Unresectable Malignant Mesothelioma Research Articles

Activity of chemotherapy and immunotherapy on malignant mesothelioma: a systematic review of the literature with meta-analysis

The role of chemotherapy for unresectable malignant mesothelioma is unclear. The aims of the present study were to evaluate the methodological quality of published papers relative to chemotherapy or immunotherapy in malignant mesothelioma and to aggregate, for trials having a similar methodology, the response rates in order to identify the most active chemotherapeutic drugs and regimens. The literature relative to this topic, published between 1965 and June 2001 was reviewed. A methodological qualitative evaluation was performed according to the European Lung Cancer Working Party scale, specifically designed for phase II trials. A study was considered as potentially positive if the upper limit of the 95% confidence interval (CI) of the response rate was greater than 20% and positive if the lower limit of the 95% CI was >20%. Eighty-three studies (88 treatment arms) were eligible for the systematic review. Fifty-three arms were considered as positive or potentially positive. No statistically significant difference in the methodological quality was observed between negative and positive studies. Studies were aggregated in four groups according to the presence of cisplatin and/or doxorubicin in the treatment regimen. The combination of cisplatin and doxorubicin had the highest response rate (28.5%; P<0.001). Cisplatin was the most active single-agent regimen. Our systematic qualitative and quantitative overview of the literature suggests that the most active chemotherapeutic regimen, in term of objective response rate, is the combination of cisplatin and doxorubicin and the best single-agent is cisplatin. The combination of these two drugs can be recommended as control arm for future randomised phase III trials.

Multicenter randomized controlled trial of the management of unresectable malignant mesothelioma proposed by the British Thoracic Society and the British Medical Research Council

Malignant mesothelioma is almost invariably fatal. The incidence of the disease is rising rapidly in many countries, and there is no generally accepted standard treatment for patients with unresectable disease. According to current British Thoracic Society (BTS) guidelines, patients should be treated with active symptom control (ASC), involving (1) regular follow-up in a specialist clinic; (2) structured assessments of physical, psychological and social problems with appropriate action; (3) rapid involvement of additional specialists; and (4) parallel nursing support. Although many nonrandomized studies have reported tumor responses to anticancer chemotherapy, few have studied palliation and it is not known whetherchemotherapy prolongs survival or provides clinically worthwhile palliation with acceptable toxicity when given in addition to ASC. We therefore plan to conduct a multicenter randomized controlled trial comparing (1) ASC alone, (2) ASC plus mitomycin vinblastine and cisplatin (MVP), and (3) ASC plus vinorelbine (N; Navelbine, Pierre Fabre Oncology, Winchester, UK). We chose these chemotherapy regimens because they have been shown in nonrandomized studies to provide good symptom control as recorded by patients. The outcome measures are overall survival, palliation of symptoms, performance status, analgesic usage, toxicity, quality of life, tumor response, and recurrence/progression-free survival. In a preliminary feasibility study, we are assessing the acceptability of the trial design to patients and the suitability of two standard quality-of-life instruments in mesothelioma. Data will help us to decide the final details of the large multicenter trial. Semin Oncol 29:97-101. Copyright © 2002 by W.B. Saunders Company.

Phase II Trial of a Single Weekly Intravenous Dose of Ranpirnase in Patients With Unresectable Malignant Mesothelioma

PURPOSE: A multicenter phase II trial of ranpirnase (Onconase; Alfacell Corp, Bloomfield, NJ) as a single agent was conducted to further assess the safety and clinical efficacy of this novel antitumor ribonuclease. Patients with unresectable and histologically confirmed malignant mesothelioma (MM) were eligible. PATIENTS AND METHODS: One hundred five patients with Eastern Cooperative Oncology Group performance status 0 to 2 were enrolled onto the study. Thirty-seven percent of patients had not responded to prior chemotherapy. The primary end point of the study was survival. Tumor responses and time to progression were also assessed. The Cancer and Leukemia Group B (CALGB) prognostic group criteria were used to define a treatment target group (TTG). Both the intent-to-treat (ITT) and the TTG populations were analyzed for survival. RESULTS: Median survival times of 6 months for the ITT and 8.3 months for the TTG populations were observed. The 1- and 2-year survival rates were 34.3% and 21.6% for ITT, respectively, and 42% and 26.8% for TTG, respectively. Among the 81 patients assessable for tumor response, four had partial responses, two had minor regressions, and thirty-five experienced stabilization of previously progressive disease. Patients with responses and stable disease demonstrated markedly prolonged survival. Ranpirnase was well tolerated in the majority of patients, and there were no drug-related deaths. CONCLUSION: Ranpirnase demonstrated activity and a tolerable toxicity profile in patients with unresectable MM. The prognostic value of the CALGB groups was confirmed.

Palliative surgical debulking in malignant mesothelioma. Predictors of survival and symptom control.

