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Tumori, 98: 588-593, 2012

Pseudomyxoma peritonei treated with cytoreductive surgery and hyperthermic chemotherapy: a 7-year single-center experience Salvatore Virzì, Domenico Iusco, Serena Bonomi, and Antonio Grassi Department of Surgery, Ospedale di Bentivoglio, Bentivoglio (Bologna), Italy

ABSTRACT

Aims and background. Pseudomyxoma peritonei (PMP) is a rare clinical entity characterized by diffuse intraabdominal gelatinous collections with mucinous implants on the peritoneal surfaces and omentum. This condition should be considered a borderline malignancy with disease progression over time. Encouraging treatment results have been recently reported with the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Methods. From December 2003 to December 2010, 18 patients with PMP were referred to our institution. All patients underwent peritonectomy and CRS combined with HIPEC in accordance with Sugarbaker’s procedure. Results. The mean Peritoneal Cancer Index score was 27.6 (range, 5-39). Twelve (67%) patients had disseminated peritoneal adenomucinosis and 6 (33%) peritoneal mucinous carcinomatosis. Optimal cytoreduction with no visible residual disease or residual disease ≤2.5 mm in diameter was achieved in all patients. The mean duration of the surgical procedure including HIPEC was 9 hours and 30 minutes (range, 5-13 hours); major morbidity occurred in 30% of patients and the mortality was 11%. The mean follow-up was 27 months (range, 1-72) and the 5-year overall survival 66%. Conclusions. In line with the existing literature, our experience suggests that patients with PMP could benefit from CRS + HIPEC in terms of survival and locoregional disease control.

Introduction Pseudomyxoma peritonei (PMP) is a rare disease characterized by diffuse collection of intraabdominal gelatinous material, the major bulk of the lesion, and an extremely poor neoplastic epithelial content. This clinical entity has an incidence of 1 to 2 cases per million people per year1,2. It has been demonstrated recently that PMP originates in most cases from the rupture and consequent intraabdominal dissemination of an appendiceal tumor. A new histological classification of this condition has been proposed, which considers 3 types of PMP: disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and an intermediate or discordant feature group (ID)3. Even though PMP is generally considered benign, its local progression with subsequent organ compression frequently results in a fatal outcome4. No controlled clinical studies have been conducted on this rare disease, and until recently palliation in order to delay the lethal outcome was the only option that could be offered to these patients. The introduction of cytoreductive surgery (CRS), followed by intraperitoneal chemotherapy, has drastically changed the outcomes of PMP treatment5. We report our 7-year experience in the treatment of this rare condition.

Key words: pseudomyxoma peritonei, cytoreductive surgery, peritonectomy, complete cytoreduction. Correspondence to: Domenico Iusco, MD, PhD, Via Bonaventura Cavalieri 7, 40138 Bologna, Italy. Tel +39-333-6192668; email [email protected] Received December 30, 2011; accepted May 4, 2012.


PSEUDOMYXOMA PERITONEI TREATMENT

Patients and methods Patient selection Patients were considered suitable for CRS and hyperthermic intraperitoneal chemotherapy (HIPEC) after complete evaluation including clinical examination, ultrasonography, computed tomography (CT) of the chest and abdomen, tumor marker assay (CEA, CA 125, CA 19.9), and diagnostic laparoscopy. Eligibility criteria included a confirmed histological diagnosis of PMP; peritoneal disease amenable to potentially complete surgical cytoreduction and absence of hepatic or extraabdominal metastases at preoperative CT; age ≤75 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2; good cardiac, renal, hepatic and bone marrow function; signature on a written informed consent form. Surgical procedure Ureteral stents were placed routinely in the preoperative period. A 3-way bladder catheter was inserted for cold lavage during HIPEC in order to avoid mucosal damage due to the hyperthermia. A xiphopubic laparotomy was performed with the patient in the supine position with the legs spread. After opening of the peritoneum the extent of peritoneal involvement was quantified using the peritoneal cancer index (PCI). PCI is calculated by dividing the abdominal cavity into 13 regions (AR0-12) and assigning a lesion size score to each (LS03). Summation of all lesion size scores results in a numeric score ranging from 0 to 39. CRS was carried out according to the peritonectomy procedures described by Sugarbaker6. In order to achieve complete surgical cytoreduction, consisting in the removal of all visible tumor, the following procedures were performed: 1) right subdiaphragmatic and parietal peritonectomy, 2) left subdiaphragmatic and parietal peritonectomy, 3) greater omentectomy with splenectomy, 4) lesser omentectomy and stripping of the omental bursa, and 5) pelvic peritonectomy with salpingo-oophorectomy in women. Furthermore, implants on the visceral serosa were removed by local electrosurgical dissection or multivisceral resections including Glisson’s capsule dissection, cholecystectomy, partial or total gastrectomy, and sigmoid, right or total colectomy. At the end of the surgical phase the completeness of cytoreduction (CC) was classified according to criteria described by Sugarbaker6: CC0: no residual disease; CC1: residual disease ≤2.5 mm in any region; CC2: residual disease >2.5 mm.

