1 48 Peritoneal Mesothelioma: The Columbia Experience Jennifer A. Wagmiller, Mary-Louise Keohan, John A. Chabot, Karen Fountain, Mary Hesdorffer, and Robert N. Taub Malignant peritoneal mesothelioma is a rare malignancy, comprising about one fifth of the 2500 cases of mesothelioma diagnosed in the United States each year (1). Though long-term spontaneous remissions have been reported (2,3), survival without treatment is typically less than 1 year. Treatment regimens employing only single modalities such as systemic chemotherapy, surgery, or intraperitoneal chemotherapy have not improved survival. Over the past 30 years, increasingly aggressive multimodality regimens have been developed that appear to have enhanced survival in selected patients. Given the rarity of this malignancy, the numbers of treated patients are small, and, until recently, prospective clinical trials of consistently used structured treatment regimens had not been carried out. At the Columbia University Mesothelioma Center, our intent has been to combine as many as possible of the most effective drugs, surgical techniques, and radiotherapy into a structured, highly intense and aggressive multimodality treatment protocol for malignant peritoneal mesothelioma. In two clinical trials that enrolled patients from 1997 to 2002, patients underwent initial cytoreductive surgery followed by normothermic and hyperthermic intraperitoneal chemotherapy, intraperitoneal gamma-interferon, second-look laparotomy, and total abdominal radiation, with encouraging results. Peritoneal Mesothelioma Background Peritoneal mesothelioma is associated with documented asbestos exposure, but less frequently than with pleural mesothelioma (15 30% vs %) and these patients often have a history of higher asbestos exposure and are younger than those with pleural mesothelioma (4). Apart from asbestos, there is evidence that chronic peritonitis, such as that seen in familial Mediterranean fever (5), and radiation (6) may predispose to peritoneal mesothelioma. Infection with the DNA tumor simian virus 40 (SV40) may as well be a risk factor for the development of mesothelioma (7), though it has been difficult to definitively establish this relationship in laboratory studies. 723
2 724 Chapter 48 Peritoneal Mesothelioma: The Columbia Experience The tumors arise from the serosal surface of the peritoneal cavity, and, just as in the pleural type (7), may be of epithelial, sarcomatous, or mixed epithelial-sarcomatous histology, sarcomatous having the worst prognosis. Rationale for Local/Regional Therapy: Debulking, Radiation, and Intraperitoneal Chemotherapy The natural history of peritoneal mesothelioma suggests that intensive local/regional treatment would be advantageous. Mesothelioma usually stays confined to the abdominal cavity, although it can extend into the pleural space or metastasize to mediastinal or other distant nodes. The epithelial variant ordinarily does not invade solid organs, but can infiltrate into the omentum, causing caking. Typically there are multiple sites of cancer on the peritoneum at presentation, but the extent of disease can vary. In patients who present with significant ascites, the fluid spreads the mesothelioma cells throughout the peritoneal cavity, causing all surfaces to be exposed (8). In the pain predominant clinical presentation (often a manifestation of sarcomatoid mesothelioma), a limited number of sites are common, with organ invasion and nerve infiltration, but distant metastases are rare. In either case, a rationale exists for debulking surgery, and possibly for total abdominal radiation. Peritoneal mesothelioma is known to be responsive to intracavitary chemotherapy. Intraperitoneal chemotherapy allows much higher levels of drug to be directed to the malignancy, while limiting the amount systemically absorbed and its toxicity. Although intraperitoneal chemotherapy has been administered as a prelude to debulking surgery (1), if massive disease is present it may not be optimal. Studies with several agents, including methotrexate, doxorubicin, 5- fluorouracil, and cisplatin, indicate that cytotoxic levels of drug penetrate tumor nodules to a depth of only 1 to 3mm (9); thus, tumor nodules larger than 1.5cm would be reduced in volume by less than one log. This suggests that intraperitoneal chemotherapy might best be applied in patients already debulked by surgery and with only small lesions (0.6 cm or less). Novel Therapies for Peritoneal Mesothelioma With refinements in intracavitary chemotherapy for pleural mesothelioma and for gastrointestinal and ovarian abdominal carcinomatosis, techniques used in their treatment have been tried in peritoneal mesothelioma. Hyperthermic Intraperitoneal Chemotherapy Since the 1980s, hyperthermic intraperitoneal chemotherapy has been attempted with multiple agents such as doxorubicin, cisplatin, gemcitabine, mitomycin C, and tumor necrosis factor (TNF), in the treat-