Malignant mesothelioma (MM) typically presents at an advanced stage. In the UK surgical intervention has been mostly reserved for tissue diagnosis or chemical pleurodesis. However, the role of debulking surgery in symptom control has not been fully explored. In a prospective cohort study, 51 consecutive patients presenting with MM underwent palliative surgical debulking for symptomatic relief (all patients presented with dyspnoea, 39 also had pain and two had a co-existing pleural empyema). Patients with early disease who underwent extrapleural pneumonectomy were excluded. The treatment aims were pleural drainage, lung re-expansion, pleurodesis and pleural debulking for symptom control. If the lung re-expanded after drainage of the effusion a subtotal parietal pleurectomy was performed via Video Assisted Thoracic Surgery (VATS). If the lung remained entrapped, a parietal and visceral decortication using VATS or thoracotomy was performed. The changes in subjective dyspnoea and pain scores were recorded at 6 weeks and 3, 6 and 12 months after surgery. Prognostic factors were analyzed to determine their influence on survival and symptom control. VATS pleurectomy was possible in 17 patients (34%), whilst decortication was required in the remainder (three by VATS and 31 by thoracotomy). Median postoperative stay was 7 days (range 2-17) with 30-day mortality of 7.8% (four of 51 patients). Morbidity included postoperative empyema in two patients (4%) and prolonged air-leak in five (9.8%). Overall significant symptomatic benefit was obtained up to 3 months after surgery but subsequently increasing mortality offset these benefits. Epithelial cell type and absence of weight loss prior to surgery were found to predict longer survival and successful symptom control. Debulking surgery has a beneficial role in symptom control for unresectable MM. However, this surgery should be reserved for those patients who present with epithelial cell type and before significant loss of weight.

Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: Results of a phase II study on 31 consecutive patients

Malignant pleural mesothelioma is often unresectable at diagnosis, is refractory to cytotoxic agents and is frequently complicated by pleural effusion. The expected survival range for patients with or without involvement of visceral pleura is respectively 1–9 and 9–12 months; mesothelioma-related pleural effusion severely impairs the patients’ quality of life and easily relapses after conservative treatments. Intrapleural administration of IL-2 is reported to be effective both in tumor-associated malignant pleurisy and on primary mesothelioma, whereas few data exist about IL-2 systemic administration. In order to assess the palliative and therapeutic activity of IL-2 in unresectable pleural malignant mesothelioma with pleural effusion, we performed a phase II study on 31 consecutive patients (M/F 16/15; median age 61 years, range 40–84; PS ECOG 0 n=7; ECOG 1 n=15; ECOG 2 n=9; stage IA n=13; IB n=9; II n=7; IV=2) who received first-line therapy with intrapleural repeated instillation of 9 000 000 I.U. IL-2 twice/weekly for 4 weeks, after needle thoracenthesis. In nonprogressing patients, 3 000 000 I.U. IL-2 were subcutaneously administered thrice weekly for up to 6 months. Toxicity (WHO criteria) with intrapleural IL-2 consisted of grade 3 fever in 6/31 (19%) patients and of cardiac toxicity (failure) grade 3 in one patient (3%); toxicity during subcutaneous treatment was mild to moderate, mainly a flu-like syndrome. In 28/31 (90%) of patients there was no further or minimal (asymptomatic) pleural fluid collection (according to Paladine criteria); pleurisy relapsed only in 1/28 patients after 19 months. Tumor objective response (WHO criteria), evaluated by CT, occurred in seven patients (one CR and six PR; ORR 22%); ten patients achieved SD and 14 patients progressed. Median overall survival was 15 months (range 5–39) in all patients. IL-2 intrapleural administration followed by low-dose IL-2 subcutaneously in pleurisy-complicated malignant mesothelioma is feasible and active both in palliation of pleural effusion and on primary tumor, with manageable toxicity. The overall survival observed in nonprogressing patients warrants further randomized studies with IL-2 aimed to the patient outcome.

A Phase II Trial of Interferon Alpha-2a and Carboplatin in Patients with Advanced Malignant Mesothelioma

We defined the antitumor activity, toxicity, and tolerability of a combined chemoim-munotherapy approach in patients with advanced malignant mesothelioma using daily low-dose integeron alpha-2a and carboplatin given every 4 weeks. This was a phase II study of 15 patients with surgically unresectable or metastatic malignant mesothelioma. All patients had measurable or assessable disease. No prior chemotherapy or immunotherapy was allowable. Carboplatin was given at 150 mg/m2 daily on days 1–3 and integeron alpha-2a at 3 million units subcutaneously daily throughout the study. Treatment was recycled every 28 days. Therapy was continued until disease progression. Fifteen patients were assessable for toxicity and 14 for response. One partial response (7%, 95% CI, 0–20%), with a response duration of 40 weeks, was seen. Most patients had early progression of disease. Toxicity was tolerable, and grade III/ IV toxicity was uncommon. The median time to progression was 14 weeks (range, 1–52 weeks). The median survival was 25 weeks (range, 8–66 weeks). The combination of low-dose integeron alpha-2a and carboplatin did not result in greater antitumor activity than that reported for single-agent carboplatin in advanced malignant mesothelioma. Although toxicity was mild, carboplatin and low-dose interferon, given at this dose and schedule, cannot be recommended for this patient group.

