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© 2003 American Society for Clinical Oncology Analysis of Factors Associated With Outcome in Patients With Malignant Peritoneal Mesothelioma Undergoing Surgical Debulking and Intraperitoneal ChemotherapyFrom the Surgical Metabolism Section, Surgery Branch, the Laboratory of Pathology, and the Biostatistics & Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. Address reprint requests to H. Richard Alexander, MD, Surgical Metabolism Section, 10 Center Dr, 10/2B07, Bethesda, MD 20892-1502; e-mail: Richard_Alexander{at}nih.gov.
Purpose: Malignant mesothelioma (MM) arising in the peritoneal cavity is a rare neoplasm characterized by peritoneal progression and for which there are limited therapeutic options. We evaluated the peritoneal progression-free and overall survival (PFS and OS, respectively) for patients with peritoneal MM after surgical resection and regional chemotherapy. Patients and Methods: Forty-nine patients (28 males, 21 females; median age, 47 years; range, 16 to 76 years) with MM underwent laparotomy, tumor resection, continuous hyperthermic peritoneal perfusion with cisplatin (median dose 250 mg/m2), and a single postoperative intraperitoneal dwell of fluorouracil and paclitaxel (n = 35) on protocols approved by the Institutional Review Board. Standard techniques for actuarial analyses of potential prognostic variables (Kaplan-Meier method with two-tailed log-rank test and Cox proportional hazards model) were performed. Results: At a median potential follow-up of 28.3 months, median actuarial PFS is 17 months and actuarial OS is 92 months. Factors associated with improved PFS and OS by the Cox proportional hazards model were a history of previous debulking surgery, absence of deep tissue invasion, minimal residual disease after surgical resection (OS only), and age younger than 60 years (OS only). Conclusion: Surgical resection and regional chemotherapy for MM results in durable PFS and OS. Favorable outcome is associated with age, tumor biology (selection of patients with a history of previous debulking), lack of invasive tumor growth, and minimal residual disease after tumor resection.
MESOTHELIOMA IS a rare primary tumor of the serosal membranes with a generally poor prognosis and an annual incidence in the United States of about 2.2 per million per year.1 Patients with primary peritoneal mesothelioma most commonly present with abdominal pain, increasing abdominal girth, weight loss, abdominal mass, and/or ascites.2–4 Disease is usually confined to the abdominal cavity until late stages of tumor progression, and death is almost always related to tumor progression in the peritoneum.5 Pathologically, the tumor arises from mesothelial cells lining the peritoneal cavity and can show a spectrum of histologic appearances, ranging from well-differentiated adenomatoid forms to poorly differentiated sarcomatoid variants.6 There have been no uniformly accepted treatment approaches for patients with malignant peritoneal mesothelioma. Systemic chemotherapy has historically had limited efficacy,7 although recent data using an outpatient regimen of combination raltitrexed and oxaliplatin have shown a 20% partial response rate and reasonable palliative benefit in patients with pleural or peritoneal mesothelioma.8 On the basis of the natural history of the disease, however, regional therapies designed to control disease progression in the peritoneal cavity seem justified and have the theoretical advantage of intensifying treatment to the site of active disease while limiting unnecessary systemic toxicity.9 A pharmacokinetic advantage of intraperitoneal chemotherapy or cytokine therapy for patients with malignant peritoneal mesothelioma has been reported by us and others.10–12 A variety of regional modalities alone or in combination, including cytoreductive surgery, whole abdominal radiation, and intraperitoneal chemotherapy administered as a dwell or a continuous intraoperative hyperthermic perfusion, has been reported in patients with peritoneal mesothelioma.4,13–19 Median survival time ranging from 5 to 34 months have been observed and seem to be influenced by the extent of disease at presentation, ability to surgically resect gross disease, sex, or intensity of treatment.4,13–15 We previously reported an 80% 2-year survival rate in 18 patients undergoing operative tumor resection and continuous hyperthermic peritoneal perfusion (CHPP) for primary peritoneal mesothelioma who were treated while enrolled onto initial phase I or II studies.2 The purpose of this report is to provide a detailed analysis of a larger cohort of 48 patients treated with surgical resection and CHPP using the maximum-tolerated dose of cisplatin on the basis of earlier investigation combined with a single postoperative intraperitoneal dwell of fluorouracil (FU) and paclitaxel. We evaluated various clinicopathologic parameters that might aid in patient selection for this type of therapy and predict outcome in this patient population.