3 ment of ovarian, gastric, and colorectal cancers, sarcoma, and peritoneal mesothelioma. The exact mechanism by which hyperthermic chemotherapy works is not understood, whether by direct effects on cells or by enhancement of drug activity. Such studies are not definitive, but support the use of hyperthermic chemotherapy, on the basis of demonstrated effectiveness and acceptable morbidity and mortality data (10,11). J.A. Wagmiller et al 725 Immunomodulator Therapy Intracavitary immunotherapy has been given to pleural mesothelioma patients with early studies suggesting safety and antitumor activity. Eighty-nine patients with early-stage pleural mesothelioma were treated with intrapleural recombinant gamma-interferon (12). Eight patients were demonstrated to have a complete pathologic response and nine to have partial responses. However, in the stage 1 patients, the overall response rate was higher, with 45% of patients showing a response. Toxicities included hyperthermia, liver toxicity, neutropenia, and catheter-related infection (12). Intrapleural interleukin-2 also showed activity and a tolerable side effect profile in a phase II mesothelioma study of 22 patients, 11 with partial response and one with complete response (13). Multimodality Treatment of Peritoneal Mesothelioma Using Cytoreductive Surgery and Intraperitoneal Chemotherapy Several U.S. centers have recently published the results of their experience with treatment of malignant peritoneal mesothelioma using cytoreductive surgery with intraperitoneal chemotherapy. In addition to variability in patient selection, surgical technique, and choice and timing of chemotherapy, different combinations of preoperative or postoperative hyperthermic intraperitoneal chemotherapy, systemic chemotherapy, abdominal radiation, and re-laparotomy, were employed. The earliest published study of aggressive multimodality therapy described six patients with nonbulky peritoneal mesothelioma who were treated with cytoreductive surgery, intraperitoneal doxorubicin, and cisplatin, some of whom were also given systemic chemotherapy followed by whole abdominal radiation (14). In the first report of these patients, all were alive with no evidence of disease at 9 to 34 months. In a later report, 25% of a larger series of patients were alive at 5 years (15), and at least one lived ~20 years when he died of lung adenocarcinoma with no evidence of persistent mesothelioma. Cytoreductive surgery immediately followed by heated intraperitoneal chemotherapy with mitomycin was used to treat 12 patients between 1992 and 2001, with a reported 33% 5-year survival, and median survival of 34 months (16).
4 726 Chapter 48 Peritoneal Mesothelioma: The Columbia Experience The investigators at the Washington Cancer Institute reported a series of 51 patients treated between 1987 and 2002 (1). They attempted to treat all patients with cytoreductive surgery with hyperthermic intraperitoneal chemotherapy immediately following the debulking. Nine patients with massive ascites had intraperitoneal cisplatin and doxorubicin prior to the initial cytoreductive surgery. The last 18 patients were also eligible to receive a course of normothermic intraperitoneal chemotherapy. In 11 patients, a second-look surgery was done, and in three, a third look. The median survival reported was 50 to 60 months. While direct comparisons of these regimens are not possible due to study design and length of follow-up, the overall picture is that in these selected patient populations, the aggressive multimodality treatments have extended median survival to at least 19 months. In addition to the survival gains, symptomatic improvement, such as ascites control, was regularly achieved by these aggressive treatments. In planning our own studies, it remained unclear how to optimally combine these interventions to prolong patient survival while minimizing side effects. One variable among the different series is the timing of the hyperthermic intraperitoneal chemotherapy, which was performed either immediately after the first cytoreductive surgery, or was delayed until second-look surgery/repeat debulking. Another consideration is that recent series did not utilize whole abdominal radiation therapy, although this was integral to the initial Boston multimodality trials. Our philosophy has been to initially maximize intensity of treatment and number of modalities administered in an attempt to improve upon current poor survival figures, with a view toward eliminating unnecessary elements of treatment in successive studies. The Columbia University Experience Patients Forty patients have been enrolled in two consecutive phase I/II studies at Columbia Presbyterian Medical Center between 1997 and Both protocols were reviewed and approved by the institutional review board. To be eligible, patients must have had histologically confirmed malignant mesothelioma. They were permitted to have had limited chemotherapy and surgery for the disease prior to enrollment (zero to two chemotherapy regimens, but at least 6 weeks must have elapsed since chemotherapy; prior surgical resection preceding disease recurrence was acceptable, but at least 1 week must have elapsed since surgery). Patients who had had prior abdominal or lower chest radiation therapy were ineligible. Pregnant or lactating females were excluded. Patients were required to have a life expectancy of at least 2 months, be over 18 years of age, and have a SWOG performance status of 0 to 2. Patients were required to have adequate hematologic, renal, and hepatic function (white blood cell count of >3000/mL, platelet count of >100,000/mL, blood urea nitrogen (BUN) <1.5 normal, calculated creatinine clearance of 45 ml/min, bilirubin <1.5 normal).
