Annals of Surgical Oncology, 13(3): 405)412

DOI: 10.1245/ASO.2006.05.041

Peritoneal Mesothelioma Treated by Cytoreductive Surgery and Intraperitoneal Hyperthermic Chemotherapy: Results of a Prospective Study C. Brigand, MD,1 O. Monneuse, MD,2,3 F. Mohamed, MBChB, MRCS,4 A. C. Sayag-Beaujard, MD,5 S. Isaac, MD,6 F. N. Gilly, MD, PhD,3,7 and O. Glehen, MD, PhD3,7

1

Department of General Surgery, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France 2 Department of Emergency Surgery, Hoˆpital Edouard Herriot, Lyon, France 3 Equipe Accueil 3738, Faculte´ de Me´decine Lyon-Sud, Oullins, France 4 Department of General Surgery, Newcastle upon Tyne, United Kingdom 5 Department of Anesthesiology, Centre Hospitalier Lyon-Sud, Pierre-Be´nite, France 6 Department of Pathology, Centre Hospitalier Lyon-Sud, Pierre-Be´nite, France 7 Department of Surgical Oncology, Centre Hospitalier Lyon-Sud, 69495 Pierre-Be´nite Ce´dex, France

Background: Peritoneal mesothelioma is a rare disease with few therapeutic options. Recently, the combination of cytoreductive surgery with intraperitoneal hyperthermic chemotherapy (HIPEC) has shown promising results. Methods: Fifteen patients with peritoneal mesothelioma who were treated by cytoreductive surgery and HIPEC between 1989 and 2004 were identified from a prospective database. HIPEC was performed with cisplatin and mitomycin C for 90 minutes by using the closedabdomen technique. Results: All patients but one (multicystic) had malignant disease of the following pathologic types: 12 epithelial and 2 biphasic. After surgical resection, 11 patients were considered to have a CC-0 or CC-1 resection (macroscopic complete resection or diameter of residual nodules <2.5 mm). No postoperative death occurred, and six postoperative complications were recorded. All but one patient had resolution of ascites. The overall median survival for the 14 patients with malignant mesothelioma was 35.6 months. The median survival was 37.8 months for patients treated with a CC-0 or CC-1 resection, whereas it was 6.5 months for those treated with a CC-2 or CC-3 resection (diameter of residual nodules >2.5 mm; P < .001). In a univariate analysis, the only other significant prognostic factor was the carcinomatosis extent (P = .02). Conclusions: A therapeutic strategy combining cytoreductive surgery with HIPEC seems to provide an adequate and efficient locoregional treatment for peritoneal mesothelioma. It is associated with acceptable morbidity when performed by an experienced surgical team. The completeness of cytoreduction is the major determinant of survival. Key Words: Peritoneal mesothelioma—Cytoreductive surgery—Intraperitoneal chemotherapy—Hyperthermia—Peritoneal carcinomatosis—Survival.

Peritoneal mesothelioma is a rare primary tumor of the peritoneal serosal membranes with a generally poor prognosis. It represents approximately one fifth to one third of all forms of mesothelioma.1–3 The role of asbestos exposure in the causation of peritoneal mesothelioma is less well defined than for pleural

Received June 15, 2005; accepted September 8, 2005; published online January 30, 2006. Address correspondence and reprint requests to: O. Glehen, MD, PhD; E-mail: [email protected]. Published by Springer Science+Business Media, Inc.
2006 The Society of Surgical Oncology, Inc.

