Mesothelioma: Treatment and Survival of a Patient Population and Review of the Literature

Mesothelioma: Treatment and Survival of a Patient Population and Review of the Literature JOHN STATHOPOULOS, DIMOSTHENIS ANTONIOU, GEORGE P. STATHOPOULOS, SOTIRIS K. RIGATOS, JOHN DIMITROULIS, JOHN KOUTANDOS, PINELOPI MICHALOPOULOU, ATHANASIOS ATHANASIADES and MARINOS VESLEMES SOLCA Study Group and First Department of Medical Oncology, Errikos Dunant Hospital, Athens, Greece Abstract. Background: Our purpose was to evaluate the survival of patients with pleural and intraperitoneal malignant mesothelioma and, particularly, to estimate the efficacy of chemotherapy as well as radiotherapy and surgery. A review of the literature with respect to these parameters is included. Patients and Methods: Thirty-five patients with malignant mesothelioma (28 with pleural and 7 with intraperitoneal) were enrolled. Twenty-eight patients underwent chemotherapy, 7/35 radiation and 9/35 surgery (2 with pleural and 7 with abdominal disease). Combination chemotherapy included cisplatin-gemcitabine, cisplatin (or carboplatin) with premetrexed and doxorubicin-cyclophosphamide. Results: In 2/28 patients with pleural mesothelioma the tumor was excised and in 7 with intraperitoneal disease, surgical therapy was palliative and there was survival prolongation. Radiotherapy was only palliative. Chemotherapy produced a very low response: 2/28 (7.14%) patients achieved a partial response. The median survival was 17 months, 4-year survival, 24.4% and 5-year survival, 12.12%. No serious toxicity was observed. Conclusion: Malignant mesothelioma of the pleura and intraperitoneum is a slow-growing disease which is indicated by the long survival, despite the failure of chemotherapy, radiation therapy and surgery. Mesothelioma is a distinct entity, recognized as such during the 1960s, until which time it had been differentially misdiagnosed as adenocarcinoma (1, 2). It is a rare disease which has been most commonly detected in some geographical regions due to certain environmental influences. The disease involves the pleura and peritoneum and, in rare cases, other sites. The appearance of groups of Correspondence to: G.P. Stathopoulos, MD, Semitelou 2A, 115 28 Athens, Greece. Tel: + 30-210-7752600, Fax: + 30-210-7251736, e-mail: dr-gps@ath.forthnet.gr Key Words: Mesothelioma, chemotherapy, survival. patients with mesothelioma, who were or had been working in certain occupations, contributed to the definition of the disease (3). The causal relationship between the disease and asbestos in workers in South African mines and, eventually, in other areas, was gradually established (4-7). The differential diagnosis between mesothelioma and lung cancer with pleural effusion was the main difficulty in the past and occasionally still is. The primary site of the disease is mainly the pleura, less commonly the peritoneum and rarely the pericardium. The disease is considered to be malignant but there have been cases classified as benign, which may account for one-third of the diagnosed cases. Some benign conditions, such as fibrous tumor of the pleura and mesothelioma of the atrioventricular node, are not to be confused with malignant mesothelioma. These are histologically and clinically very different benign conditions and the term mesothelioma is a misnomer (8, 9). Apart from the three main mesothelioma locations, other very rare sites are the vagina, testicles, scrotum, sinus and heart ventricles, mediastinum, liver and adrenal glands (9). The discrimination between malignant and benign is pathological. The patient s age is commonly 40-70 years. Benign disease is also characterized as adenomatoid tumor (10). Malignant mesothelioma is considered by some authors to be a highly symptomatic and rapidly progressive malignancy (11). The great majority of the published data is related to mesothelioma of the pleura. Treatment effectiveness is very poor when the disease is inoperable, although there are exceptions to the rule. In the present article, we review the literature and present our experience in a specific patient population. Our objectives were to evaluate the disease, survival and treatment effectiveness. Patients and Methods Patient eligibility was based on histological confirmation of the diagnosis, and all ages of patients and stages of disease were included. Patients had to have bidimensionally measurable or 0250-7005/2005 $2.00+.40 3671