Patients This study reviews data from 49 patients (18 of whom were the subjects of an earlier report2) with histologically proven peritoneal mesothelioma who underwent tumor debulking and CHPP on clinical protocols approved by the Institutional Review Board at the National Cancer Institute (Bethesda, MD) from September 1993 through June 2002. The nature of the treatment for the 49 patients included in this report was based on the design of the protocol in which they were enrolled and included laparotomy and tumor resection or debulking in all patients, CHPP with cisplatin in 14 patients, and CHPP with cisplatin followed by intraperitoneal chemotherapy in 35 patients. Informed consent was obtained from all patients. Additional eligibility criteria were Eastern Cooperative Oncology Group performance status  2; no comorbid diseases; a life expectancy  8 weeks; adequate renal function (serum creatinine < 2.0 or 24-hour creatinine clearance 75 mL/min); normal hepatic function (normal bilirubin level, prothrombin time, and partial thromboplastin time, and liver enzymes < 1.5 x normal); adequate hematopoietic parameters (WBC > 3,000/mL and platelet count > 75,000/mL); no chemotherapy, radiotherapy, or immunotherapy in the 30 days before treatment; and no evidence of extra-abdominal metastases.
CHPP Technique Thirty-five patients were treated on a protocol that included chemotherapy given as a single intraperitoneal dose between 7 and 10 days after the operation of FU 800 mg/m2 and paclitaxel 125 mg/m2, each diluted in 1 L normal saline and administered sequentially over 2 to 4 hours. All patients received 100 mg hydrocortisone, 50 mg diphenhydramine, and 50 mg ranitidine intravenously 30 minutes prior to treatment.
On-Study and Follow-Up Evaluation
Histologic Categorization of Tumors Independent of histologic type, tumors were classified according to the presence or absence of deep tissue invasion and desmoplasia. Deep tissue invasion was defined as invasion of tumor more than 0.5 mm from a defined mesothelial surface. As described previously,23 desmoplasia was defined as the presence of dense fibrous stroma within the tumor; these fibrous areas could be nondescript in appearance, or have more distinctive patterns, such as branching collagenous bands, whorls or complex meshworks, or a dense, basket-weave pattern. Immunohistochemical stains for p53, p27, and Ki-67 were performed on 5-µm sections from representative paraffin blocks of the tumor specimens. Adequate material for the performance of immunostaining was available for 38 (81%) of the 47 patients. Staining was carried out with adequate positive and negative controls as previously described24 with minor modifications, using the p27 monoclonal antibody Kip-1 (dilution 1:250; Transduction Laboratories, Lexington, KY), the p53 monoclonal antibody DO7 (dilution 1:50; DAKO, Carpinteria, CA), and the Ki-67 antibody MIB-1 (dilution 1:100; Immunotech, Westbrook, ME) on an automated immunostainer (Ventana Medical Systems Inc, Tucson, AZ). Antigen retrieval was carried out using 10 mmol citrate at pH 6.0 with 0.1% Tween 20. Stains were scored by a single investigator (A.L.F.) for each antibody. The percentage of positive tumor cells was determined using a counting grid and based on a minimum of 500 cells.
Statistical Analysis
Patient demographic and clinical data are shown in Table 1  . The median age was 47 years, with a slight male preponderance. Only 16% of patients had received previous systemic chemotherapy, whereas almost half had undergone previous debulking surgery. Almost two-thirds of patients had histologically high-grade tumors (epithelioid or sarcomatoid). The operative and perfusion data are shown in Table 2. The extent of surgery was dependent on the nature of the operative findings; the overall goal was to render an individual free of gross disease. At a minimum, individuals underwent complete lysis of adhesions to promote complete and even distribution of the perfusate to the peritoneal surfaces during CHPP. Most individuals had additional procedures including omentectomy in half of the patients (25 of 49 patients) and additional organ resection in approximately one third of the patients (14 of 49 patients). Peritonectomy was performed for grossly involved areas of peritoneum as described.28,29 The operating surgeon quantitated RD status after surgery; 10% of patients had complete resection of gross disease (RD 0) and one third of the patients had fewer than 100 tumor implants all less than 5 mm in diameter (RD 1). Almost half of the patients had small volume diffuse disease in situ at the end of the procedure (> 100 small tumor implants or any one greater than 5 mm in diameter, RD 2) and just more than 10% had at least a solitary residual tumor implant greater than 1 cm in diameter (RD 3).
The mean total cisplatin dose was 450 mg (250 mg/m2 of ideal body weight). The cisplatin was added to the circuit once stable circulation of the perfusate had been achieved and the average intraperitoneal temperature had generally reached 41°C. The total volume of perfusate was generally kept to about 4 L, but in some circumstances up to 6 L was used. Thirty-five patients (72%) were also treated with a single postoperative intraperitoneal dwell of FU and paclitaxel. The mean total doses were based on doses of 800 and 125 mg/m2, respectively.