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pelvic area and the mesogastric area. Two thermocouples were placed in the abdominal cavity for continuous monitoring of the peritoneal temperature during perfusion. After abdominal skin closure, the 5 catheters were connected to the extracorporeal circuit. A preheated polysaline perfusate (4-6 L) containing cisplatin (25 mg/m2/L) plus mitomycin C (3.3 mg/m2/L) was instilled into the peritoneal cavity by means of an integrated system multifunction device (Performer-LRT, RanD-Medtronic, Medolla, Italy) at a mean flow of 600 mL/min for 60 minutes, starting from the true hyperthermic phase (42.5 °C). At the end of perfusion, after careful inspection of the intestinal loops in order to prevent HIPEC-related mechanical complications (suction effect on small bowel wall, hematoma formation on the mesentery), new abdominal drains were inserted and the abdomen was closed. Patients spent the early postoperative period, at least 3 days, in the intensive care unit (ICU), where they were assessed daily by laboratory and imaging examinations. Postoperative complications were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) version 3.0. Only grade 3-5 adverse events were considered in this study. Follow-up and statistics Patients underwent long-term follow-up every 6 months for the first 2 years and every year thereafter. Follow-up included physical examination, tumor marker monitoring, and total-body CT. Overall survival was calculated from the date of surgery to the date of death due to any cause or time of last follow-up; disease-free survival was calculated from the date of surgery to the date of disease relapse. To evaluate disease-free survival the 2 patients who died 1 month after the operation of causes unrelated to the disease were not considered as an event in disease-free survival estimation. The estimated survival curves were calculated according to the Kaplan-Meier method.

Results From December 2003 to December 2010, 18 patients with PMP were referred to our institution (10 women and 8 men). These patients represent 8% of the 223 patients treated by our surgical team for peritoneal carcinomatosis. The patient characteristics are shown in Table 1.

Intraperitoneal hyperthermic perfusion

Surgical outcomes

After CRS, HIPEC was performed according to the closed-abdomen technique. Two inflow and 3 outflow catheters were inserted. The inflow catheters were positioned in the right subphrenic cavity and in the deep pelvis, the outflow ones in the left subphrenic cavity, the

Seven patients had previously undergone surgical debulking elsewhere; 2 had received systemic chemotherapy before the procedure. At laparotomy, all patients had mucinous ascites and the mean PCI score was 27.6 (range, 5-39). Twelve and 6 patients were pathologically


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bleeding. Perioperative death occurred in 2 patients (11%); 1 patient died of pulmonary embolism and the other died of septic shock due to pneumonia.

Table 1 - Patient characteristics Variable Gender M/F Age (y), median (range) ECOG performance status 0 1 2 Previous chemotherapy None FOLFOX Previous surgical procedures Only biospsy 1 region dissected 2-5 regions dissected >5 regions dissected Histology DPAM PMCA PCI mean (range)

N 8/10 60 (34-75) 12 4 2 16 2 10 3 4 1 12 6 27.6 (5-39)

N, number; M, male; F, female; y, year; ECOG, Eastern Cooperative Oncology Group; DPAM, disseminated peritoneal adenomucinosis; PMCA, peritoneal mucinous carcinoma; PCI, peritoneal cancer index.

