Vinblastine

Study objective: To determine the efficacy of methotrexate, vinblastine, and platinum chemotherapy in patients with diffuse unresectable malignant mesothelioma.

Design: 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.

Setting: All patients were initially evaluated at the University of Washington Medical Center and received chemotherapy at the University of Washington or in the community.

Interventions: Between 1990 and 1994, 17 patients received this chemotherapy. Ten patients received cisplatin, 100 [mg/m.sup.2] IV on day 1, methotrexate, 30 [mg/m.sup.2] IV on days 8, 15, and 22, and vinblastine, 3 [mg/m.sup.2] 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.

Measurements and results: 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%).

Conclusions: 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.

Key words: carboplatin; chemotherapy; cisplatin; mesothelioma; methotrexate; vinblastine

Abbreviations: CI=confidence interval

Unresectable malignant mesothelioma is a uniformly fatal disease for which treatment is largely ineffective. Reported median survival times for patients who have unresectable mesothelioma are in the 6- to 12-month range.(1),(2),(3),(4),(5),(6) Phase 2 chemotherapy regimens tested in this disease have shown little benefit over supportive care alone,(1),(4),(7),(8) with response rates commonly less than 20%.

Since 1990, we have been treating patients with unresectable malignant mesothelioma with a combination of methotrexate and vinblastine, with or without cisplatin. This particular regimen was chosen because this combination had not been tested in mesothelioma (to our knowledge), and because of reports of the efficacy of weekly methotrexate and vinblastine in desmoid tumors and retroperitoneal fibromatosis.(9),(10) We combined these drugs with cisplatin, an agent with response rates in mesothelioma between 13% and 36% when used as a single agent.(11),(12),(13)

MATERIALS AND METHODS

This is a retrospective analysis of patients with malignant mesothelioma seen at the University of Washington Medical Center between 1990 and 1994, and treated with methotrexate and vinblastine, with or without platinum chemotherapy. All had histologically confirmed malignant mesothelioma, and all were deemed to have unresectable disease because of local invasion or poor overall condition. Patients were offered this chemotherapy program providing they had a creatinine concentration within normal limits, a granulocyte count of [1,500/mm.sup.3] or more, a bilirubin level of 2 mg/dL or less, a platelet count of more than [100,000/mm.sup.3], and a Karnofsky performance status of 50% or greater (ie, they were at least capable of self-care and were spending no more than 50% of the day in a chair or bed). Cisplatin was not employed in patients who had significant hearing loss, peripheral neuropathy, or borderline performance status.

Patients who were eligible for cisplatin received this drug at 100 [mg/m.sup.2] IV on day 1, with precisplatin and postcisplatin hydration and antiemetics. Patients treated at the University of Washington received dexamethasone and ondansetron as the primary antiemetics. They then received methotrexate at a dose of 30 [mg/m.sup.2] IV, and vinblastine at 3 [mg/m.sup.2] IV, on days 8, 15, and 22, in 28-day cycles. For patients with large pleural effusions, the starting dose of methotrexate was 15 [mg/m.sup.2], and was escalated up to 30 [mg/m.sup.2] providing no mucositis or cytopenias occurred. One patient with preexisting hearing loss received carboplatin in substitution for cisplatin at a dose of 235 [mg/m.sup.2]. Patients who were not eligible for platinum therapy received methotrexate and vinblastine alone on a weekly basis at the same doses. Doses were modified for hematologic, allergic, and neurologic toxic reactions.

In regards to known unfavorable prognostic factors in mesothelioma,(6),(8),(15),(16) 7 patients had thrombocytosis, 11 had 6 months or less of symptoms before diagnosis, and 9 patients had chest pain; 1 additional patient, who had peritoneal mesothelioma, had abdominal pain. Weight loss was documented in only nine patients, with a median weight loss of 4.5 kg.

Median follow-up for all patients was 12 months (range, 4.6 to 44 months). The ten patients who were treated with cisplatin, methotrexate, and vinblastine received a median of 5 monthly cycles of chemotherapy (range, 3 to 20+ months). The six patients who received only methotrexate and vinblastine received a median of 5 months (range, 3 to 12 months) of treatment, and the one patient receiving carboplatin, methotrexate, and vinblastine continues to receive therapy after receiving 8 months of treatment.

