view of the morbidity and decreased survival rates after CC-2 and CC-3 resections, the peritonectomy and HIPEC procedure is controversial in cases for which optimal cytoreduction cannot be achieved. Furthermore, careful patient selection irrespective of age appears essential for optimizing outcomes.

ACKNOWLEDGEMENTS This work was supported by the Dutch Cancer Foundation and the Uppsala University Hospital (ALF-medel), Sweden.

REFERENCES 1. Sadeghi B, Arvieux C, Glehen O, et al. Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer 2000; 88:358– 63. 2. Gonzalez-Moreno S. Peritoneal surface oncology: a progress report. Eur J Surg Oncol 2006; 32:593–6. 3. Murphy EM, Sexton R, Moran BJ. Early results of surgery in 123 patients with pseudomyxoma peritonei from a perforated appendiceal neoplasm. Dis Colon Rectum 2007; 50:37–42. 4. Smeenk M, Verwaal VJ, Antonini N, et al. Survival analysis of pseudomyxoma peritonei patients treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Ann Surg 2007; 245:104–9. 5. Esquivel J, Sticca R, Sugarbaker P, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: a consensus statement. Ann Surg Oncol 2007; 14:128–33.

Ann. Surg. Oncol. Vol. 15, No. 3, 2008

6. Raspagliesi F, Kusamura S, Campos Torres JC, et al. Cytoreduction combined with intraperitoneal hyperthermic perfusion chemotherapy in advanced/recurrent ovarian cancer patients: the experience of National Cancer Institute of Milan. Eur J Surg Oncol 2006; 32:671–5. 7. Piso P, Dahlke MH, Loss M, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from ovarian cancer. World J Surg Oncol 2004; 2:21. 8. De Roover A, Detroz B, Detry O, et al. Adjuvant hyperthermic intraperitoneal peroperative chemotherapy (HIPEC) associated with curative surgery for locally advanced gastric carcinoma. An initial experience. Acta Chir Belg 2006; 106:297–301. 9. Fujimoto S, Takahashi M, Mutou T, et al. Improved mortality rate of gastric carcinoma patients with peritoneal carcinomatosis treated with intraperitoneal hyperthermic chemoperfusion combined with surgery. Cancer 1997; 79:884–91. 10. Sugarbaker PH, Yan TD, Stuart OA, et al. Comprehensive management of diffuse malignant peritoneal mesothelioma. Eur J Surg Oncol 2006; 32:686–91. 11. Begossi G, Gonzalez-Moreno S, Ortega-Perez G, et al. Cytoreduction and intraperitoneal chemotherapy for the management of peritoneal carcinomatosis, sarcomatosis and mesothelioma. Eur J Surg Oncol 2002; 28:80–7. 12. Natarajan N, Shuster TD. New agents, combinations, and opportunities in the treatment of advanced and early-stage colon cancer. Surg Clin North Am 2006; 86:1023–43. 13. Sugarbaker PH. Peritonectomy procedures. Surg Oncol Clin N Am 2003; 12:703–727; XIII. 14. Sarnaik AA, Sussman JJ, Ahmad SA, et al. Technology of intraperitoneal chemotherapy administration: a survey of techniques with a review of morbidity and mortality. Surg Oncol Clin N Am 2003; 12:849–63. 15. Van Ruth S, Verwaal VJ, Zoetmulder FA. Pharmacokinetics of intraperitoneal mitomycin C. Surg Oncol Clin N Am 2003; 12:771–80. 16. Elias DM, Sideris L. Pharmacokinetics of heated intraoperative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis. Surg Oncol Clin N Am 2003; 12:755–69; XIV. 17. Elias DM, Pocard M. Treatment and prevention of peritoneal carcinomatosis from colorectal cancer. Surg Oncol Clin N Am 2003; 12:543–59. 18. Harmon RL, Sugarbaker PH. Prognostic indicators in peritoneal carcinomatosis from gastrointestinal cancer. Int Semin Surg Oncol 2005; 2:3–13. 19. NCI DHHS DTCD. Common terminology criteria for adverse events v3.0 (CTAE). Anonymous. Anonymous. Cancer Therapy Evaluation Program, 2006. 20. Glehen O, Mithieux F, Osinsky D, et al. Surgery combined with peritonectomy procedures and intraperitoneal chemohyperthermia in abdominal cancers with peritoneal carcinomatosis: a phase II study. J Clin Oncol 2003; 21:799–806. 21. Verwaal VJ, Van Tinteren H, Ruth SV, et al. Toxicity of cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy. J Surg Oncol 2004; 85:61–7. 22. Stephens AD, Alderman R, Chang D, et al. Morbidity and mortality analysis of 200 treatments with cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy using the coliseum technique. Ann Surg Oncol 1999; 6:790–96. 23. Moran BJ. Establishment of a peritoneal malignancy treatment centre in the United Kingdom. Eur J Surg Oncol 2006; 32:614– 8. 24. Mahteme H, Hansson J, Berglund A, et al. Improved survival in patients with peritoneal metastases from colorectal cancer: a preliminary study. Br J Cancer 2004; 90:403–7. 25. Mahteme H, Graf W. Pseudomyxoma peritonei: a syndrome with varying prognosis. La¨kartidningen 2003; 38:2936–40. 26. Rouers A, Laurent S, Detroz B, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal