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mesothelioma.4,5 Patients usually present with abdominal pain, increasing abdominal girth, weight loss, and abdominal masses, with or without ascites.6,7 Disease is usually confined to the abdominal cavity until the late stages of tumor progression, and death is almost always related to tumor progression in the peritoneum.8 Several different pathologic types of peritoneal mesothelioma have been identified. These pathologic subtypes have a prognostic role and are broadly divided into multicystic, epithelioid, epithelial, biphasic, sarcomatous, and deciduoid.5 Most treatment options, including systemic therapy, have failed to demonstrate a significant effect in terms of palliation or disease-free and overall survival. In the 1980s, a renewed interest in peritoneal surface malignancies developed through new multimodal therapeutic approaches. Previously unexplored locoregional treatment options, such as peritonectomy procedures,9 intraperitoneal hyperthermic chemotherapy (HIPEC),10,11 and early postoperative intraperitoneal chemotherapy,12 have been reported in the literature. Intraperitoneal anticancer drug administration has many pharmacokinetic advantages and gives high response rates within the abdomen because the peritoneal plasma barrier provides dose-intensive therapy. Higher concentrations of drug in direct contact with tumor cells can be achieved, with reduced systemic concentrations and lower systemic toxicity. The direct cytotoxicity of heat has been demonstrated in vitro at 42.5C.13 Hyperthermia at 42C has been shown to enhance the antitumor effects of agents such as oxaliplatin, mitomycin C, doxorubicin, or cisplatin by augmenting cytotoxicity, increasing the penetration of drugs into tissue, or both.14–16 Reducing tumor volume has always been considered an important factor in achieving tumor response to chemotherapy.17 The idea of reducing tumor volume for peritoneal surface malignancies has been reported for ovarian cancer.18 The combination of both cytoreductive surgery and peritonectomy procedures with HIPEC may act as a dose-intensification device and may lead to improved outcomes. From a theoretical perspective, cytoreductive surgery is performed to treat macroscopic disease and HIPEC is performed to treat microscopic residual disease; the end result is complete eradication of disease with a single procedure. It is well known that the penetration of intraperitoneal chemotherapy into peritoneal carcinomatosis nodules is limited to between 2 and 5 mm, even when combined with heat.19 Thus, the goal of cytoreductive surgery for curative intent is to achieve maximum reduction of tumor volume. Ann. Surg. Oncol. Vol. 13, No. 3, 2006

Recent phase II trials suggest that the therapeutic locoregional approach combining cytoreductive surgery with HIPEC may be a potentially effective salvage therapy for patients with peritoneal mesothelioma with a limited extent of disease.5,6,20,21 We present a prospective phase II trial of 15 patients with peritoneal mesothelioma treated by extensive cytoreductive surgery combined with HIPEC. PATIENTS AND METHODS Patients From a prospective database, all patients with peritoneal mesothelioma treated between January 1989 and December 2004 at Centre Hospitalier Lyon Sud (Pierre Be´nite, France) by cytoreductive surgery and HIPEC were selected. Charts were reviewed for demographic data, surgical procedures performed, operative complications, length of hospital stay, and histopathologic classification. Diagnosis was confirmed or suspected before surgery by peritoneal cytological results and/or by pathologic examination of biopsy samples (by using immunostains: vimentin, carcinoembryonic antigen [CEA], epithelial membrane antigen, cytokeratin 7, cytokeratin 20, calretinin, CD15, MOK-31, and HBEM1) from patients who had initial surgery at their referring institution. Protocol Inclusion criteria were (1) no sign of distant metastasis on computed tomography (CT) of the abdomen and chest and (2) cardiorespiratory and renal function sufficient to allow the required resection. Exclusion criteria were (1) a World Health Organization index score >2, (2) administration of chemotherapy 1 month before inclusion, and (3) central nervous system disease. Before treatment, all patients underwent a physical examination and blood tests, including serum electrolytes and creatinine, hepatic function, and tumor markers (CEA, CA 19-9, and CA-125). Diagnostic tests included cardiac ultrasonography as well as CT of the head, thorax, abdomen, and pelvis. Gastroscopy and colonoscopy were used to exclude synchronous malignancies. The treatment protocol was approved by the local ethics committee, and informed consent was obtained from all patients. Surgical Procedure All patients underwent general anesthesia in the lithotomy position. A midline incision from the

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TABLE 1. Gilly peritoneal carcinomatosis score Stage 0 I II III IV

