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Phase II Study of Vinorelbine in Patients With Malignant Pleural Mesothelioma

From the Department of Medical Oncology, St Bartholomew’s Hospital, and the London Lung Cancer Group, London, United Kingdom.

Address reprint requests to Jeremy P.C. Steele, MD, MRCP, Department of Medical Oncology, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, United Kingdom; email j.p.steele@ mds.qmw.ac.uk.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate the response rate and impact on quality of life of vinorelbine given as cycles of 30 mg/m² weekly for 6 weeks to patients with malignant pleural mesothelioma.

PATIENTS AND METHODS: Twenty-nine patients with histologically proven malignant pleural mesothelioma were enrolled (26 male patients and three female patients; median age, 58 years [range, 29 to 77 years]). Seventeen patients had epithelioid tumors, two had sarcomatoid tumors, and 10 had biphasic tumors. The International Mesothelioma Interest Group staging system was used: one patient had stage Ib disease, 10 had stage II disease, eight had stage III disease, and 10 had stage IV disease. Patients were treated with weekly injections of vinorelbine 30 mg/m². A cycle consisted of six weekly injections. The new guidelines to evaluate the response to treatment in solid tumors were used. Responses were measured by spiral computed tomography scan.

RESULTS: All twenty-nine patients had measurable disease and were assessed for response. There were seven partial responses (24% [95% confidence interval, 10% to 44%]), 16 patients had stable disease (55%), and six patients had disease progression on therapy (21%). The median number of vinorelbine injections was 12 (range, 2 to 30). Quality-of-life analyses showed a benefit for vinorelbine therapy.

CONCLUSION: Vinorelbine shows promise in the palliation of patients with malignant pleural mesothelioma. The relatively low toxicity of the drug suggests that trials of vinorelbine in combination with other agents should be feasible.

	INTRODUCTION

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MALIGNANT PLEURAL mesothelioma has been steadily increasing in incidence over the last 30 years, and the annual total in the United Kingdom is expected to increase to more than 3,000 from the present 1,300 cases.¹ A continuing increase in new cases of malignant mesothelioma is also expected throughout the rest of Europe over the next 20 years,² although the disease may have already peaked in the United States because of earlier control of asbestos use.³

Malignant pleural mesothelioma is generally considered to be resistant to therapy. Radical surgery is not possible for most patients. Palliative radiotherapy may provide pain relief but does not prolong survival.⁴ Most available chemotherapeutic agents have been evaluated in mesothelioma but no drug has consistently produced a response rate greater than 20%.⁵ Agents that have been reported to produce response rates of 10% to 20% include doxorubicin, epirubicin, mitomycin, cyclophosphamide, ifosfamide, cisplatin, carboplatin, and antifolates. Trials of combination chemotherapy have not demonstrated consistently greater response rates compared with single agents. There are no published randomized trials that demonstrate improved survival in patients treated with chemotherapy compared with supportive care.⁵

Vinorelbine is a semisynthetic derivative of vinblastine that is structurally modified on the catharanthine nucleus and is approved for treatment of non–small-cell lung cancer (as a single agent or in combination) and breast cancer. After intravenous (IV) administration, drug concentrations of vinorelbine in human lung are 300-fold greater than plasma levels and 3.4-fold to 13.8-fold higher than lung tissue concentrations achieved with vincristine.⁶ There are little data, however, on vinorelbine levels in pleural fluid. The usual dose of vinorelbine is 30 mg/m² administered weekly or on days 1 and 8 of a 21-day cycle.

Vinorelbine has demonstrated a high level of activity in preclinical studies compared with other vinca alkaloids.⁷ Vinorelbine is significantly more toxic to non–small-cell cancer cell lines and small-cell lung cancer cell lines implanted in nude mice as well as non–small-cell lung cancer cell lines in vitro.⁷ There are little data on the activity of vinorelbine against mesothelioma cell lines. In a phase II study in non–small-cell lung cancer, vinorelbine produced promising results in terms of response and time to progression (median, 34 weeks) and survival (median, 33 weeks).⁸ Le Chevalier et al⁹ reported a multicenter three-arm study in non–small-cell lung cancer in which vinorelbine was administered weekly at 30 mg/m². The median number of administrations was 11, with 83% of doses being delivered on schedule. Other established clinical uses of vinorelbine include breast cancer and head and neck cancer.