evaluable disease and patients that were eligible for treatment (chemotherapy, surgery or even radiotherapy) had to have a World Health Organisation (WHO) performance status of 0-2 and a life expectancy of at least 3 months. Also, patients were required to have adequate bone marrow reserves (granulocyte count 1,500/dl, platelet count 120,000/dl), normal renal (serum creatinine concentration <1.2 mg/dl) and liver function tests (total serum bilirubin concentration <3 mg/dl, provided that serum transaminases and serum proteins were normal), normal cardiac function with no history of clinically unstable angina pectoris or myocardial infarction, or congestive heart failure within the previous 6 months, and no central nervous system involvement. Patients with active infection, malnutrition or a second primary tumor (except for a non-melanoma skin epithelioma or in situ cervix carcinoma) were excluded. Evaluation of patients. Patient evaluation included complete medical history and physical examination, full blood count including differential leukocyte and platelet counts, a standard biochemical profile (and creatinine clearance when necessary), electrocardiogram, chest X-ray and computed tomography (CT) scans of the chest and upper and lower abdomen. Additional imaging studies were performed upon clinical indication. In patients who underwent chemotherapy, a full blood count with differential was performed weekly. Treatment. The treatment plan was to include surgery, radiation therapy and chemotherapy on the basis of disease location and stage. All patients with abdominal mesothelioma were designated for surgery, although in this location the surgical procedure is mainly of a palliative nature, aiming at cytoreduction. In pleural mesothelioma, surgery should be performed only in earlyoperable stages. Radiation therapy was planned only in inoperable cases of pleural mesothelioma, for pain relief and possible cytoreduction. Pleurodesis with bleomycin or talc was very selectively decided upon for pleural effusion reduction. Chemotherapy does not bring about major response but it has a place, mainly as a palliative treatment, rendering clinical benefit in a percentage of patients. Three different chemotherapy schedules were given: a) cisplatin 80 mg/m 2 combined with gemcitabine 1 g/m 2, repeated every 3 weeks and in some patients (with reasonable bone marrow tolerance) gemcitabine was also given on day 8; b) doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 plus or minus vincristine 1.2 mg/m 2 or vinblastine 6 mg/m 2, every 3 weeks and, c) cisplatin 80 mg/m 2 or carboplatin 6 AUC with premetrexed 500 mg/m 2 every 3 weeks. Two patients received carboplatin 6 AUC and paclitaxel 175 mg/m 2 every 3 weeks. Some patients underwent second-line chemotherapy either with gemcitabine 1 g/m 2 alone or with irinotecan 135 mg/m 2 and oxaliplatin 135 mg/m 2 every 3 weeks. Out of the 35 patients, 9 were treated by surgery either as a firstline treatment or after chemotherapy; 7 of the 9 patients had abdominal mesothelioma and 2 pleural. Seven patients with pleural disease were treated with radiotherapy (30-40 Gy). Two patients had early-stage pleurodesis. Twenty-eight patients were treated with chemotherapy: 12 with cisplatin-gemcitabine, 6 with doxorubicin-cyclophosphamide, 3 with gemcitabine as single-agent chemotherapy, 5 with cisplatin (or carboplatin) combined with premetrexed and 2 patients received irinotecan-oxaliplatin as second-line treatment. Table I. Patients characteristics. Definition of response. Complete response (CR) was defined as the disappearance of all measurable or evaluable disease, signs and symptoms and biochemical changes related to the tumor for at least 4 weeks, during which time no new lesions may appear. Partial response (PR) was defined as >50% reduction in the sum of the products of the perpendicular diameters of all measurable lesions compared with pretreatment measurements, lasting for at least 4 weeks, during which time no new lesions may appear and no existing lesions may enlarge. Stable disease (SD) was defined as <50% reduction or a <25% increase in the sum of the products of the two perpendicular diameters of all measured lesions and the appearance of no new lesions for 8 weeks. Progressive disease (PD) was defined as an increase in the product of the two perpendicular diameters of any measurable lesion by >25% over the size present at entry into the study treatment, or, for patients who responded, the size at the time of maximum regression and the appearance of new areas of malignant disease. A two-step deterioration in performance status, a >10% loss in pretreatment weight or increasing symptoms did not, by themselves, constitute progression of the disease; however, the appearance of these complaints was followed by a new evaluation of the extent of the disease. All responses had to be maintained for at least 4 weeks and be confirmed by an independent panel of radiologists. Statistics. Survival distribution was estimated by the Kaplan-Meier method. Results No. % Patients enrolled 35 100 Age (yr) Median 60 Range 23-74 Gender Male 21 60 Female 14 40 Performance status (WHO) 0 2 5.71 1 22 62.86 2 11 31.43 Disease stage I 2 5.71 II 19 54.29 III 14 40.00 Histology-Mesothelioma Epithelial 33 94.30 Papillary 1 2.90 Fibrosarcomatous 1 2.90 Primary site Pleura 28 80.00 Pericardium (metastasis from pleura) (2) (5.71) Abdomen (omentum) 7 20.00 In this study, the patients, who were of multicenter origin, were enrolled, analyzed and evaluated over the past 8 years; 3672