diagnosed with the DPAM and PMCA histological subtypes, respectively. The mean duration of the surgical procedure, including HIPEC, was 9 hours and 30 minutes (range, 5-13). After CRS, all cases were optimally cytoreduced with no residual disease (CC0, n = 8) or residual disease ≤2.5 mm in diameter (CC1, n = 10). The procedures performed in this group of patients are described in Table 2. Five major (grade 3-4) complications requiring reoperation, ICU admission or interventional radiology occurred, namely gastric perforation, colon perforation, pulmonary embolism, septic shock, and postoperative

Survival and failure At the time of the present analysis, 10 patients were alive with no evidence of disease, 2 were alive with disease, and 6 had died, accounting for a mean follow-up period of 27.1 months (range, 1-72) and a 5-year overall survival rate of 65% (median not reached) (Figure 1). The cause of death was unrelated to the disease in 3 cases: 2 were postoperative deaths, and 1 patient died 72 months after the operation because of a car accident, being apparently disease free. PMP-related deaths were caused by local-regional (intraabdominal) disease progression in 2 patients and liver metastasis in 1. During the study period, disease relapse occurred in 6 patients, in the form of locoregional recurrence in 5 patients and liver metastases in 1. Three patients underwent surgery because of disease recurrence: 1 patient affected by PMCA died of further disease relapse and 2 patients with DPMA are currently disease free and alive with disease, respectively. The 5-year recurrence-free survival was 66% (Figure 2). The small size of the present series precluded a meaningful prognostic analysis. However, it is noteworthy that the histological subtype seemed to strongly impact long-term outcome. Among 6 patients with PMCA, only 2 are currently disease free, while 3 have died of disease and 1 is alive with disease. In contrast, among 12 patients with DPAM, 8 are alive and disease free, 3 have

1.0 Table 2 - Cytoreductive surgical procedures Procedures

N

17 17 17 17 17 15 17

Multivisceral resection Glisson’s capsule resection Cholecystectomy Partial/total gastrectomy Splenectomy Right colectomy Sigmoidectomy Total colectomy Hysterectomy + oophorectomy Other

6 15 6 15 16 15 1 8 6

Completeness of cytoreduction No visible residual tumor Residual tumor ≤2.5 mm

8 10

Cumulative survival

0.8 Peritonectomies Right upper quadrant Left upper quadrant Right parietal Left parietal Pelvic Greater omentectomy Lesser omentectomy

0.6

0.4

0.2

0.0 0.00

20.00

40.00 Follow-up

60.00

80.00

Figure 1 - Overall survival of our patients calculated with the KaplanMeier method.



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1.0

Cumulative survival

0.8

0.6

0.4

0.2

0.0 0.00

20.00

40.00 Follow-up

60.00

80.00

Figure 2 - Disease-free survival of our patients calculated with the Kaplan-Meier method.

died of disease-unrelated causes, and 1 is alive with disease (Figure 3).

Discussion The main features of PMP are intraabdominal mucinous accumulation (jelly belly) and mucinous tumor implants in the peritoneum and intraperitoneal viscera7. Recent pathological, molecular and immunohistochemical studies have proved that most cases of PMP originate from the intraabdominal neoplastic dissemination of ruptured low-grade appendiceal mucinous

Survival of PMP according to histologycal type

8 7 6 5 4

DPAM NED

3 2 1

PMCA NED

DPAM DOC DPAM AWD

DPAM DOD

PMCA DOD

PMCA AWD

0 1 Figure 3 - Survival of pseudomyxoma peritonei patients according to histological type. DPAM, disseminated peritoneal adenomucinosis; PMCA, peritoneal mucinous carcinomatosis; NED, no evidence of disease; AWD, alive with disease; DOD, died of disease; DOC, died of other causes without disease.