We conducted an single-center, open-label, phase II study of vinorelbine 30 mg/m² administered weekly in patients with histologically proven malignant pleural mesothelioma with first radiologic assessment after 6 weeks of chemotherapy. The major end points were objective response to chemotherapy and quality of life.

	PATIENTS AND METHODS

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Patients and Methods
Between April 1998 to January 1999, patients with malignant pleural mesothelioma were enrolled onto a single-center trial of single-agent vinorelbine. The study had appropriate institutional ethical review board approval, and all patients provided written, informed consent according to institutional guidelines. All patients were required to have measurable, histologically confirmed, inoperable malignant pleural mesothelioma and to be 18 years old, with Eastern Cooperative Oncology Group performance status of 0 to 2 and no uncontrolled cardiac or hepatic disease. Patients with concurrent malignancies of another type (other than nonmelanoma skin cancer) were excluded. Hematologic and biochemical criteria included adequate bone marrow function (total leukocyte count 4 x 10⁹ cells/L, platelet count 100 x 10⁹ cells/L, and hemoglobin 10 g/dL), hepatic function (alkaline phosphatase 1.5 times the upper limit of normal). No prior chemotherapy was permitted. Prophylactic superficial irradiation of chest drain or biopsy scars was allowed before commencement of chemotherapy, provided that the patient had measurable disease outside the irradiated site. All patients had computed tomography (CT) chest scans performed at the time of enrollment. Where possible, pleural effusions were drained before commencing therapy. The International Mesothelioma Interest Group (IMIG) staging system was used.¹⁰

All treatment was administered on an outpatient basis. Vinorelbine (Navelbine; Pierre-Fabre Oncology, Paris, France) 30 mg/m² to a maximum dose of 60 mg was administered in 20 mL of normal saline by IV injection into a peripheral vein over 5 minutes. No antiemetic was prescribed routinely. Treatment was given weekly, with each six administrations termed a cycle of therapy. Weekly complete blood cell counts and chemistry panels were performed. Treatment was delayed by 1 week in the event of bone marrow suppression (total leukocyte count < 3 x 10⁹/L, neutrophil count < 1.5 x 10⁹ cells/L, or platelet count < 100 x 10⁹ cells/L). No provision for dose reductions was provided or required.

Assessment of Response
Patients were assessed for response by CT chest scan after each cycle of chemotherapy. We used the new guidelines to evaluate the response to treatment in solid tumors (Response Evaluation Criteria in Solid Tumors).¹¹ Spiral CT scans were used to measure response. Measurable lesions were identified at baseline. If there were clearly identifiable mass lesions, then all such lesions up to maximum of five were selected for measurement of their longest diameter. If there were not separately identifiable mass lesions, then the thickness of circumferential pleural tumor was measured at three separate levels on transverse sections, as previously described for the assessment of response to treatment in mesothelioma.¹² The sum of the measurements was taken as the baseline sum longest diameter. Repeat measurements were made at the same levels on subsequent scans.

The baseline sum longest diameter was used to characterize response as follows: complete response was defined as the disappearance of all target lesions, and partial response was defined as a decrease of at least 30% in the sum longest diameter. Responses were confirmed by repeat CT assessment not less than 4 weeks after criteria for response were first met. Responses that were not thus confirmed were classified as stable disease. Progressive disease was defined as an increase of at least 20% in the sum longest diameter, taking as reference the smallest sum longest diameter recorded since treatment started, or the appearance of one or more new lesions. A patient was considered to have stable disease if neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease had occurred, taking as reference the smallest sum longest diameter recorded since treatment started. The criteria had to be met at least once after the first six weekly treatments of vinorelbine.

Duration of response was defined as the interval from the time that the criteria for partial response were first met to the time that criteria for progressive disease were first met, taking as reference the smallest sum longest diameter recorded since treatment started. Duration of stable disease was defined as the interval from start of treatment to the time that criteria for progressive disease were first met, taking as reference the smallest sum diameter recorded since treatment started.

Quality of Life
Quality of life was assessed in all patients at baseline (before chemotherapy) and subsequently after each cycle of chemotherapy and at the first follow-up visit after completion of chemotherapy. The Rotterdam Symptom Checklist was used.¹³ A single questionnaire covered general and respiratory symptoms, psychologic well-being, and physical activity. Patient scores of improvement, deterioration, or no change in quality-of-life indices were collated individually and recorded.