HIPEC IN PERITONEAL CARCINOMATOSIS

27.

28. 29.

30.

31. 32.

33.

34. 35.

peritoneal carcinomatosis: higher complication rate for oxaliplatin compared to mitomycin C. Acta Chir Belg 2006; 106:302–6. Liberale G, Pocard M, Manganas D, et al. Hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis of digestive and peritoneal origin: rationale. Acta Chir Belg 2006; 106:291–6. Gilly FN. Phase II studies: International registry of colorectal carcinomatosis. Eur J Surg Oncol 2006; 32:648–54. Gomez PA, Barrios P, Rufian S, et al. Management of peritoneal surface malignancy with cytoreductive surgery and perioperative intraperitoneal chemotherapy. Eur J Surg Oncol 2006; 32:628–31. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006; 24:4085–91. Verwaal VJ, Van Ruth S, Witkamp A, et al. Long-term survival of peritoneal carcinomatosis of colorectal origin. Ann Surg Oncol 2005; 12:65–71. Cavaliere F, Valle M, De Simone M, et al. 120 peritoneal carcinomatoses from colorectal cancer treated with peritonectomy and intra-abdominal chemohyperthermia: a S.I.T.I.L.O. multicentric study. In Vivo 2006; 20:747–50. Elias D, Benizri E, Di Pietrantonio D, et al. Comparison of two kinds of intraperitoneal chemotherapy following complete cytoreductive surgery of colorectal peritoneal carcinomatosis. Ann Surg Oncol 2007; 14:509–14. Yonemura Y, Bandou E, Kawamura T, et al. Quantitative prognostic indicators of peritoneal dissemination of gastric cancer. Eur J Surg Oncol 2006; 32:602–6. Bristow RE, Tomacruz RS, Armstrong DK, et al. Survival effect of maximal cytoreductive surgery for advanced ovarian

36. 37. 38. 39.

40. 41.

42.

43.

753

carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002; 20:1248–59. Garcia-Carbonero R, Paz-Ares L. Systemic chemotherapy in the management of malignant peritoneal mesothelioma. Eur J Surg Oncol 2006; 32:676–681. Hadi R, Saunders V, Utkina O, et al. Review of patients with peritoneal malignancy treated with peritonectomy and heated intraperitoneal chemotherapy. ANZ J Surg 2006; 76:156–61. Gilly FN, Cotte E, Brigand C, et al. Quantitative prognostic indices in peritoneal carcinomatosis. Eur J Surg Oncol 2006; 32:597–601. Brigand C, Monneuse O, Mohamed F, et al. Peritoneal mesothelioma treated by cytoreductive surgery and intraperitoneal hyperthermic chemotherapy: results of a prospective study. Ann Surg Oncol 2006; 13:405–12. Witkamp AJ, de Bree E, Van Goethem R, et al. Rationale and techniques of intra-operative hyperthermic intraperitoneal chemotherapy. Cancer Treat Rev 2001; 27:365–74. Verwaal VJ, Van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003; 21:3737–43. Schmidt U, Dahlke MH, Klemnauer J, et al. Perioperative morbidity and quality of life in long-term survivors following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Eur J Surg Oncol 2005; 31:53–8. McQuellon RP, Loggie BW, Lehman AB, et al. Long-term survivorship and quality of life after cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis. Ann Surg Oncol 2003; 10:155–62.

Ann. Surg. Oncol. Vol. 15, No. 3, 2008