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Combination chemotherapy with cisplatin-vinblastine in malignant mesothelioma
LUNC3 CANCER
Lung Cancer 11(1994)299-303
ELSEVIER
Short communication
Combination chemotherapy with cisplatin-vinblastine in malignant mesothelioma Nicolas Tsavaris*, Nicolas Mylonakis, Nicolas Karvounis, Charalambos Bacoyiannis, Evagelos Briasoulis, Dimosthenis Skarlos, Nicolaos Pavlidis, George Stamatelos, Paris Kosmidis Hellenic Cooperative Oncology Group, Department of Pathologic Physiology, University of Akns. School of Medicine, Luiko Hospital, Athens I I5 27, Greece
Received 26 November 1993; revision received 23 February 1994; accepted I March 1994
AlJStlltCt
From June 1985 to March 1993, 20 consecutive patients with histologically proven malignant mesothelioma were treated with cisplatin 100 mg/m2 i.v. infusion on day I and vinblastine 6 mg/m2 i.v. on day I and 8. Treatment was repeated every 4 weeks until progression. All patients were evaluated clinically and by CT-scan and were staged (Stage IV), according to Butchard’s criteria, on entry to the study. None had prior surgical excision. Eighty-one chemotherapy cycles were administered to 20 patients. One complete response, four partial responses, nine stable diseases and six progressions were noted. One partial responder entered complete response following an operation. Toxicity was acceptable and no treatment-related deaths occurred. The median survival for responders was 19.3 months; for patients with stable disease 15.7 months and for non-responders, 5.2 months. The mean duration of response was 13 months. We conclude that for this small group of patients, the combination cisplatinvinblastine is effective, with acceptable toxicity in malignant mesothelioma. Further study with a larger number of patients is necessary. Keywords:
??
Malignant Mesothelioma; Chemotherapy;
Cisplatin; Vinblastine
Corresponding author.
0169~5002B4&07.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved SSDI 0169-5002(94)00355-Q
300
N. Tsovoriser ol./Lung Cancer II (1994) 299-303
Malignant mesothelioma (MM), is highly chemo-resistant, although occasional responses have been noted with various drugs. The most widely studied of these drugs are adriamycin, with a 1%20% response rate [l-3], and cisplatin [l-4], with a response rate of lo- 15% and a mean duration of response of about 4 months. We elected to use the combination of cisplatin with vinblastine, in a schedule already tested with encouraging results in non-small cell lung cancer [5], in an effort improve upon the response rate in mesothelioma. 2. Patients and methods From June 1986 to March 1993,20 consecutive patients with unsurged MM of the pleural or the peritoneum, entered into this study. They presented with histologically proven MM (a pathological review was mandatory), measurable disease, age less than 70 years, Kamofsky performance status equal to or greater than 70, life expectancy >2 months, adequate liver and renal functions and no previous or concomitant malignancies. Apart from biopsy, none of the patients had surgical excision. Evaluation of all patients was carried out by CT-scan prior to chemotherapy. The stage of disease was classified according to the criteria described by Butchart [6]; all patients were Stage IV. The characteristics of the 20 patients are shown in Table 1. Table 1 Patients characteristics Clinical characteristics
Number of patients
Total Age-range (years) Age-median (years) Sex Male Female Kamofsky performance status 100 90 80 70 Previous treatment Chemotherapy
20 36-70 53
Sur.WY Radiotherapy Tumor histologic type Epithelial Sarcomatous Mixed Presenting in Pleural Peritoneum
12 8 2 3 7 8 3 II 0 13 3 4 17 3
N. Tsavaris et al. /Lug
Cancer II (1994) 299-303
301