Statistical Considerations
An objective response rate of at least 20% would be of sufficient interest to encourage further investigation of vinorelbine. Conventional statistical considerations indicate that an open study of 14 patients would have a 95% chance of detecting at least one response if the true response were 20% or greater.¹⁴ If at least one response occurred in the first 14 patients, it was planned to increase the number of patients to assess the response rate with more precision. The Kaplan-Meier method was used for calculation of overall survival and progression-free survival.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Twenty-nine patients entered the study (Table 1); 26 were male and three were female. Histologic subtypes were as follows: epithelioid, 17 patients (59%); sarcomatoid, two patients (7%); biphasic, 10 patients (34%). IMIG staging was as follows: one patient (3%) had stage Ib disease, 10 patients (34%) had stage II disease, eight patients (28%) had stage III disease, and 10 patients (34%) had stage IV disease. Eastern Cooperative Oncology Group performance status (PS) of patients was as follows: PS 0, 13 patients (45%); PS 1, 11 patients (38%); PS 2, five patients (17%). Ten of the 29 patients had received prior superficial radiotherapy outside the area of measurable disease. Two patients received less than one full cycle of vinorelbine and had no follow-up CT scan assessment. Both patients died of progressive mesothelioma and were included in the response analysis as having progressive disease.

View larger version (79K): [in this window] [in a new window]   Fig 1. CT scans from patient no. 21. (A) Before and (B) after one cycle of six treatments of vinorelbine 30 mg/m2.

Quality-of-life improvements were recorded in patients with stable disease as well as those with responses. Quality-of-life data after one and two cycles of vinorelbine according to response showed that the majority of responding patients had improved psychologic symptoms, physical symptoms, and lung-related symptoms, although overall activity levels were less. At these same time points, patients with stable disease showed a similar result, with improved psychologic symptoms, physical symptoms, and lung-related symptoms, but reduced activity levels. For the six patients with progressive disease, lung-related symptoms, general physical symptoms, and activity levels deteriorated, whereas psychologic symptoms were unchanged when assessed after one cycle. Overall quality-of-life data are shown in Fig 2.

View larger version (28K): [in this window] [in a new window]   Fig 2. Results of quality of life (QoL) assessments. (A) Change in summary QoL scores between baseline and after one cycle of vinorelbine (n = 29), (B) change in summary QoL scores between baseline and after two cycles of vinorelbine (n = 23), and (C) change in summary QoL scores between baseline and after three cycles of vinorelbine (n = 10). Gray bars, better; black bars, no change; white bars, worse.

Toxicity
The median number of weekly administrations of vinorelbine was 12 (range, 2 to 30). Table 3 lists numbers of chemotherapy administrations. A total of 372 administrations of vinorelbine were assessable for toxicities. Important World Health Organization grade 3/4 toxicities were neutropenia, leucopenia, constipation, and phlebitis (Table 4). Although grade 3 or 4 neutropenia occurred at least once in 62% of patients, only one patient experienced neutropenic sepsis requiring hospital admission and IV antibiotics. Patients required a median of 1 week’s delay due to asymptomatic neutropenia during each cycle. Fatigue was a common toxicity reported by all patients at different stages of treatment but was never more than grade 2. There was no significant alopecia, nausea and vomiting, or anorexia.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Quality-of-life analyses demonstrated improvements in psychologic and physical indices for patients receiving treatment with vinorelbine. Patients who benefited reported reduction or resolution of pain, cough, and breathlessness as well as enhanced overall well-being. Symptom relief was maximal after two cycles of treatment and was seen in patients with radiologically stable disease as well as those with proven partial responses. Activity levels worsened in all patients whether their disease was responding, stable, or progressing. This finding can be attributed to the toxicity of chemotherapy and possibly the need to visit the hospital weekly for treatment. This would have to be a consideration when discussing the likely palliative benefit to an individual patient. The quality of life of patients who experienced disease progression on chemotherapy worsened, although it is not possible to know how much of this symptomatic deterioration was due to progressive mesothelioma and how much to the treatment.