Description No macroscopic disease Tumor nodules <5 mm Localization in 1 part of the abdomen Tumor nodules <5 mm Diffuse to the entire abdomen Tumor nodules 5–20 mm Tumor nodules >20 mm

xiphoid process to the pubic symphysis was performed to explore the abdominal cavity. The tumor distribution was recorded by using GillyÕs peritoneal carcinomatosis staging system22 (Table 1). A judgment was made regarding the anatomical sites of prior surgical dissections by using the prior surgical score, as described by Sugarbaker and Chang23 (Table 2). When tumor deposits involved only a small part of the parietal peritoneal surface, local resection of these surfaces was performed. For major involvement of the parietal peritoneal surface, peritonectomy procedures were performed as described by Sugarbaker.9 The main goal of cytoreductive surgery was to remove all macroscopic tumors, leaving no nodules >5 mm. When tumors involved visceral surfaces such as the stomach or bowel, local resection of these deposits was attempted. For major visceral involvement, segmental resection with anastomosis was performed. Assessment of the completeness of cancer resection (CC score) with cytoreductive surgery was performed by the surgeon at the end of the procedure and classified into 3 categories: CC-0 indicated that no macroscopic residual cancer remained; CC-1, that no nodule >2.5 mm in diameter remained; CC-2, that nodules between 2.5 mm and 2.5 cm in diameter remained; and CC-3, that nodules >2.5 cm in diameter remained. Intraperitoneal Hyperthermic Chemotherapy At the end of each surgical procedure, HIPEC was performed with the patient under general anesthesia. Before closure of the laparotomy, an inflow drain was inserted under each hemidiaphragm (30F Silicone William Harvey drain; Bard-Cardiopulmonary Division, Boston, MA), and a third drain (outflow) was inserted into the pouch of Douglas (32F). Monotherm temperature probes (Mallinckrodt SA and Cair SA, Lozanne, France) were also placed into the abdominal cavity (behind the liver pedicle and near the first jejunal loop).

The laparotomy incision was then closed, and inflow and outflow drains were connected to a closed sterile circuit device (Cavitherm; EFS Electronique, Millery, France), in which 4 to 6 L of isotonic dialysis fluid (Travenol Laboratory, Norfolk, UK) was circulated at a flow rate of 500 to 700 mL/min and heated to achieve an intraperitoneal temperature between 42C and 42.5C. The intraperitoneal chemotherapy administered consisted of mitomycin C (.5 mg/kg) and cisplatin (.7 mg/kg). HIPEC was performed for 90 minutes, with monitoring of flow rate; inflow, outflow, and intraperitoneal temperatures; and respiratory and hemodynamic variables. Patient Follow-Up All patients were transferred to an intensive care unit for the first 24 hours after surgery before returning to a standard surgical ward. Patients were reviewed in the outpatient clinic every 4 months for the first 2 years after surgery, every 6 months for the next 3 years, and then annually thereafter. Abdominal and pelvic CT was performed at 6-month intervals for 2 years and then annually. Data Analysis Data were collected and analyzed with a commercially available computer program (StatView 4.5 [Abacus Inc., Berkeley, CA] and StatXact 2.02 [Cytel Software Corporation, Cambridge, MA]). The Kaplan-Meier test was used to analyze survival, and the log-rank test was used to identify differences between survival curves. Survival was measured from the time of diagnosis. No patient was lost from follow-up. The cutoff date was January 1, 2005. The case of multicystic peritoneal mesothelioma was excluded from the survival analysis.

RESULTS Patient Characteristics From 1989 to 2004, 15 patients (10 men and 5 women) with a median age of 53.6 years (range, 42–67 years) were treated. Twelve patients had no history of exposure to asbestos, three worked in close contact with asbestos, and two patients were born and spent their childhood in Turkey. Peritoneal mesothelioma presented as abdominal pain in nine patients, increasing abdominal girth in seven, loss of weight in three, and an umbilical hernia in three. Two Ann. Surg. Oncol. Vol. 13, No. 3, 2006

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TABLE 2. Prior surgical score (PSS) PSS 0 1 2 3 Total

Description

No. of patients

Biopsy only Exploratory laparotomy, 1 abdominopelvic region dissected Exploratory laparotomy, 2 to 5 abdominopelvic regions dissected Extensive prior cytoreduction, >5 abdominopelvic regions dissected

3 1 7 4 15

TABLE 3. Characteristics of the tumor and treatment Patient no.