None of the three patients with prior chemotherapy had received any agent such as cisplatin and vinca alkaloids. Chemotherapy consisted of cisplatin 100 mg/m2 i.v. on day 1 given by infusion over 1 h, with pre- and post-hydration and mannitol diuresis, and vinblastin 6 mg/m2 i.v. on day 1 and 8 of each course. Cycles were repeated every 4 weeks until progression or completion of six courses of treatment was achieved. No dosage modifications were permitted. Response was evaluated every two cycles. Miller’s criteria were used for response and toxicity [7]. Response was categorized as complete, partial, stable disease or progression, by clinical examination, chest X-ray and computerized tomography (every three cycles). Survival was calculated from the start of treatment, by means of the life-table method. 3. Results Overall, 8 1 chemotherapy cycles were administered to the 20 treated patients (median, four cycles/patient). One patient with MM of the peritoneum presented complete response. Two patients with MM of the peritoneum and two with MM of the pleural, presented a partial response. Histologically, all responders had epithelial type MM. In one partial responder with pleural mesothelioma, a durable complete response was achieved with thoracic surgery. Eight patients had stable disease. Four patients presented progressive disease. The mean survival for responders was 19.3 months (range, 7-35 months), for patients with stable disease 15.7 months (range, 2-66 months) and for non-responders 5.2 months (range, 2-8 months). The mean duration of response was 13 months (range, 5-28 months) and the mean time to progression was 5.2 months (range, 2-31 months) (Table 2). The patient with peritoneal mesothelioma presented a complete response for 31 months, but died after 3 months from a relapse. The survival of the patient who
Table 2
Response and survival Item
Details
Responses (number of patients) Complete Partial Stable disease Progressive disease Survival in months (range) Responders Stable disease Progressive disease Duration of response Time to progression Number of cycles Alive patients
19.3 (7-35) 15.7 (2-66) 5.2 (2-8) I3 (5-28) 5.2 (2-31) 81 3
302
N. Tsavaris ef al. /Lung Cancer II (1991) 299-303
Table 3 Toxicity Toxicity
Grade (WHO)
Percent
Anemia
I
41 19 0 14 16 40 32 20 88 80
Thrombocytopenia Neutropenia Nausea, vomiting
Anorexia Fatigue Patients Nephrotoxicity Neurotoxicity Alopecia Weight lost
2 -
I 2 I 2 3 -
I I 9 4
entered complete response following surgery was 67 months. After 56 months this patient had a relapse in the axillary lymph nodes, however this node was removed and since then the patient has remained free of disease. Toxicity was acceptable and no treatment-related deaths occurred. Myelosuppression, mild anemia, nausea-vomiting, anorexia and fatigue were the main toxicity factors (Table 3). 4. Dlscusslon MM remains a chemo-resistant tumor and appears to fail because of its unresponsiveness to the existing forms of treatment and the advanced stage of the disease at clinical presentation [8-lo]. There was no significant difference in survival between treatment groups or between treated and untreated patients in different reports. Furthermore, there was no difference when mesotheliomas of epithelial, sarcomatous, and mixed type were examined separately [lo]. Objective assessment of responses to chemotherapy with cytostatics is difficult in malignant mesothelioma [ 111. In this study, the use of an already tested combination of cisplatin and vinblastine in NSCLC IS] proved to be active in MM, because live out of 20 patients responded to this regimen with a significant improvement to their quality of life. In particular, the level of toxicity was acceptable. Although the number of patients is small, it is interesting to note that all responders had an epithelial type of MM. It is reasonable to report that in certain instances surgery has a role to play as an adjuvant treatment to chemotherapy, as was shown in our study. Certainly the number of patients is small to draw statistical conclusions, but the responses and the improvement to the quality of life cannot be rejected.
