British Journal of Urology (1992), 70,641442 0 1992 British Journal of Urology
Phase II Study of Epirubicin in Advanced Hormoneresistant Prostatic Carcinorna K. P. J. DELAERE, H. LELIEFELD, F. PEULEN, E. W. STAPPER, J. SMEETS and J. WlLS Department of Urology, De Wever Hospital, Heerlen; Departments of Urology and Oncology, Laurentius Hospital, Roermond, The Netherlands; Farmitalia Carlo Erba Benelux, Nivelles, Belgium
Summary-Twenty-nine patients with metastatic prostate cancer that had progressed following orchiectomy were treated with intravenous epirubicin 90 mg/m2 every 28 days. Their median age was 71 years (range 49-78) and the median Zubrod scale (WHO score) was 1. Two patients had soft tissue lesions, 20 had bone metastases and 7 had both. Tumour response was assessed according to the National Prostatic Cancer Project criteria. Of 29 patients, 11 (38%) achieved a partial remission. The median duration of response was 6 months and the median survival time of all patients was 9 months (range 2-27). It seemed that treatment with epirubicin was not associated with an increase in survival. Toxicity was moderate and consisted of alopecia and mild nausea/ vomiting. There was no significant haematological toxicity and no clinical cardiotoxicity. It was concluded that epirubicin was active in hormone-resistant metastatic prostate cancer in approximately 33% of the patients.
No effective treatment exists after hormonal failure in advanced prostate cancer. Chemotherapy is advocated by some, but must still be considered experimental. Subjective improvement may be achieved but objective partial responses occur in only 20 to 30% of patients, without measurable impact on survival. Combination chemotherapy does not appear to be superior to single agents. Doxorubicin can be regarded as one of the single drugs with reported activity. Because of the better therapeutic index of epirubicin, it appeared worthwhile to assess this drug. Tolerance of therapy and decreased cardiotoxicity are particularly important in these patients, who are usually elderly and often have concomitant cardiovascular disease.
Patients and Methods Eligibility criteria included metastatic prostate carcinoma that progressed following orchiectomy, age less than 80 years, performance status (WHO score) 0-2, normal radioisotope left ventricular ejection fraction and adequate general condition. Treatment consisted of intravenous epirubicin 90 mg/m2 every 4 weeks. Treatment was withheld in the case of >grade 1 haematological toxicity on the scheduled day of treatment. Accepted for publication 19 November 1991
Response in patients with bone metastases was assessed according to the criteria of the National Prostatic Cancer Project, i.e. partial response in the case of >SO% reduction in areas of increased uptake on radioisotope bone scans, with >50% decrease in acid phosphatase and no new sites of disease. In patients with soft tissue lesions the WHO criteria were used, i.e. partial response in the case of a 50% reduction in the sum of the products of the largest perpendicular diameters of measurable lesions for at least 4 weeks. Patients with both soft tissue and bone metastases who showed a response in soft tissue without progression in bone metastases were classified as a partial response. The duration of partial response and of survival was measured from the start of treatment. A total of 29 patients entered the phase I1 study and all were fully evaluable. Their median age was 71 years (range 49-78). Their median performance status was grade 1 (range 0-3). Twenty patients had only bone metastases, 2 only soft tissue lesions, and 7 had both. Results There were no complete responses. Eleven patients (38%) achieved a partial response. Of 9 patients with soft tissue lesions 5 (55%) responded, while of