PSS

Histological subtype

Gilly score

1

2

Epithelial

4

2 3

2 2

Epithelial Epithelial

2 4

4 5 6

3 2 3

Epithelial Multicystic Epithelial

4 2 2

7

0

Epithelial

4

8 9 10

3 0 0

Epithelial Epithelial Biphasic

4 3 2

11

3

Biphasic

4

12 13

2 1

Epithelial Epithelial

4 4

14

2

Epithelial

3

15

2

Epithelial

4

Surgical procedure

CC

Omentectomy, debulking Cholecystectomy, antrectomy, omentectomy, multiple Peritonectomies Biopsies only; palliative surgery Omentectomy, multiple Peritonectomies Peritonectomies Total gastrectomy, splenectomy, omentectomy, peritonectomies Biopsies only; palliative surgery Hysterectomy + bilateral annexectomy, rectosigmoidectomy, ileocecal resection, omentectomy, splenectomy, multiple Peritonectomies Biopsies only; palliative surgery Peritonectomy Small-bowel resections, omentectomy, left splenopancreatectomy, cholecystectomy, multiple Peritonectomies Right hemicolectomy, omentectomy, multiple Peritonectomies Cholecystectomy, omentectomy, multiple peritonectomies Cholecystectomy, omentectomy, multiple peritonectomies Cholecystectomy, omentectomy, orchidectomy, subtotal gastrectomy, appendicectomy, multiple peritonectomies

3

0 3

Complications —

Superficial wound infection —

1 0 0

— — —

3

—

0 2 1

Bilateral pleuritis — Septicemia (staphylococcus)

1

Postoperative ileus

1 1 0

— Renal impairment + wound necrosis —

1

Superficial wound infection

PSS, prior surgical score; CC, completeness of cancer resection.

patients initially underwent diagnostic laparoscopy for abdominal pain (suspected appendicitis and endometriosis). Twelve patients presented with ascites. The median interval between symptom appearance and diagnosis was 2 months (range, .7–53.9 months). The interval between diagnosis and surgical intervention in our surgical department was 1 month in all but three patients. One patient was initially treated by intraperitoneal chemotherapy with interferon for 6 months before referral. The second patient was treated by surgery and IPHC in another surgical center 16 months before referral for recurrence. The third received six cycles of systemic chemotherapy Ann. Surg. Oncol. Vol. 13, No. 3, 2006

with fluorouracil and oxaliplatin after an exploratory laparotomy. Details of pathologic results, carcinomatosis extent, surgical procedure, and complications are reported in Table 3. After the surgical procedure, 11 patients were considered to have a CC-0 or CC-1 resection, and 4 patients had a CC-2 or CC-3 resection. Immunocytochemical studies were performed to confirm diagnosis. All cases stained negatively for CEA. Immunostains were performed with calretinin for 11 patients and with cytokeratin 7 for 13 patients: all were positive. The final histopathologic classification was of epithelial type in 12 patients, biphasic

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PERITONEAL MESOTHELIOMA TREATED BY HIPEC

Survival

1

1

,8

,8

,6

,6

,4

,4

,2

,2

0

CC-0 or 1 CC-2 or

0

0 0

1

2

3

4

6

Months FIG. 1. Overall survival of 14 patients with malignant peritoneal mesothelioma according to the Kaplan-Meier method.

type in 2, and multicystic type in 1. All diagnoses were confirmed or suspected before surgery after specimens were reviewed by the same pathologist in Centre Hospitalier Lyon Sud. The median length of stay was 16.3 days (range, 7–69 days). No perioperative death occurred. Six postoperative complications were recorded. No reintervention was necessary. Two of these complications were specifically related to the IPHC procedure. One patient developed a superficial wound necrosis, probably because of extravasation of chemotherapeutic perfusate during IPHC. Another patient experienced acute renal failure that resolved with intravenous rehydration. No second-look operation was performed to assess response to treatment. One patient underwent a second procedure for recurrence 36 months after the first. A CCR-1 resection with multiple small-bowel resections combined with HIPEC was performed. No complications occurred, and this patient is alive with no evidence of recurrence 88 months after the first procedure. In all patients but one, resolution of preoperative ascites was observed. Survival The median follow-up was 46.7 months (range, 1–190 months). The patient with multicystic peritoneal mesothelioma was alive without recurrence at 67 months. By using the Kaplan-Meier method, the overall median survival of patients with malignant peritoneal mesothelioma was 35.6 months . The actuarial 1-, 2-, 3-, and 5-year survival rates were 69.3%, 57.7%, 43.3%, and 28.9%, respectively (Fig. 1). There was a statistically significant difference in survival according to the completeness of