N. Tsavaris et al. /L.ung Cancer I1 (1994) 299-303
303
We concluded that the combination of cisplatin-vinblastine is effective with acceptable toxicity, in the small group of patients with MM in this study. Further studies with a larger number of patients is necessary. Referemxs VI Rossof AH, Chemotherapy
in the management of mesothelioma. In: Kitte CF, editor. Mesothelioma diagnosis and management. Chicago-London: Year Book Medical Publishers Inc.. 1987. 121Yap BS, Benjamin RS, Burgess MA, Bodey GP. The value of Adriamycin in the treatment of diffuse malignant pleural mesothelioma. Cancer 1978; 42: l692- 1696. 131 Kosmidis P, Tsavaris N. Pavlidis N, Briasoulis V, Primikirios N, Vavourakis G, Skarlos D. Cisplatin or Doxorubicin based chemotherapy for malignant mesothelioma. Proceedings of the 6th World Conference of Lung Cancer, 10-14/l l/1991, Melbourne. 141 Mintzer DM, Kelsen D, Frimmer D, Heelan R, Gralla R. Phase II trial of high dose in patients with malignant mesothelioma. Cancer Treat Rep 1985; 69: 71 I-712. 151 Mylonakis N, Tsavaris N, Bacoyiannis N, Karvounis N, Kakolyris S, Karabelis A, Beer M. Kosmidis P. A randomized prospective of cisplatin, vinblastine and mitomycin in advanced nonsmall cell lung cancer. Ann Oncol 1992; 3: 127-130. VI Butchart EG, Ashcroft T, Bamsley WC, Holder MP. Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experience with 29 patients. Thoracic 1979; 31: 5-24. 171 Miller AB, Hoogstraten B, Staquet M, Wrinkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207-214. 181 Cantwell BM, Franks CR, Harris AL. A phase II study of the platinum analogues JM8 and JM9 in malignant pleural mesothelioma. Cancer Chemother Pharmacol 1986; 18: 286-288. PI Magri MD, Foladore A, Veronesi A, Serra C, Nicotra M, Tommassi M, Granti G, Monfardini S, Bianchi C. Treatment of malignant mesothelioma with epirubicin and ifosfamide: a phase II cooperative study. Ann Oncol 1992; 3: 237-238. [lOI Law MR. Gregor A, Hodson ME, Bloom HJ. Turner-Warwick M. Malignant mesothelioma of the pleural: a study of 52 treated and 64 untreated patients. Thoracic 1984; 39: 255-259. 1111 Kittle F. Mesothelioma: diagnosis and treatment, 1st ed. Chicago-London: Year Book Medical Publishers Inc., 1987.
Lung Cancer 11(1994)299-303
ELSEVIER
Short communication
Combination chemotherapy with cisplatin-vinblastine in malignant mesothelioma Nicolas Tsavaris*, Nicolas Mylonakis, Nicolas Karvounis, Charalambos Bacoyiannis, Evagelos Briasoulis, Dimosthenis Skarlos, Nicolaos Pavlidis, George Stamatelos, Paris Kosmidis Hellenic Cooperative Oncology Group, Department of Pathologic Physiology, University of Akns. School of Medicine, Luiko Hospital, Athens I I5 27, Greece
Received 26 November 1993; revision received 23 February 1994; accepted I March 1994
AlJStlltCt
From June 1985 to March 1993, 20 consecutive patients with histologically proven malignant mesothelioma were treated with cisplatin 100 mg/m2 i.v. infusion on day I and vinblastine 6 mg/m2 i.v. on day I and 8. Treatment was repeated every 4 weeks until progression. All patients were evaluated clinically and by CT-scan and were staged (Stage IV), according to Butchard’s criteria, on entry to the study. None had prior surgical excision. Eighty-one chemotherapy cycles were administered to 20 patients. One complete response, four partial responses, nine stable diseases and six progressions were noted. One partial responder entered complete response following an operation. Toxicity was acceptable and no treatment-related deaths occurred. The median survival for responders was 19.3 months; for patients with stable disease 15.7 months and for non-responders, 5.2 months. The mean duration of response was 13 months. We conclude that for this small group of patients, the combination cisplatinvinblastine is effective, with acceptable toxicity in malignant mesothelioma. Further study with a larger number of patients is necessary. Keywords:
??
Malignant Mesothelioma; Chemotherapy;
Cisplatin; Vinblastine
Corresponding author.