5 Patients with a history of malignancy within the past 5 years other than curatively treated carcinoma in situ of the cervix or skin cancer were ineligible. Additionally, patients could not have a serious medical or psychiatric condition that would prevent intensive treatment. J.A. Wagmiller et al 727 Treatment Cytoreduction All patients underwent exploratory laparotomy through a midline vertical incision, with total omentectomy and excision of all gross peritoneal, retroperitoneal, and pelvic disease. The surgeon attempted to remove all nodules of >1cm diameter. Peritoneal catheters were placed bilaterally and tunneled through the abdominal wall to prevent leakage of the intraperitoneal chemotherapy. Parenchymal organs were not ordinarily removed as part of the surgery, except for resection of segments of ileum or colon judged to be involved by invasive tumor. If debulking resection was not possible without organ removal, the patient was dropped from the protocol. Normothermic Intraperitoneal Chemotherapy Three to 4 weeks following surgery, intraperitoneal therapy was initiated. In the first trial, patients received four courses each of intraperitoneal cisplatin (100mg/m 2 ) alternating with doxorubicin (25mg) weekly, followed by four weekly courses of gamma-interferon (9 million units initial dose, followed by 30 million units weekly for three doses) (17). In the second trial, patients continued to receive doxorubicin (25mg, weeks 1, 4, 7, 10) but the cisplatin was given in combination with gemcitabine (cisplatin 50mg/m 2 plus gemcitabine 100mg/m 2 ; weeks 2, 5, 8, 11) and followed by gamma-interferon (300mg week 13, 1000mg weeks 14, 15, 16). Second-Look Surgery and Hyperthermic Intraperitoneal Chemotherapy Two to 4 weeks after the last dose of gamma-interferon, the patients underwent second-look surgical exploration of the abdomen and pelvis. If no gross disease was seen (no nodules >1cm), multiple biopsies were obtained and hyperthermic intraperitoneal chemotherapy was given. A recirculating perfusion circuit with a roller pump heat exchanger connected to suprahepatic inflow and pelvic outflow catheters was employed to administer the hyperthermic intraperitoneal chemotherapy while the patient was still under general anesthesia (18). In the first protocol, patients received mitomycin 10mg/m 2 and cisplatin 100mg/m 2 in 2L normal saline at 40.5 to 42.5 C infused over 90 minutes. In the second protocol, the dose of cisplatin was reduced to 75mg/m 2. Cisplatin was not given if the creatinine clearance was less than 45 ml/min. If technically resectable disease, gross disease (nodules >1 cm) was found, intraoperative hyperthermic chemotherapy was given as described above. Patients with technically unresectable disease were taken off protocol and considered for systemic chemotherapy.
6 728 Chapter 48 Peritoneal Mesothelioma: The Columbia Experience Radiation Therapy Two to 4 weeks following surgery, all patients except those with unresectable residual disease, began a course of radiation therapy lasting 5 to 7 weeks. All fields were treated each day with blocks over the lower portion of the heart and femoral heads and associated soft tissue of the pelvis. Treatment breaks were given for white blood cell counts of less than 1500 or platelets of less than 75,000, or for intractable nausea and vomiting. For patients who had not received the full course of intraperitoneal chemotherapy, a 67% transmission block was used to attenuate the dose given to the abdomen above a line drawn through the L5-S1 interspace. They were given daily fractions of 120 cgy in the upper abdomen and 180cGy in the pelvis (prescribed to the central axis) five times weekly to parallel and opposed anteroposterior (AP) to posteroanterior (PA) portals, utilizing a 6-MV photon beam. After 1800 cgy, full-thickness AP and PA kidney blocks were added. These patients were treated to a total dose of 3000cGy to the upper abdomen and 4500cGy to the pelvis. With patients who did receive the full course of intraperitoneal chemotherapy, patient transmission blocks were not used. The upper abdomen and pelvis were treated uniformly at the rate of 100 to 150cGy per fraction. Kidney blocks were added after 1400 to 1550cGy to both the anterior and posterior portals. They were treated to a total dose of 3000 to 3080cGy to the upper abdomen and 4500cGy to the pelvis. Results and Discussion Twenty-seven patients were enrolled in the first protocol between 1997 and 2000, 23 with the epithelial subtype and four with sarcomatous or mixed (sarcomatous-epithelial) disease (Table 48.1). At this time, median survival for the entire cohort has not been reached (Table 48.2). Table Tobacco and asbestos exposure in 27 patients with peritoneal mesothelioma treated at Columbia-Presbyterian Medical Center Median age at enrollment 51 years Gender Female 7 patients Male 20 patients Asbestos exposure Yes 18 patients No 9 patients Tobacco history Yes 17 patients No 10 patients Status No evidence of disease 10 patients Alive with disease 6 patients Died of disease 11 patients