1

2

3 Months

4

6

FIG. 2. Survival of 14 patients with malignant peritoneal mesothelioma according to the completeness of cytoreductive surgery using the Kaplan-Meier method.

cytoreduction (P < .001; Fig. 2). The median survival was 37.8 months, and the actuarial 5-year survival rate was 43.8% for patients treated with a CC-0 or CC-1 resection, whereas the median survival was 6.5 months for those treated with a CC-2 or CC-3 resection. The median survival of patients with stage I or II carcinomatosis was not reached, whereas it was 21.8 months for patients with stage III or IV disease. This difference was significant (P = .02). Sex, age, and prior surgical score did not significantly influence survival in a univariate analysis. Survival data are summarized in Table 4.

DISCUSSION Because of the rarity of malignant peritoneal mesothelioma, current understanding of its epidemiology and pathophysiology is limited. Prognostic indicators and effective therapeutic approaches remain elusive. Although an increase in the incidence of pleural mesothelioma in Western countries (1% of men born in the 1940s, with a peak of incidence expected in the 2010s)24 is well documented, its natural history differs1 from that of peritoneal disease, and this makes comparisons and extrapolation of treatment strategies inappropriate. Moreover, a broad spectrum of pathologic types of peritoneal mesothelioma has been reported from low to high malignant potential.25 The interpretation of published reports is made difficult by the heterogeneity of pathologic subtypes and differences in therapeutic approaches with ill-defined eligibility criteria, an absence of control groups, and short follow-up. Although some studies identify asbestos exposure as a significant factor in the development of peritoneal mesothelioma, this relationship, especially in women,5 Ann. Surg. Oncol. Vol. 13, No. 3, 2006

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TABLE 4. Univariate analysis of survival of 14 patients with malignant peritoneal mesothelioma Variable

n

Median survival (mo)

P value

Overall Age (y) £ 52 >52 Sex Female Male Gilly score 1 or 2 3–4 PSS 0 or 1 2 or 3 CC-0 or CC-1 CC-2 or CC-3

14

35.6

7 7

NR 21.8

.168

4 10

NR 35.6

.469

3 11

NR 21.8

.020*

4 10 10 4

21.8 35.6 37.8 6.5

.996 <.001*

NR, not reached; PSS, prior surgical score; CC, completeness of cancer resection. *Statistically significant.

has not been established as it has in pleural mesothelioma.24,26 In our series, only three patients had a history of asbestos exposure, and all were men. It has been suggested that the epidemiology and progress of peritoneal mesothelioma may differ between men and women.5 Our data confirm this: women did not reach their median survival, but men had a median survival of 35.6 months, although this difference did not reach statistical significance. Roushdy-Hammady et al.27 reported a possible genetic susceptibility to malignant mesothelioma in the Cappadocian region of Turkey in which mesothelioma segregated in an autosomaldominant fashion after exposure to erionite. Two of our patients were born and spent their childhood in this region of Turkey. Definitive diagnosis of peritoneal mesothelioma can be problematic. Diagnosis cannot be established with simple cytological examination and requires generous sampling of peritoneal surface tissue.5 Because this type of tumor is extremely efficient in its ability to implant within a needle tract or abdominal incision, tissue biopsies should be performed in the midline along the linea alba. Disease dissemination within the abdominal wall may result from careless placement of lateral port sites for diagnostic laparoscopy. Moreover, the distinction of peritoneal mesothelioma from adenocarcinoma is often difficult and requires appropriate immunocytochemical stains. A positive calretinin and cytokeratin 7 stain accompanied by a negative CEA immunostain is highly suggestive of peritoneal mesothelioma. Because prognosis is poor28,29 with conventional systemic chemotherapy-based treatment regimens, new therapeutic strategies for the treatment of periAnn. Surg. Oncol. Vol. 13, No. 3, 2006