Treatment of Malignant Mesothelioma With Methotrexate and Vinblastine, With or Without Platinum Chemotherapy

To determine the efficacy of methotrexate, vinblastine, and platinum chemotherapy in patients with diffuse unresectable malignant mesothelioma. Patients with histologically confirmed malignant mesothelioma were evaluated for treatment with methotrexate, vinblastine, and cisplatin chemotherapy. If the patient had preexisting hearing loss or neuropathy, or was significantly disabled (eg, spending greater than half of the day in bed or a chair), cisplatin therapy was withheld. All patients were initially evaluated at the University of Washington Medical Center and received chemotherapy at the University of Washington or in the community. Between 1990 and 1994, 17 patients received this chemotherapy. Ten patients received cisplatin, 100 mg/m2 IV on day 1, methotrexate, 30 mg/m2 IV on days 8, 15, and 22, and vinblastine, 3 mg/m2 IV on days 8, 15, and 22, in 28-day cycles. One patient had carboplatin substituted for cisplatin due to preexisting hearing loss. Six patients received weekly methotrexate and vinblastine at the same doses without platinum. Nine of the 17 (53%; 95% confidence interval [CI], 28 to 77%) patients responded, including two complete remissions, two partial remissions, and five regressions. Median time to progression is 8 months. The median survival time for all patients is 14 months. Projected 2-year survival is 35% (95% CI, 12 to 60%). Although the number of the patients in this study is small, the response rate and projected 2-year survival of 35% are better than those typically reported for unresectable malignant mesothelioma. Further investigation is warranted in confirmatory trials.

TREATMENT OF MALIGNANT MESOTHELIOMA (REVIEW)

Malignant mesothelioma (MM) has a very variable natural history. Its known relationship to asbestos exposure is often difficult to establish in a particular patient in view of a long preceding latency period of up to 40+ years. Survival depends on several prognostic factors including histological type, stage, performance status, resectability, and response to radiation and chemotherapy (CT). The assessment of the therapeutic impact on survival is usually difficult due to the different treatment philosophies and selections of patients in various clinical trials. Combined modality treatment approaches seem to offer the best outcomes, with occasional long-term disease-free survivors. Unresectable MM presents a difficult therapeutic challenge. In patients treated with systemic CT the median survival time (MST) in the range of 6 to 12 months and the 2 year survival of <20% are typical. The MST in excess of 20 months and the 2 year survival in the range of 40% have been reported in a few multimodality therapy trials in patients with at least partially resectable MM. Despite some encouraging therapeutic results in selected patients, the overall response to treatment(s) remains unsatisfactory, and new treatments must be sought.

A phase II study of VP-16 and cisplatin in patients with unresectable malignant mesothelioma. An NCI Canada Clinical Trials Group Study.

The National Cancer Institute of Canada (NCIC) Clinical Trials Group has carried out a phase II study of VP-16 100 mg/m2 daily x 3 and cisplatin 25 mg/m2 daily x 3 in untreated patients with malignant mesothelioma. Twenty-seven eligible patients were entered on the trial and the majority had pleural and/or soft tissue disease. Myelosuppression and gastrointestinal symptoms were the most common toxicities, and were usually mild or moderate in severity. Only 3 partial responses were seen in the 26 patients evaluable (12%). We conclude that the combination of VP-16 and cisplatin when used in this fashion has only minimal activity in mesothelioma.

A phase II evaluation of cisplatin in unresectable diffuse malignant mesothelioma: a Southwest Oncology Group Study.

Cisplatin was given intravenously to 35 evaluable patients with unresectable malignant mesothelioma on Southwest Oncology Group (SWOG) Study 8418. Five patients (14.3%) achieved partial response with median response duration of six months (range 2-12 months); eleven patients (31.4%) had stable disease of median duration of 5.5. months (range 2-21 months). Median survival for all patients was 7.5 months, 9 months for responders. Toxicity was as expected except that 12 patients (34.2%) discontinued cisplatin because of side effects. Cisplatin has moderate activity in mesothelioma and further studies with platinum analogues should be pursued.

Treatment of six cases of mesothelioma with doxorubicin and cisplatin

Six patients with unresectable malignant mesothelioma were treated with chemotherapy consisting of doxorubicin and cisplatin every 3 weeks. One patient with paratesticular mesothelioma metastatic to lungs entered complete remission for 8 months; his disease has relapsed but he is alive 32 months after initiation of chemotherapy. One patient with peritoneal mesothelioma achieved partial response for 12 months. Two patients with pleural mesothelioma achieved a partial response of 5- and 6-month durations, respectively. Two patients with pleural mesothelioma failed to respond to this regimen. Thus, four of six patients responded to doxorubicin-cisplatin chemotherapy. These preliminary results merit further study and confirmation; future investigations of cisplatin alone are necessary to better define the role of this agent in mesothelioma.