7 J.A. Wagmiller et al 729 Table Outcome of patients treated with trimodal regimen Subtype of Number of mesothelioma patients NED AWD DOD Epithelial patients 6 patients 7 patients survival mo survival mo survival 9 42 mo (median 40 mo) (median 42 mo) (median 20 mo) Sarcomatous and 4 0 patients 0 patients 4 patients mixed sarcomatous- survival 1 11 mo epithelial (median 4 mo) NED, no evidence of disease; AWD, alive with disease; DOD, died of disease. Of the 23 with epithelial disease, 10 patients show no evidence of disease after a median >40 months. Six patients had persistent disease at 27 to 62 months (median >42 months). Seven patients succumbed to progressive disease at 9 to 42 months (median 20 months). The four patients with sarcomatoid or mixed disease did not benefit from multimodal treatment; all progressed and succumbed at 1 to 11 months (median 4 months). The Kaplan-Meier survival curve for the cohort is shown in Figure The second trial has enrolled 13 patients and is still accruing; data from that trial are not yet available. Our experience at the Columbia University Mesothelioma Center, as well as that at other centers, suggests that with aggressive multimodality treatment, peritoneal mesothelioma can be a treatable disease, with some patients achieving long-term disease-free survival. Although the initial patients treated in 1984 all had a minimal disease burden, many of our recent patients had extensive omental disease, or significant nodular disease in the pelvis and colic gutters. This would suggest that our results are due only in part to selection of patients by Figure Kaplan-Meier survival curve for 27 patients treated with trimodal protocol by subtype. Note that overall median survival has not been reached.
8 730 Chapter 48 Peritoneal Mesothelioma: The Columbia Experience performance status, histology, and operability, and whose likelihood of survival may have been intrinsically better. A recent report of 25 cases of peritoneal mesothelioma in women suggested that prolonged survival after therapy could not be predicted by histology or extent of disease at presentation (19). Certainly the achievement of the diseasefree state is almost never achieved without active intervention. Our results agree with and extend the observation in malignant pleural mesotheliomas (20) of much poorer outcomes for patients with sarcomatous pathology than for those with primary peritoneal disease. We have recently noted that the microarray gene profiles of these patients differ significantly from those with epithelial disease (21). We have noted that our patients with sarcomatous or mixed histology often presented with bulky disease invading solid organs, which persisted or recurred rapidly after surgery. As additional results from genomic studies and from our second phase II trial become available, we hope to better assess which patients should receive aggressive treatment, and whether abdominal radiation contributes to survival. References 1. Sugarbaker PH, Acherman YI, Gonzalez-Moreno S, et al. Diagnosis and treatment of peritoneal mesothelioma: the Washington Cancer Institute experience. Semin Oncol 2002;29(1): Schwartz E, Maayan C, Mouallem M, Engelberg S, Friedman E. Malignant peritoneal mesothelioma: long-term spontaneous clinical remission. Med Pediatr Oncol 1991;19(4): Norman PE, Whitaker D. Nine-year survival in a case of untreated peritoneal mesothelioma. Med J Aust 1989;150(1): Sebbag G, Sugarbaker PH. Peritoneal mesothelioma proposal for a staging system. Eur J Surg Oncol 2001;27(3): Gentiloni N, Febbraro S, Barone C, et al. Peritoneal mesothelioma in recurrent familial peritonitis. J Clin Gastroenterol 1997;24(4): Antman K, Pass H, Schiff P. Management of mesothelioma. In: DeVita V, Rosenberg S, Hellman S, eds. Cancer: Principles and Practice of Oncology, 6th ed. Philadelphia: Lippincott Williams & Wilkins, Testa J, Pass H, Carbone M. Molecular biology of mesothelioma. In: DeVita V, Rosenberg S, Hellman S, eds. Cancer: Principles and Practice of Oncology, 6th ed. Philadelphia: Lippincott Williams & Wilkins, Sugarbaker PH, Yan H, Grazi RV, Shmookler BM. Early localized peritoneal mesothelioma as an incidental finding at laparoscopy. Report of a case and implications regarding natural history of the disease. Cancer 2000;89(6): Markman M. Intraperitoneal chemotherapy. Crit Rev Oncol Hematol 1999; 31(3): Ceelen WP, Hesse U, de Hemptinne B, Pattyn P. Hyperthermic intraperitoneal chemoperfusion in the treatment of locally advanced intraabdominal cancer. Br J Surg 2000;87(8): Park BJ, Alexander HR, Libutti SK, et al. Treatment of primary peritoneal mesothelioma by continuous hyperthermic peritoneal perfusion (CHPP). Ann Surg Oncol 1999;6(6):
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