0169~5002B4&07.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved SSDI 0169-5002(94)00355-Q
300
N. Tsovoriser ol./Lung Cancer II (1994) 299-303
Malignant mesothelioma (MM), is highly chemo-resistant, although occasional responses have been noted with various drugs. The most widely studied of these drugs are adriamycin, with a 1%20% response rate [l-3], and cisplatin [l-4], with a response rate of lo- 15% and a mean duration of response of about 4 months. We elected to use the combination of cisplatin with vinblastine, in a schedule already tested with encouraging results in non-small cell lung cancer [5], in an effort improve upon the response rate in mesothelioma. 2. Patients and methods From June 1986 to March 1993,20 consecutive patients with unsurged MM of the pleural or the peritoneum, entered into this study. They presented with histologically proven MM (a pathological review was mandatory), measurable disease, age less than 70 years, Kamofsky performance status equal to or greater than 70, life expectancy >2 months, adequate liver and renal functions and no previous or concomitant malignancies. Apart from biopsy, none of the patients had surgical excision. Evaluation of all patients was carried out by CT-scan prior to chemotherapy. The stage of disease was classified according to the criteria described by Butchart [6]; all patients were Stage IV. The characteristics of the 20 patients are shown in Table 1. Table 1 Patients characteristics Clinical characteristics
Number of patients
Total Age-range (years) Age-median (years) Sex Male Female Kamofsky performance status 100 90 80 70 Previous treatment Chemotherapy
20 36-70 53
Sur.WY Radiotherapy Tumor histologic type Epithelial Sarcomatous Mixed Presenting in Pleural Peritoneum
12 8 2 3 7 8 3 II 0 13 3 4 17 3
N. Tsavaris et al. /Lug
Cancer II (1994) 299-303
301
None of the three patients with prior chemotherapy had received any agent such as cisplatin and vinca alkaloids. Chemotherapy consisted of cisplatin 100 mg/m2 i.v. on day 1 given by infusion over 1 h, with pre- and post-hydration and mannitol diuresis, and vinblastin 6 mg/m2 i.v. on day 1 and 8 of each course. Cycles were repeated every 4 weeks until progression or completion of six courses of treatment was achieved. No dosage modifications were permitted. Response was evaluated every two cycles. Miller’s criteria were used for response and toxicity [7]. Response was categorized as complete, partial, stable disease or progression, by clinical examination, chest X-ray and computerized tomography (every three cycles). Survival was calculated from the start of treatment, by means of the life-table method. 3. Results Overall, 8 1 chemotherapy cycles were administered to the 20 treated patients (median, four cycles/patient). One patient with MM of the peritoneum presented complete response. Two patients with MM of the peritoneum and two with MM of the pleural, presented a partial response. Histologically, all responders had epithelial type MM. In one partial responder with pleural mesothelioma, a durable complete response was achieved with thoracic surgery. Eight patients had stable disease. Four patients presented progressive disease. The mean survival for responders was 19.3 months (range, 7-35 months), for patients with stable disease 15.7 months (range, 2-66 months) and for non-responders 5.2 months (range, 2-8 months). The mean duration of response was 13 months (range, 5-28 months) and the mean time to progression was 5.2 months (range, 2-31 months) (Table 2). The patient with peritoneal mesothelioma presented a complete response for 31 months, but died after 3 months from a relapse. The survival of the patient who
Table 2
Response and survival Item
Details
Responses (number of patients) Complete Partial Stable disease Progressive disease Survival in months (range) Responders Stable disease Progressive disease Duration of response Time to progression Number of cycles Alive patients
19.3 (7-35) 15.7 (2-66) 5.2 (2-8) I3 (5-28) 5.2 (2-31) 81 3
302
N. Tsavaris ef al. /Lung Cancer II (1991) 299-303
Table 3 Toxicity Toxicity
Grade (WHO)