Stathopoulos et al: Treatment and Survival of Patients with Mesothelioma Figure 1. Kaplan-Meier overall survival. the median follow-up was 4 years, range 1-8 years. The patients characteristics are shown in Table I: median age 60 years (range 23-74 years), WHO performance status of 0, 1 and 2 in 2, 22, and 11 patients, respectively. Twenty-eight patients had primary disease in the pleura and 7 in the abdomen. Two patients had advanced disease in the pericardium and 2, metastases (extension) from the pleura to the abdomen. All patients had histological confirmation of malignant mesothelioma based on biopsy specimens. Twelve patients with pleural disease were cytologically diagnosed. Thirty-three patients had histologically-confirmed malignant mesothelioma of the epithelial type, 1, the fibrosarcomatous type and 1, the papillary type; in 5 patients, the differentiation was high, while in the others, it was low. Compliance with treatment. A total of 168 chemotherapy cycles were administered with a median of 6 cycles per patient (range 2-15). The median interval between cycles was 21 days (range 7-28). Thirty-two cycles (19.05%) were delayed due to either hematological toxicity (20 cycles) or to non-hematological toxicity (asthenia, GI tract toxicity). The median time of delay was 7 days (range 5-14). At the time of analysis, 4 patients were still alive (11.43%) and 31 were dead (88.57%). The cause of death was the disease in 34 patients (97.14%) and acute leukemia (second primary) in 1. Response to treatment and survival. Responses were analyzed on an intention-to-treat basis. Out of 35 patients, 9 underwent surgical treatment; 2 (5.71%) of these patients had a pneumonectomy with complete remission of the disease: 1 patient showed recurrence in 6 months and the other in 3 years. Seven (20%) patients with abdominal disease achieved partial remission and the time to tumor progression (TTP) was median 6 months (range 3-12 months). Of the 7 patients with the tumor in the pleura who had undergone radiotherapy, no complete or partial remission was observed. In 5 out of these 7 patients, there was only clinical benefit (pain relief). Of the 28 patients who had chemotherapy, 2 (7.14%) patients achieved a partial response; 1 of these patients was treated with cisplatin and gemzar and the other with cisplatin and premetrexed. TTP was 6 months for the former patient and 12 months for the latter. Twenty-one/28 (75%) had stable disease and 5/28 had disease progression (17.86%). The median survival was 17 months, range 1-96 months (95% CI 6.5-27.5). Figure 1 shows the overall survival. Toxicity. Chemotherapy treatment was accompanied by acceptable toxicity. Myelotoxicity with grade 3-4 neutropenia was observed in 2 (7.14%) patients, grade 2 anemia in 9 (32.14%) and grade 2 thrombocytopenia in 1 (3.57%) patient. 3673

Review and Discussion From our study of our 35 patients, one could suggest that mesothelioma of either the pleura or the peritoneum is not a rapidly progressive malignancy and this has been reported in the literature (11). Out of 35 patients, only 4 (11.43%) survived from 1-3 months, whereas more than half of the patients survived over a year, and 24.24% and 12.12% survived for 4+ and 5+ years, respectively. A small minority of our patients were treated successfully by surgery, whereas the effectiveness of chemotherapy was almost negligible. Therefore, the extent of survival appears to conform with the natural history of the disease, which permits survival and a reasonable quality of life for some years, despite the failure of chemotherapy and/or radiation therapy. The great majority of studies are related to pleural mesothelioma and very few to the abdominal (intraperitoneal) site of the disease (12). Much data are concerned with the pathogenesis of mesothelioma in relation to asbestos (13-17), even though only in one of our patients was this pathogenic factor confirmed. Although a rare disorder, a higher number of cases of mesothelioma have been reported in certain geographic regions (in contrast to the general population) with factories where asbestos was a dominant factor (13, 17, 18). Mesothelioma is more common in men than women (5:1), usually in the 60-64-year age range (as was the case in our material), although other age groups can be affected (18). Survival varies substantially and median survival is reported to be 4-18 months, as indicated in several reviews. Nonetheless, survival can range from a few weeks up to 16 years, as has been documented (19); this variation concurs with our data. At diagnosis, it is difficult to classify cases that will be more aggressive than others. Highly symptomatic cases are observed particularly when the disease is advanced and it affects certain anatomical sites (11). There are asymptomatic cases, but symptoms such as cough or pain may be intolerable. The thoracic wall may be affected in 10% of cases, as well as the esophagus, ribs, vertebrae, nerves and upper vena cava, with symptoms such as dysphagia, pain and spinal nervous system compression; Horner s or upper vena cava syndrome may be present. Thrombotic events, such as pulmonary emboli or intraarterial coagulation, are some of the most serious complications (20, 21). The treatment of mesothelioma is often disappointing. Surgical management is considered controversial and doubts about curative surgery have been reported. Failure to achieve long survival after surgery and high surgical or postsurgical mortality, as well as the common recurrence of the disease, have created skepticism about surgical treatment (22). In a large series of 183 patients, 66 of whom had surgical excision with disease-free resection margins, the 2- and 5-year survivals were 68% and 46%, respectively (23). The role of radiotherapy in mesothelioma is very limited with only occasional responses observed; it is considered to be palliative therapy with some symptomatic relief, as observed in our study. Up to 50-55 Gy is the suggested dosage, which might also serve for large mass reduction. Survival after radiotherapy is not prolonged. In a randomized study where 52 patients received radiation therapy and 64 remained with best supportive care, it was shown that the 2- year survival was 33% in both arms and the 4-year survival, 0% for those treated and 11% for the non-treated (24). Other data suggest that, when radiotherapy is added to the other treatments (surgery-chemotherapy), the dosage variation or technique does not change effectiveness (25, 26). With the difficulties involved in applying surgery and radiotherapy, patient management is concentrated on chemotherapy with cytotoxic agents. A large number of drugs have been tested with three modes of chemotherapy application: single-agent treatment, the combination of drugs intravenously and intracavitary injection of the agents. Alkylating agents, anthracyclines, vinca alkaloids antimetabolites, taxanes, cisplatinum analogs and campto- thecins are used (9). Responses of 3-18% have been observed with single-agent chemotherapy. It has been reported that doxorubicin, cisplatin and antimetabolites (methotrexate, premetrexed) are the most efficacious (27-30). The combination of cytotoxic agents in some trials has shown responses from 0-48% (9). A high response rate of 48%, in a small number of patients, was produced by the combination of cisplatin and gemcitabine, but this has not been confirmed in other trials. Stable disease and clinical benefit have also been described (31). A quite high response rate (44%) was also documented in another trial where cisplatin was combined with bleomycin, adriamycin and mitomycin-c (32). The combination of cisplatin and doxorubicin has produced a 28% response rate (33). Intracavitary infusion of cytotoxic agents has offered some temporary benefit with a repeated number of infusions. In 47 patients, with the combination of cisplatin and cytarabine, a 49% objective response was reported (34). A pharmacokinetic study of intracavitary infusion showed a higher concentration in the pleural fluid than in the plasma (35). Trials with interferon-á and interleukin-2 have also shown some temporary effectiveness in a small percentage of patients (36, 37). Our data concur with the majority of reported data from other trials with respect to response to treatments and survival. In selective cases, neoadjuvant chemotherapy with cisplatin and gemcitabine, which rendered a response rate of 32%, led to extrapleural pneumonectomy in 16 out of 19 patients (38); the median survival was 23 months. This presurgical treatment may offer hope for a better prognosis in some cases of mesothelioma. The survival of patients with malignant mesothelioma following chemotherapy treatment was documented in a 3674

Stathopoulos et al: Treatment and Survival of Patients with Mesothelioma recent study: the median survival was 7 months and 1- and 2-year survivals were 31% and 11%, respectively. Patients with a PS of 0-1 had a median survival of 10 months (39). Other researchers have reported that the natural history of the disease may involve aggressive local growth invasion of vital mediastinal structures and death within 4-12 months without treatment (40). Long survival with multi-modality treatment (surgery, radiation and chemotherapy) has been reported in selected cases (41). There is, however, a type of malignant mesothelioma which progresses slowly and patients may be asymptomatic for long periods (42). The present study describes a group of patients with malignant mesothelioma, their response to treatment and survival; this tumor is, for the most part, resistant to chemotherapy and radiotherapy. 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