Pathologic material was available from 47 of 49 patients (96%). Of the 47 tumors, one (2%) was adenomatoid, 16 (34%) were tubulopapillary, 26 (55%) were solid-epithelioid, and four (9%) were sarcomatoid. Morphology of these subtypes was similar to that described previously.30–32 The adenomatoid tumor consisted of glandular formations of flattened epithelial cells in a lacy, vacuolated configuration (features shared with microcystic mesothelioma). Tubulopapillary tumors (Fig 1A
On the basis of the small numbers of adenomatoid and sarcomatoid tumors, two groups were distinguished for the purpose of statistical analyses: low grade (adenomatoid and tubulopapillary, 42%) and high grade (solid-epithelioid and sarcomatoid, 58%). Deep invasion was present in 22 of 38 evaluated tumors (58%) and desmoplasia was present in 16 of 38 tumors (42%). Although most low-grade tumors in this series were tubulopapillary without evidence of deep tissue invasion or desmoplasia (Fig 1A  and 1B), some low-grade lesions did show features of invasion and/or desmoplasia (Fig 1C). Most high-grade tumors were epithelioid, showing invasion and/or desmoplasia (Fig 1D and 1E). Sarcomatoid tumors were rare (Fig 1F). Forty tumors were analyzed immunohistochemically. Mean scores (percentage of positive tumor cells) were 9.8% (range, 1% to 73%) for MIB-1, 90.2% (range, 41% to 99%) for p27, and 8.0% (range, 0% to 60%) for p53 (including five tumors that were completely negative).
There were 18 complications in 12 patients (25%) related to the operative procedure (Table 3
At a median potential follow-up of 28.3 months (range, 1 to 106 months), the median actuarial PFS and OS were 17 and 92 months, respectively; the 1- through 5-year estimates of PFS and OS are shown in Table 5 . Twenty-six of 49 patients (53%) had symptomatic ascites preoperatively. After tumor resection and intraperitoneal therapy, ascites was completely resolved in 15 of 26 patients (58%) and those 15 patients had complete resolution for a median duration, determined actuarially, of 25.3 months (range, 4 to 53+ months; Fig 2). Notably, RD status in 11 of 15 patients who experienced resolution of ascites was RD 2, suggesting that complete tumor resection in this subset was not the explanation, and that CHPP with or without postoperative intraperitoneal therapy may provide palliative benefit even in those with gross RD.
An analysis was performed to identify prognostic factors associated with PFS and OS. The results of the initial univariate analysis of factors associated with either PFS or OS are shown in Table 6 . For continuously measured variables the nature of the pooling for the univariate analyses is shown. In view of the large number of factors evaluated, as shown in Table 6, without formal adjustments for the number of factors evaluated and the exploratory nature of the evaluation, only small P values (< .01) should be interpreted as indicating statistically significant factors from the univariate analysis, whereas P values between .01 and .05 would suggest strong trends. RD was coded as defined in Table 2. On the basis of the results presented in Table 6, the following variables were initially evaluated in the Cox regression analysis of PFS: race, age, tumor grade, p27% (percentage of tumor cells with positive staining), deep invasion, previous debulking, and RD status. A backward selection process indicated that no history of previous debulking surgery and the presence of deep invasion were simultaneously important independent adverse prognostic variables with respect to PFS (Table 7). For OS, the following variables were initially evaluated in the Cox regression analysis: sex, age, grade, deep invasion, previous debulking surgery, RD, and duration of illness. The final model included age older than 60 years, no history of previous debulking surgery, the presence of deep invasion, and the presence of RD nodules larger than 1 cm as important independent adverse prognostic variables associated with a greater risk of death. Table 7 shows the parameter estimates, P values, and hazard ratios for these variables. Kaplan-Meier actuarial OS curves based on the presence or absence of the independent adverse prognostic parameters are shown in Fig 3.
