Although malignant pleural mesothelioma (MPM) remains a rare tumor, epidemiologic studies confirm the increasing incidence of this malignancy. An estimated 19,000-80,000 new cases are expected between 1980 and 2030. The need for innovative treatment is clear because there are no universally accepted standard treatments for malignant mesothelioma, and the efficacy of current therapies remains disappointing. The median survival for patients with diffuse MPM is 6-16 months.
Data from single-agent as well as combination modality therapies for MPM vary. The reported response rate for doxorubicin ranges from 0% to 40%. Other agents with reported single-agent activity include cyclophosphamide, with a 28% (four of 14) response rate; high-dose methotrexate with rescue, 44% (four of nine); mitomycin-C, 17% (two of 12); 5-fluorouracil, 14% (four of 28); and cisplatinum (CDDP), 10% (five of 49). Response rates for doxorubicin or cisplatinum combination chemotherapy regimens range from 30% to 40% among 10 to 20 patients (in single-institution series) to 0% to 14% (for cooperative group trials) for the same combinations. Overall, the response rate for must-drug trials has not differed significantly from the single-agent regimens.
Recently, there has been an interest in the combination of standard chemotherapeutic drugs with biologic response modifiers for the treatment of solid malignancies. Reports have documented a synergistic antitumor effect with the combination of CDDP and interferon-a in both in vitro and in vivo studies. Synergistic activity in vitro has been reported against ovarian, human myeloma, P388 murine leukemia, HeLa human cervical, and human renal cell cancer lines.
In nude mice tumor xenograft models, synergistic antitumor effects have been displayed against human mesothelioma and non-small-cell lung cancer. Based on these preclinical investigations, which demonstrated a synergistic antitumor effect with CDDP and interferon-a, several phase I and II clinical trials have been undertaken. These trials demonstrated that the maximum tolerated weekly dose of CDDP when combined with 5mU/m� of interferon-a given s.c. three times weekly was 25-30 mg/m�. Objective response rates of 25% were reported in lung cancer melanoma, and other malignancies.
The mechanism of this synergy is unclear and theoretically may be due to a direct antiproliferative action of interferon or upregulation of tumor and major histocompatibility antigens on the surface of tumor cells. Tamoxifen has been demonstrated to augment the efficacy of a CDDP-containing regimen against melanoma..... A combination regimen of cisplatinum, interferon-a, and tamoxifen would incorporate the key interactions of cisplatinum and interferon-a as well as cisplatinum and tamoxifen. Hence, the purpose of this trial was the evaluation of a novel immunochemotherapeutic regimen (CIT) using the biologic response modifier interferon alpha, the nonsteroidal antiestrogen tamoxifen, and the conventional chemotherapeutic agent cisplatinum in the treatment of patients with unresectable primary pleural of metastatic malignant mesothelioma to establish its activity.
In a second series of patients who were felt to be candidates for maximal cytoreductive debulking of their disease, the feasibility of using this regimen as a postoperative adjuvant was investigated. . . . .
DISCUSSION
The ineffectiveness of standard therapies in the treatment of MPM has been frustrating. Supportive care of patients with MPM usually has been associated with median survival periods of 4.2 to 9.1 months, but non-uniform initial staging and lead time bias make these studies notoriously difficult to interpret. It is likewise difficult to compare the results of any phase II chemotherapy program with the results of a supportive care program unless both cohorts can be followed in a randomized or prospective fashion.
The use of an immunotherapy regimen for MPM is not unique. Systemic interleukin-2 (IL-2)-based therapy has been associated with significant toxicity and no responses in a limited number of patients. IL-2 administered intrapleurally resulted in responses in seven of 15 patients, but all the responders had early disease. Administration of interferon produced no responses , and administration of systemic interferon-a alone yielded a partial response rate of 15%.
Based on the results of these previous studies, we designed the CIT to incorporate the elements of a biologic modifier with at least one drug that was thought to be partially active in mesothelioma, i.e., CDDP. The decision to add tamoxifen was empiric, at least for use in MPM, and was mainly influenced by the impressive results seen in melanoma when tamoxifen was combined with other drugs.
The patient population with MPM referred for CIT treatment at our institution certainly did not represent patients with early disease. The majority presented with advanced disease an average of 5 months after diagnosis. The mean volume of disease measured pretreatment was 840 ml, which if compared with a perfectly spherical solid tumor would represent a tumor with a diameter of ~12cm.
Despite the advanced nature of the disease in most of the patients, therapy was well tolerated. A minority of patients required emergent treatment for hydration or interferon fatigue; the majority received the regimen on an outpatient basis, allowing them to carry on their lives in their own communities.
The treatment-related mortality rate, including the 10 patients who underwent surgery and received CIT, was an acceptable 2%. Moreover, we found that it was feasible to deliver the CIT safely within 1-2 months after major debulking surgery without any increase in drug-related morbidity or the need for dose modification. The response rate of 19% is disappointingly low. Nevertheless, it represents the results from a large cohort of patients at a single institution who received the same regimen for mesothelioma compared with other series in the literature. Moreover, the method of tabulating the responses is probably the most stringent in the literature because it was based on total assessment of pleural disease, not on the thickness changes focally in the pleura, which are used to guide response criteria in other studies.
Specific prognostic variables may predict who will have long-term survival with mesothelioma. Various studies have commented on the influence of stage, histologic type, age, performance status, chest pain, symptom duration, sex, race, platelet count, asbestos exposure, and therapy. Our study reinforces that epithelial histology seems to be associated with a longer survival, and all of our responders were of epithelial origin. Moreover, none of our responders had tumors> 1,200 ml, five of seven had platelet counts of <360,000/ml, and four of seven were <60 years of age. Therefore, they seem to fit into a good prognosis category according to the model based on all patients. It is too early to make any definitive conclusions regarding any effect that adjuvant CIT may have after debulking surgery. The only way to test the effect of CIT is to design a phase III trial with careful documentation of disease stage comparing debulking surgery with debulking and postoperative CIT. However, close inspection of the recurrence patterns of our patients receiving postoperative CIT show a continued propensity for local failure. A predominant cause of death in these patients was from local progression or recurrence. Besides systemic therapy, newer methods for increasing local control must be investigated.