neoplasms8-10. Exceptional cases of PMP have been reported to originate from the stomach, colon11, pancreas12, urachus13, breast14, and ovary (mucinous ovarian tumor)15. Misdraji and coworkers16 recently proposed a new classification of appendiceal mucinous neoplasms: lowgrade appendiceal mucinous neoplasm (LAMN) and mucinous adenocarcinoma (MACA). The former is associated more frequently with DPAM, the latter with the more aggressive PMCA. Management of PMP by the combination of macroscopic surgical cytoreduction with microscopic chemical cytoreduction to eradicate minimal residual disease is supported by a strong rationale. This is due to the typical dissemination pattern of PMP that has been defined as a redistribution phenomenon, indicating that tumor cells with low biological aggressiveness are not able to directly invade the peritoneal surfaces but just distribute within the abdominal cavity following a predictable pattern determined by mucinous fluid flow, gravity, and anatomical structures. In the past, repeated debulking surgery was the treatment of choice for PMP. In the series of the Memorial Sloan-Kettering Cancer Center, the traditional approach was associated with a 91% relapse rate at the price of 1-6 operations performed for each patient (mean 2.2 ± 0.1) during the study period17. When feasible, the innovative treatment is associated with increased long-term survival and better quality of life (QOL)18-21: in the present series, 65% recurrence-free survival was achieved with only 3 patients needing a second operation. Furthermore, since Sugarbaker described his excellent results with cytoreduction and intraperitoneal chemotherapy as curative treatment19,20, this therapeutic strategy has been supported by data reported by different authors5,22-26. In fact, systemic chemotherapy, as in most peritoneal neoplasms of different origins, has little impact on PMP, while locoregional treatments allowing to achieve an elevated and persistent drug concentration in the abdominal cavity with limited systemic effects are considered a new frontier in the treatment of this condition19. On the other hand, despite the high morbidity of CRS and HIPEC, the impact on QOL in the long term may be acceptable when a disease-free status is achieved5,21. In fact, McQuellon et al.27 stated that this combined approach may have a strong impact on QOL during the early postoperative period, but the general condition of the patient is usually recovered within 4-6 months. Consequently, in the long term the patient’s QOL will be much more impaired by repeated debulking surgery after incomplete cytoreduction than by the potential morbidity associated with complete cytoreduction. The combined approach proved to impact the overall survival and disease-free interval in patients affected by carcinomatosis of mucinous cancers such as PMP. Bryant et al.18 reviewed the available literature on conventional treatments for PMP and found that patients


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treated conventionally with debulking surgery had an estimated 10-year survival rate of about 20%. This result differs significantly from those reported when the Sugarbaker procedure was used: 90% at 2 years, 60-90% at 5 years, and 55% at 10 years. Our survival rates are in line with those reported in the literature19. This procedure is, however, expensive in terms of financial resources, operative time and technological facilities. In fact, specific training and experience are needed to create a skilled team for the Sugarbaker procedure. The reported morbidity and mortality after this approach range from 12% to 56% and from 0% to 12%, respectively; again, our mortality and morbidity are in line with these figures28. Morbidity has been reported to be correlated with the extent of surgery as well as with the PCI and the duration of surgery. Age, the number of organs resected, and blood loss are also risk factors for increased morbidity. Among the prognostic factors reported in the literature, histological grade and cytoreduction score are the most important12,29. We managed to reach 100% optimal cytoreduction (CC0-CC1) probably because, as a high-volume center, we performed most of the operations, i.e. 14, in the last 4 years, when we had already completed our learning curve as a team. In fact, the mean number of CRS + HIPEC procedures performed in our institution is 30-35 per year, so in the first 3 years we performed approximately 100 procedures. A recent study shows in fact that 140 cases with appropriate supervision are needed to complete the learning curve29. Although we have gained acceptable proficiency in the treatment of all-type peritoneal surface malignancy, our results in terms of mortality and morbidity may seem slightly worse than those of centers fully dedicated to PMP treatment30. Indeed, Youssef et al.31 in a recent study of 546 patients with PMP reported a mortality rate of 1.7% and a morbidity rate of 7%. PMP is a rare peritoneal surface malignancy with particular biological features that require more extensive cytoreduction with an aggressive surgical policy than other types of peritoneal carcinomatosis such as those from colorectal cancer. Therefore, our experience comprising 18 cases could mean that our learning curve in the context of PMP is still ongoing and that further cases would be necessary to gain proficiency in this particular subset. Our experience being in line with that reported in the literature suggests that this subset of patients could benefit from Sugarbaker’s combined approach in terms of overall and disease-free survival, and even though no randomized study has been carried out to assess its real efficacy, we believe that this approach should be considered the best therapeutic option.

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