Percent
Anemia
I
41 19 0 14 16 40 32 20 88 80
Thrombocytopenia Neutropenia Nausea, vomiting
Anorexia Fatigue Patients Nephrotoxicity Neurotoxicity Alopecia Weight lost
2 -
I 2 I 2 3 -
I I 9 4
entered complete response following surgery was 67 months. After 56 months this patient had a relapse in the axillary lymph nodes, however this node was removed and since then the patient has remained free of disease. Toxicity was acceptable and no treatment-related deaths occurred. Myelosuppression, mild anemia, nausea-vomiting, anorexia and fatigue were the main toxicity factors (Table 3). 4. Dlscusslon MM remains a chemo-resistant tumor and appears to fail because of its unresponsiveness to the existing forms of treatment and the advanced stage of the disease at clinical presentation [8-lo]. There was no significant difference in survival between treatment groups or between treated and untreated patients in different reports. Furthermore, there was no difference when mesotheliomas of epithelial, sarcomatous, and mixed type were examined separately [lo]. Objective assessment of responses to chemotherapy with cytostatics is difficult in malignant mesothelioma [ 111. In this study, the use of an already tested combination of cisplatin and vinblastine in NSCLC IS] proved to be active in MM, because live out of 20 patients responded to this regimen with a significant improvement to their quality of life. In particular, the level of toxicity was acceptable. Although the number of patients is small, it is interesting to note that all responders had an epithelial type of MM. It is reasonable to report that in certain instances surgery has a role to play as an adjuvant treatment to chemotherapy, as was shown in our study. Certainly the number of patients is small to draw statistical conclusions, but the responses and the improvement to the quality of life cannot be rejected.
N. Tsavaris et al. /L.ung Cancer I1 (1994) 299-303
303
We concluded that the combination of cisplatin-vinblastine is effective with acceptable toxicity, in the small group of patients with MM in this study. Further studies with a larger number of patients is necessary. Referemxs VI Rossof AH, Chemotherapy
in the management of mesothelioma. In: Kitte CF, editor. Mesothelioma diagnosis and management. Chicago-London: Year Book Medical Publishers Inc.. 1987. 121Yap BS, Benjamin RS, Burgess MA, Bodey GP. The value of Adriamycin in the treatment of diffuse malignant pleural mesothelioma. Cancer 1978; 42: l692- 1696. 131 Kosmidis P, Tsavaris N. Pavlidis N, Briasoulis V, Primikirios N, Vavourakis G, Skarlos D. Cisplatin or Doxorubicin based chemotherapy for malignant mesothelioma. Proceedings of the 6th World Conference of Lung Cancer, 10-14/l l/1991, Melbourne. 141 Mintzer DM, Kelsen D, Frimmer D, Heelan R, Gralla R. Phase II trial of high dose in patients with malignant mesothelioma. Cancer Treat Rep 1985; 69: 71 I-712. 151 Mylonakis N, Tsavaris N, Bacoyiannis N, Karvounis N, Kakolyris S, Karabelis A, Beer M. Kosmidis P. A randomized prospective of cisplatin, vinblastine and mitomycin in advanced nonsmall cell lung cancer. Ann Oncol 1992; 3: 127-130. VI Butchart EG, Ashcroft T, Bamsley WC, Holder MP. Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experience with 29 patients. Thoracic 1979; 31: 5-24. 171 Miller AB, Hoogstraten B, Staquet M, Wrinkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207-214. 181 Cantwell BM, Franks CR, Harris AL. A phase II study of the platinum analogues JM8 and JM9 in malignant pleural mesothelioma. Cancer Chemother Pharmacol 1986; 18: 286-288. PI Magri MD, Foladore A, Veronesi A, Serra C, Nicotra M, Tommassi M, Granti G, Monfardini S, Bianchi C. Treatment of malignant mesothelioma with epirubicin and ifosfamide: a phase II cooperative study. Ann Oncol 1992; 3: 237-238. [lOI Law MR. Gregor A, Hodson ME, Bloom HJ. Turner-Warwick M. Malignant mesothelioma of the pleural: a study of 52 treated and 64 untreated patients. Thoracic 1984; 39: 255-259. 1111 Kittle F. Mesothelioma: diagnosis and treatment, 1st ed. Chicago-London: Year Book Medical Publishers Inc., 1987.