Mesothelioma Information

Introduction

The incidence of peritoneal mesotheliomas appears to be increasing in the United States and Europe, and these now account for 25% to 33% of all mesotheliomas. The median age at diagnosis is 60 years, and the male to female ratio is 3:1. There is a clear statistical relationship between mesothelioma and a particularly heavy exposure to airborne asbestos fibers.

Patients with peritoneal mesothelioma most frequently present with increased abdominal girth (49%) from ascites (fluid accumulation), pain (43%), and weight loss (22%). Peritoneal mesothelioma presents as a "pain-predominant" or "ascites-predominant" clinical type, and 14% of patients have concomitant abdominal distention and abdominal pain. Patients with localized abdominal pain usually have a dominant tumor mass (6%) with little or no ascites, and the abdominal mass usually represents a cake of tumor in the omentum. Most patients have had symptoms for six months to two years before the diagnosis. Men can present with an inguinal or umbilical hernia, and women can present with a pelvic mass. Some patients present with a new-onset hernia. Other signs of advanced disease include fever, leukocytosis, and thrombocytosis, and these are associated with a poor prognosis.

Diagnosis of Peritoneal Mesothelioma

Radiography and Tissue Procurement
The workup of the patient with a peritoneal mesothelioma usually includes abdominal ultrasonography, CT of the abdomen, MRI, and, most recently, PET scanning. Definitive diagnosis requires CT-guided core biopsy of tumor masses or infiltrated omentum, paracentesis with cell block for immunohistochemical staining, or, preferably, laparoscopy with biopsy. Ultimately, definitive diagnosis requires adequate tissue sampling, preferably from laparoscopy or an open, directed biopsy. The endoscopic appearance of mesothelioma is indistinguishable from that of metastatic tumors, with nodules, plaques, and masses that involve the parietal and visceral peritoneum. The absence of hepatic parenchymal metastases should alert the physician to the possibility that the pathology is mesothelioma, and careful examination of the ovaries and the bowel to rule out nonmesothelioma neoplasms should be performed.

Peritoneal mesotheliomas must be differentiated from so-called papillary tumors of the peritoneum (also known as well-differentiated papillary mesothelioma or cystic mesotheliomas of the peritoneum) as these tumors have a completely different natural history. Asbestos exposure is much less frequently associated with these neoplasms compared to true abdominal mesotheliomas, and the papillary tumors are predominantly seen in women but can occur in men. The tumor's differential diagnosis from malignant mesothelioma may be based on the lack of immunostaining for keratin 5/6 and calretinin. Although the ability to diagnose cystic mesotheliomas of the peritoneum before or at the time of exploratory laparotomy is limited, there has been advocacy for the avoidance of treatment unless there is evidence of progressive disease. Differential diagnosis from ovarian cancer or true mesothelioma, however, may be possible only after the pathologic examination of the surgically resected ovaries along with the tumor to document that the tumor has minimal or no superficial invasion of the ovarian cortex or through immunohistochemical methods. There have been recent anecdotal reports of an aggressive approach to these tumors either by adding adjuvant platinum-based chemotherapy after resection or primary treatment with cytoreductive surgery and heated chemoperfusion.

Staging and Natural History of Malignant Peritoneal Mesothelioma
There is no staging system for peritoneal mesothelioma, although suggestions have been proposed in the literature. The tumor generally remains confined to the abdomen until late in the course and even then is more likely to spread to one or both pleural cavities than to disseminate hematogenously. Most patients die without metastases or involvement of the chest. Involvement of the serosa overlying the small and large bowel, the liver, the spleen, and other organs leads to encasement of these organs in tumor tissue and repeated bowel obstructions. The median survival of untreated patients is 5 to 12 months.

Treatment
Due to the low response rates of systemic chemotherapy in the disease, novel approaches involving either induction therapy followed by surgery or postoperative intraperitoneal drug delivery after surgical debulking have been explored. Intraperitoneal chemotherapy with a variety of agents, including cisplatinum, mitomycin C, doxorubicin, epidoxorubicin, etoposide, and cytarabine used either singly or in combination, has been reported, with responses up to 50% in small phase II studies. Whole abdominal radiotherapy as an adjunct to intraperitoneal chemotherapy and surgery was first described in ten patients with peritoneal mesothelioma who were treated at the Joint Center for Radiation Therapy between 1968 and 1985. Six of the ten patients remained free of disease at 19+ to 78+ months after diagnosis. Four patients not treated with this multimodality approach died from the disease.

Intraperitoneal Chemotherapy
The use of intraperitoneal chemotherapy for mesothelioma has been extensively reviewed. Intraperitoneal cisplatin and intravenous thiosulfate protection have resulted in a 59% complete response rate. However, many patients have relapsed quickly after treatment, implying incomplete eradication of tumor using cisplatin alone. Intraperitoneal cisplatin in 19 patients (with mitomycin as well in 18) resulted in two (10%) disease-free responses more than 5 years after therapy. Cisplatin and etoposide resulted in one complete response in five patients with measurable disease.