toneal mesothelioma have been explored. The disease is primarily confined to the peritoneal cavity, and this makes it well suited for locoregional treatments. Surgical resection combined with adjuvant treatments, including radioactive colloid gold,30 abdominal radiotherapy,31 and bleomycin,2 have all been described, but with little benefit. Intraperitoneal cisplatin chemotherapy, alone or with other agents, has shown more promise.32,33 However, major surgical cytoreduction seems to govern prognosis. Langer et al.33 described a survival improvement from 5 to 22 months when surgical resection removed nodes >2 cm before administration of intraperitoneal cisplatin. In our study, median survival was 37.8 months when cytoreductive surgery achieved a CC-0 or CC-1 resection, whereas it was 6.5 months with a CC-2 or CC-3 resection, even if major visceral resections were necessary. Sebbag et al.34 reported similar results in 33 patients, with a median survival of 13 and 41 months for CC-3 and CC-0 to CC-2 resections, respectively. In a study by Eltabbakh et al.,35 15 women with malignant peritoneal mesothelioma were treated with surgery followed by systemic chemotherapy. One patient underwent cytoreductive surgery and survived longer than those who underwent biopsy only. Feldman et al.,6 in their analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma, found that minimal residual disease after surgical resection was an independent predictor of improved overall survival. The completeness of cytoreductive surgery seems to be an important prognostic indicator, as it is in carcinomatosis of colonic36 or ovarian37 origin. The natural history of peritoneal carcinomatosis from digestive and gynecological cancers was described by Sugarbaker.14 The concept of cell entrapment in surgical wounds highlights the need for adjuvant intraperitoneal therapy soon after surgical resection. Recent phase II studies have reported more promising results with HIPEC than older trials. From pharmacokinetic studies, the most effective chemotherapeutic agents for malignant mesothelioma seem to be cisplatin,32 doxorubicin,1,21 paclitaxel associated with cisplatin,35 and mitomycin C.8,38 In light of our previous experience with other peritoneal malignancies,17,39 we chose a combination of mitomycin C with cisplatinum. It is not possible to draw any conclusions about the advantage of one combination over the other in terms of tumor response on the basis of current literature. Feldman et al.6 reported an actuarial overall survival of 92 months in 49 patients treated by surgery plus IPHC with cisplatin followed by a single postoperative dwell of fluorouracil and paclitaxel.

PERITONEAL MESOTHELIOMA TREATED BY HIPEC

Sugarbaker et al.5 reported similar results with a median survival of 67 months in 68 patients treated by surgery, HIPEC, and early postoperative intraperitoneal chemotherapy with paclitaxel. With a shorter follow-up, Deraco et al.21 reported a series of 19 patients treated by cytoreductive surgery and IPHC with cisplatin plus mitomycin C or doxorubicin, with a 2year survival of 70%. They observed a resolution of ascites in 94% of cases. Our results in this small cohort of patients with a variety of malignant types of peritoneal mesothelioma treated by IPHC with cisplatin and mitomycin C approach published results, with 2and 5-year survival rates of 57.7% and 28.9%, respectively. Moreover, all but one of our patients had no further symptoms from ascites after treatment. Careful patient selection is vital for this aggressive but comprehensive therapeutic approach if morbidity due mainly to the extent of cytoreductive surgery40,41 is to be minimized. In our series, overall results may have been better with more rigorous patient selection based on the Gilly score and CC score. However, preoperative assessment of peritoneal invasion and resectability remains difficult. Recently, the Washington Cancer Institute identified two radiological features on CT scan that may predict with accuracy a potential inadequate cytoreduction: the presence of a tumor mass >5 cm in the epigastric region and the loss of normal architecture of the small bowel and its mesentery.42 The development of such preoperative tools may aid appropriate selection of patients for comprehensive treatment strategies. On the basis of this study and those previously reported,5,6,21 the combination of cytoreductive surgery with HIPEC needs to be considered as a research tool for the standard of practice for the treatment of patients with malignant peritoneal mesothelioma. Unexpected long-term results in a disease that in the past was always rapidly fatal were observed with this therapeutic approach. Although prospective randomized trials of this approach are theoretically attractive, the rarity of the disease makes accrual to appropriately powered trials highly unlikely. A greater understanding of the epidemiology, prognostic factors, and effective therapeutic strategies for the treatment of peritoneal mesothelioma may come from a multicenter cooperative study such as those performed for colorectal carcinomatosis.36

2. 3.

4. 5. 6.

7. 8. 9. 10.

11. 12. 13. 14.

15.

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18.

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