Malignant mesothelioma is a rare but lethal neoplasm; only approximately 10% to 15% of patients with mesothelioma have a primary peritoneal condition.33 Usually it is considered fatal, with median survival durations in some series of untreated patients ranging from 6 to 10 months.34 However, it does have a variable biology, with some patients surviving for many years after treatment.15,35 Others4,18–20 and our group2,12,20 have reported results using intraoperative and early postoperative chemotherapy via CHPP after tumor resection for patients with this condition.20 In general, treatment strategies using surgical debulking and intraperitoneal chemotherapy have been associated with median OS between 5 and 34 months.4,13–15 The median PFS and OS of 17 and 92 months in this study, respectively, suggest efficacy associated with this type of combined therapy for selected patients with malignant peritoneal mesothelioma, although the relative contribution of the different components of treatment is not known. A number of parameters have been associated with favorable outcome in malignant pleural or peritoneal mesothelioma, including performance status, female sex, early stage at presentation, and younger age.15,33,35 Histology has been associated with outcome of peritoneal mesothelioma in some series.6,33 Attempts at developing a histologic grading system have been hampered by small sample size and inclusion of patients with peritoneal mesothelioma into series of patients with pleural mesothelioma.1,7,33,36,37 In this study, we evaluated various clinical, treatment, and pathologic characteristics with respect to their association with PFS and OS for patients undergoing a combined treatment program consisting of tumor resection, CHPP, and intraperitoneal chemotherapy. We used histologic morphology to categorize tumors into a two-tiered grading system (high or low grade). The majority (94%) of low-grade tumors demonstrated tubulopapillary histology, whereas the majority of high-grade tumors (87%) demonstrated epithelioid histology. Stromal invasion is a well-characterized marker of malignancy in mesothelial proliferation,30 and in the setting of CHPP may relate to the ability to perform adequate surgical debulking. The presence of desmoplasia also has been considered an indicator of malignancy in mesothelial proliferation,30 and desmoplastic pleural mesotheliomas have been reported to behave more aggressively than nondesmoplastic tumors.23 The immunohistochemical detection of proliferation markers (such as MIB-1) and tumor suppressor gene products such as p5338 have had important clinical and prognostic significance in a variety of human cancers. p53 is a human nuclear protein with tumor suppressor function that may be lost when mutations occur. Several studies have suggested an association between p53 mutations or overexpression and pleural malignant mesothelioma.39–41 p27 (also known as p27kip1) is a kinase inhibitor protein with cell cycle regulatory and putative tumor suppressor functions.42 Recent studies have demonstrated a survival advantage for patients with pleural malignant mesothelioma who demonstrated high p27 immunoreactivity, as well as for those with a low proliferative index on the basis of MIB-1 staining.43,44 These data prompted us to evaluate the potential prognostic significance of these markers in peritoneal mesothelioma. Among the histologic features evaluated, histologic grade and extent of invasion were associated with statistically significant survival differences in the univariate analysis. In the Cox model analysis, only the presence of deep invasion was identified as an independent predictor of both PFS and OS. Thus, the presence of deep invasion has prognostic implications beyond limiting the extent of resection, suggesting possible biologic differences in those tumors with the ability to invade deeply. Invasion was a stronger independent prognostic variable than morphologic subtype, and no additional prognostic information was gained by evaluating the presence of desmoplasia or immunohistochemical staining with the markers employed. Minimal RD after surgical resection was an independent predictor of improved OS and may have related to some degree to pretreatment tumor burden, which was not quantitated in this study. Patients were selected for treatment on the basis of CT scans showing disease that was estimated to be debulkable to at least minimal RD. Some bias toward better outcome may have been introduced by not treating those patients who had advanced tumor burden. To that end, Sebbag and Sugarbaker45 showed that pretreatment advanced tumor burden, expressed as the Peritoneal Cancer Index, was found to be predictive of shortened survival in patients undergoing subsequent surgical debulking and intraoperative hyperthermic chemotherapy. The median survival of six patients in this study with RD 3 (tumors > 1 cm) was only 12 months, suggesting that alternative treatment strategies must be considered in this high-risk group. The association between advancing age and shortened survival has been observed previously for patients with peritoneal mesothelioma15 and the exact reasons for this are not clear. Patients who had a history of previous debulking surgery had an improved PFS and OS and this may have been related to a more indolent biologic behavior of the tumor. There might have been a tendency to offer patients a second procedure if they had a durable PFS after an initial operation. Selection bias, treatment effect, or a combination of the two may have influenced outcome in this group. On a broader plane the most pressing issue related to surgical debulking and intraoperative or early postoperative intraperitoneal chemotherapy for patients with peritoneal surface malignancies relates to the lack of standardized criteria for patient selection, staging, operative, and treatment procedures among centers offering this type of treatment. Efficacy and outcome may be related to any one or more of these parameters and yet the extent of peritonectomy; the optimal type, doses, and duration of chemotherapy; the amount of tissue hyperthermia; and even technique of peritoneal perfusion are not consistent among centers. Some consensus on these issues and the conduct of multicenter trials will serve to advance meaningfully the use of this form of combined therapy for patients with this condition. Factors such as age, history of previous debulking surgery, presence of deep tissue invasion, and RD status will be potentially important stratification parameters for patients with peritoneal mesothelioma.
The authors indicated no potential conflicts of interest.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