Of four patients receiving cisplatin-based intraperitoneal therapy in a Dutch study, two responded, one completely. At 2 years, he developed intestinal obstruction, and laparotomy revealed only adhesions. A case report noted continuing complete response at 53 months in a patient treated with intraperitoneal cisplatin and cytarabine.

Combined Modality Approachs for Peritoneal Mesothelioma
Combined modality approachs for peritoneal mesothelioma have been studied at several institutions and usually involve surgery with cytoreduction, intraperitoneal chemotherapy, intraoperative treatment with cytotoxic chemotherapy, and postoperative chemotherapy and/or RT. Researchers described the use of surgery, intraperitoneal chemotherapy, and abdominal radiation in four patients. In a retrospective review of 15 women with peritoneal mesothelioma, researchers reported that the response rate to first-line chemotherapy regimens was 30% overall, but 67% to paclitaxel and cisplatin. The median survival of all patients was 12 months. The median survival, however, was longer for patients who underwent cytoreductive surgery versus biopsy only (14 vs. 6 months, P = .24) and chemotherapy versus none (29 vs. 1 month, P = .03).

Three sequential series of patients (1980 to 1982, 1982 to 1985, and 1986 to 1988) were treated at the Dana Farber Cancer Institute and Joint Center for Radiation Therapy. In the initial trial, one of nine patients treated with surgery, intravenous cyclophosphamide, doxorubicin, and dimethyltriazenoimidazole carboxamide (before and after whole abdominal radiotherapy) survived longer than 10 years after diagnosis. On the second phase I trial between 1982 and 1985, 6 of 13 patients having a debulking resection of all lesions of more than 1 cm in size were treated with intraperitoneal doxorubicin (6 to 50 mg/m²) and cisplatin (60 to 100 mg/m²) for a total of 8 to 12 treatments. At the time of the second laparotomy for removal of the access device, all six patients had an objective decrease of at least 50% in the size of the tumor. The complete treatment package of surgical resection and chemotherapy followed by whole abdominal irradiation was completed in four patients. Four of the six patients (including three of the four who received irradiation) remained disease free for at least 36, 48, 60, and 61 months after diagnosis. In the third phase II series, patients were treated with surgical debulking and intraperitoneal cisplatin and doxorubicin every 2 weeks for 20 weeks. Patients with no visible disease at second-look laparotomy received whole abdominal external-beam radiotherapy, and patients found at second-look laparotomy with macroscopic residual disease were treated with intravenous cyclophosphamide and doxorubicin, and then RT. Thirteen patients responded to therapy (seven partially and six completely, although random biopsies were positive in all patients). Three patients with partial responses relapsed at 8, 24, and 25 months. At the time of reporting, all six patients with complete responses had remained in remission from 9 to 30 months (median, 25 months). Toxicity was generally mild; nausea and vomiting occurred secondary to cisplatin, transient elevation in creatinine was as high as 2.4, and mild to moderate hematologic toxicity was reported. Two episodes of small bowel obstructions in responding patients resolved without surgical intervention.

No patient discontinued therapy due to toxicity. In a series of 17 early-stage patients between 1984 and 1999 who underwent cytoreductive surgery followed by five cycles of intraperitoneal doxorubicin (25 mg/m²) and cisplatin (75 mg/m²), 11 patients responded (65%) as assessed by second laparotomy or CT scan and received total abdominal radiation (30 Gy; n = 3), intravenous chemotherapy (n = 3), or both (n = 4); ten patients completed all planned treatment. Toxicity included nausea, fatigue, and myelosuppression. Median survival for this group was 27.6 months (3.6 to 66.0). Eight patients were alive at follow-up of median 24 months (3 to 49 months).

Other investigators have combined hyperthermia to 42°C with chemotherapy at the time of the cytoreduction. Of 18 patients with primary peritoneal mesothelioma who underwent tumor debulking followed by a 90-minute continuous hyperthermic peritoneal profusion with cisplatin as part of three consecutive phase I trials conducted at the National Cancer Institute, 13 had associated ascites. Nine of ten patients had resolution of their ascites postoperatively. Three patients with recurrent ascites at 10, 22, and 27 months after initial treatment had resolution of their ascites with ongoing responses at 4, 6, and 24 months after the second perfusion. The median progression-free survival is 26 months, and the overall 2-year survival is 80% at early follow-up. In another series, 12 patients underwent exploratory laparotomy with cytoreduction followed by a 2-hour hyperthermic chemoperfusion using mitomycin C. One patient died 50 days postoperatively from complications relating to small bowel perforation. Ascites was controlled in all patients and permanently in 86% of patients presenting with ascites. To date, median survival is 34.2 months, with median follow-up of 45.2 months; however, long-term follow-up is lacking, and whether any of these patients had cystic mesothelioma must be determined. Dr. Sugarbaker’s series of 51 patients reports an encouraging median survival of 50 to 60 months using cytoreduction and heating chemotherapy with adriamycin and cisplatinum followed by paclitaxel. Further delineation of the histology of the patients is needed.