Response

All patients were evaluable for response. Four patients had bidimensionally measurable disease; of these, two had a partial remission. Of the 13 patients with evaluable disease, 2 had a complete remission and 5 had regressions. Overall response rate is 9 of 17 patients, or 53% (95% confidence interval [CI], 28 to 77%). Eight of the nine responders received three-drug therapy. The median time to progression (Fig 1) is 8 months (range, 4 to 20 months). Seven patients had stable disease, for a median duration of 5 months (range, 4 to 15 months). The median survival time of all patients is 14 months (Fig 2). Projected 2-year survival is 35% (95% CI, 12 to 60%).

Toxicity

Toxicity of the this regimen was as expected from these chemotherapy agents. There were no treatment-related deaths. One patient had vomiting requiring hospitalization (grade 4 toxicity), and three other patients had six to ten episodes of vomiting in a 24-h period (grade 3 toxicity). Myelosuppression was mild to moderate: three patients developed a neutrophil nadir of between 500 and [900/mm.sup.3], and one patient had a platelet count nadir of [49,000/mm.sup.3]. The myelosuppression lasted 2 weeks and resolved after holding the methotrexate and vinblastine for 1 week, then reducing the doses upon hematologic recovery. Other toxic reactions included one episode of methotrexate-induced pneumonitis and one of methotrexate-induced hepatitis, both of which were reversed by discontinuation of this drug therapy. Six patients developed moderate paresthesias and three developed tinnitus, necessitating discontinuation of cisplatin therapy in two patients and of vinblastine therapy in one.

DISCUSSION

This particular regimen was chosen because of reports of the efficacy of weekly methotrexate and vinblastine in desmoid tumors and retroperitoneal fibromatosis. Although desmoid tumors are histologically distinct from mesothelioma and technically benign, they share a similar pattern of locally aggressive, infiltrating spread. Methotrexate and vinblastine have a reported response rate in desmoid tumors of 72%.(9),(10) We combined these drugs with cisplatin, an agent with modest activity(11),(12),(13) in patients who we believed could tolerate the drug.

Although the number of patients in this analysis is small, we are encouraged by the results. The 53% response rate and projected 2-year survival of 35% for these patients with unresectable mesothelioma are better that those typically reported in phase 2 trials of chemotherapy, although we acknowledge that these results could be due to patient selection factors. The 18 to 77% CI for response overlaps with the response rates seen with single-agent cisplatin (13 to 36%). The small number of patients precludes determining if our response rate could be due to the platinum compound alone.

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Many prognostic factors have been identified by multivariate analyses that are associated with a worse outcome for patients with malignant mesothelioma. These include the following: chest pain, age younger than 50 years, less than 6 months of chest pain (for pleural mesothelioma), performance status of 2 (unable to work, but ambulatory [greater than]50% of the day) or performance status greater than 2 (limited ability for self-care, confined to bed or chair [greater than]50% of the day), thrombocytosis of 400,000 or more, advanced stage, and asbestos exposure.(6),(8),(15),(16) We believe that it is unlikely that our results are explained by a preponderance of good prognostic factors, since most of our patients were older than 50 years, had chest pain as a predominant symptom, and had a less than 6-month duration of symptoms. Most (ten) of our patients had epithelial mesothelioma, which can have a relatively indolent course. Responses to treatment, however, were seen in patients having either epithelial (six of ten) or mixed (three of six) histologic type; the one patient with sarcomatoid mesothelioma had stable disease. Toxic reactions were moderate overall, as expected from these drugs.

Regression by comparison of serial CT scans was used as a measure of response in this analysis, as has been done in many phase 2 reports of mesothelioma response to treatment. Because mesothelioma typically infiltrates the pleura or peritoneum without producing a bidimensionally measurable mass, assessment can be difficult. We considered our patients to have had a regression if two different investigators agreed that there was a definite decrease in the tumor's size and no new lesions appeared for 8 weeks. In non-small cell lung cancer, regression carries the same prognostic implications as partial remission.(17)

Although the small number of patients and the retrospective nature of this study make it difficult to draw valid comparisons of subsets, we observed a differential response rate for patients receiving three-drug therapy compared with those receiving methotrexate and vinblastine alone. Of the 11 patients who received platinum, methotrexate, and vinblastine, 1 had a complete remission, 2 had partial remissions, and 5 had regressions (8 of 11 patients). Of the six receiving methotrexate and vinblastine alone, there was only one responder (a patient who had a complete remission). This differential response rate for the three-drug combination may be due to a synergistic effect among the three drugs or perhaps due to the platinum compound alone. Further investigation of the three-drug regimen is warranted in confirmatory trials.

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