Other toxicities were generally low, with only one patient requiring admission for neutropenia-related infection. Mild constipation was a relatively common side effect reported mostly by patients on concomitant opioid analgesics. Constipation was usually easily controlled. Fatigue was reported by most patients, although it was never severe enough during the first two cycles of treatment to require cessation of therapy. Phlebitis at the site of injection, which generally resolved after three or four days, was reported in 10% of patients. In this trial, vinorelbine chemotherapy was administered by peripheral veins, and it is our view that the risk of phlebitis from weekly vinorelbine administration is insufficient to warrant the routine placement of tunnelled central lines. There was no significant nausea and vomiting or alopecia. The toxicities reported in this study are similar to those reported in the published data on vinorelbine used in non–small-cell lung cancer⁹ and breast cancer.¹⁵

The weekly schedule used in this trial was chosen empirically but was practical from the patients’ perspective. One explanation for the encouraging response rate and quality of life gains observed might be that this schedule is relatively dose-dense compared with other commonly used vinorelbine protocols. Approximately 1 week’s treatment out of each six-week cycle was delayed because of asymptomatic neutropenia. In patients with stable disease or partial responses, it was possible to continue therapy to three or more cycles. It is not possible in the context of a single-arm trial to establish whether overall survival had been prolonged by vinorelbine, but the median overall survival of 10.6 months (from time of commencement of vinorelbine therapy) is encouraging. It is unclear why vinorelbine is active in this disease when other vinca alkaloids and taxanes are not. The explanation could be that vinorelbine has a different pharmacology from the other microtubule agents,^6,7 with the high drug levels demonstrated in human lung⁶ being particularly significant.

Other groups have recently reported trials of newer cytotoxic agents in patients with malignant mesothelioma. The results have been mixed. Vogelzang et al¹⁶ used high-dose paclitaxel with granulocyte colony-stimulating factor in 35 patients with mesothelioma and reported a response rate of 9% in assessable patients. O’Reilly et al¹⁷ used carboplatin with interferon alfa-2a in patients with advanced mesothelioma and showed a response rate (7%) equivalent to that seen with single-agent carboplatin. The new antimetabolite, gemcitabine, has been evaluated by several groups. The Cancer and Leukemia Group B treated 17 patients with 1,500 mg/m² of gemcitabine on days 1, 8, and 15 of a 28-day cycle.¹⁸ No partial responses were seen, and the median survival duration was 4.1 months. The European Organization for Research and Treatment of Cancer tested gemcitabine 1,250 mg/m² on days 1, 8, and 15 of a 28-day cycle in 27 patients with malignant pleural mesothelioma, with an objective response rate of 7% and a median survival of 8 months.¹⁹ Byrne et al¹² used gemcitabine 1,000 mg/m² on days 1, 8, and 15 of a 28-day cycle in combination with cisplatin 100 mg/m² to give a response rate of 47.6%, although hematologic toxicity was appreciable. Responses were assessed according to criteria similar to the new Response Evaluation Criteria in Solid Tumors guidelines,¹¹ which we used to measure the responses to vinorelbine. The median survival from start of first treatment was 41 weeks, less than the 46 weeks in the present study.

Combination chemotherapy can produce response rates greater than 20%, although toxicity accumulates often with no clear palliative gain. Recent data from Kasseyet et al²⁰ reported a 38% response rate and a median survival time of 16 months in 45 patients treated with cisplatin, etoposide, fluorouracil, mitomycin, and growth factors. All patients were stage II and 33 (73%) of 45 patients in this trial had epithelioid histology, indicating a relatively favorable prognostic group. Data on quality-of-life benefits of chemotherapy are limited. Middleton et al²¹ reported symptom relief in 62% of patients treated with mitomycin, vinblastine, and cisplatin therapy, which produced a 20% partial response rate but a median survival of only 6 months. In common with our data, quality-of-life improvements were seen in patients without objective response as well as in those responding, although palliative benefit, if seen, came early in the treatment period.

The results reported here suggest that vinorelbine is an active drug for the treatment of malignant pleural mesothelioma. In the United Kingdom, the Medical Research Council and British Thoracic Society will be commencing a three-arm randomized phase III trial comparing single-agent vinorelbine with mitomycin, vinblastine, and cisplatin and best supportive care to determine whether chemotherapy truly improves either quality or length of life in this disease. Other combinations of vinorelbine, platinum agents, and gemcitabine also warrant investigation.

	ACKNOWLEDGMENTS

 
We acknowledge the following physicians for administration of chemotherapy at local cancer centers: Drs M.G. Bond, J. Boote, M. Daly, D. Gilligan, and P. Fisher.

	NOTES

 
The authors acknowledge the support of Pierre-Fabre Oncology for subsidized drug costs.

	REFERENCES

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Submitted December 9, 1999; accepted June 28, 2000.

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