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rate of 16% or improvement in 84% of 25 patients was reported (Torti et al., 1983), or good symptomatic improvement in 10 of 21 patients (50%) (Robinson et al., 1983).However, Fossg et al. (1987) found no objective responses with weekly doxorubicin in 21 patients. Epirubicin in a low-dose weekly schedule of 12 mg/m2 has been assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Urological Group. There was a 12% response rate with 42% stabilisation in 33 evaluable patients with soft tissue, liver or lung metastases as indicator lesions (Jones et al., 1987). The difficulty in measuring response in patients with osteoblastic bone metastases is well recognised. The response rate in the present study might be regarded as inflated because we modified the criteria developed by the NPCP and qualified a 50% reduction instead of normalisation of the tumour marker in patients with bone metastases as a partial response. With strict criteria, however, the overall response rate was 28%. Thus epirubicin can produce responses with acceptable toxicity in patients with metastatic symptomatic prostate cancer refractory to hormonal manipulation. The Discussion optimal administration schedule and comparison The response in this trial is within the confidence with other treatment options in these patients limits of that reported with doxorubicin and other require comparative studies. single agents (Jones et al., 1986). Doxorubicin has been assessed in several phase I1 and I11 studies as References a single agent and in combination chemotherapy. Fossi, S. D., Urnes, T.and Kaalhus, 0.(1987). Weekly low-dose Response rates ranged between 0 and 50%. In adriamycin in hormone-resistant cancer of the prostate. particular, a weekly “low-dose’’ schedule has Scand. J . Urol. Nephrol., 21, 13-16. aroused interest. In 2 studies an objective response Jones, W. G., Fossi,S. D., Bono, A. V. e t d (1986). Mitomycin-
20 patients with only bone metastases 6 (30%) achieved partial remission. All responders experienced clear subjective improvement. Three of the 6 responders with only bone metastases had normal acid phosphatase. The median duration of response was 6 months (range 3-19). Transient relief of symptoms was observed in 14 patients (48%). It was remarkable that obvious symptomatic relief occurred in 3 patients who did not show any objective response. Bone pain-a major symptom in 26 patients-diminished in 13 cases (50%). The symptoms of general malaise, present in 5 patients, disappeared in 3 cases. In general, the WHO performance scale improved in approximately onethird of patients. With the exception of alopecia, toxicity was moderate and all patients were ambulatory. The median number of cycles was 6 (range 1-1 2). There was no significant haematological toxicity. Nausea/vomiting was grade 1-2 only. There was no clinical cardiotoxicity. All patients have now died. Their median survival was 9 months (range 2-27) (Fig.).
entered died
29 29
C in the treatment of metastatic prostate cancer: report on an EORTC phase I1 study. World J . Urol., 4, 182-185. Jones, W. G., Fossi, S. D., Bono, A. V. et d (1987). European Organisation for Research and Treatment of Cancer (EORTC) phase I1 study of low-dose weekly epirubicin in metastatic prostate cancer. Cancer Treat. Rep., 71, 1317. Robinson, M. R. G., Chandrysekran, S., Newling, D. W. W. et d (1983).Low-dose doxorubicin in the management of advanced carcinoma of the prostate. Br. J . Urol.,55,747-748. Torti, F. M., Aston, D., Lum, B. L. et d (1983). Weekly doxorubicin in endocrinerefractory carcinomaof the prostate. J . Clin. Oncol., 1,477-482.
The Authors K. P. J. Delaere, MD, PhD, Urologist, De Wever Hosuital. H. Leliefeld, MD, PhD, Urologist,-LaurentiusHospital. F. Peulen, MD, PhD, Urologist, Laurentius Hospital. E. W. Stapper, MD, Urological Resident, De Wever Hospital. J. Smeets, Statistician, Farmitalia Carlo Erba. J. Wils, MD, PhD, Oncologist, Laurentius Hospital. 0
3
6
9
12
15
18 21
Months
Fig. Survival of all patients.
24 2 7 30
Requests for reprints to: K. P. J. Delaere, Department of Urology, De Wever Hospital, P.O. Box 4446,6401 CX Heerlen, The Netherlands.
Phase II Study of Epirubicin in Advanced Hormoneresistant Prostatic Carcinorna K. P. J. DELAERE, H. LELIEFELD, F. PEULEN, E. W. STAPPER, J. SMEETS and J. WlLS Department of Urology, De Wever Hospital, Heerlen; Departments of Urology and Oncology, Laurentius Hospital, Roermond, The Netherlands; Farmitalia Carlo Erba Benelux, Nivelles, Belgium
Summary-Twenty-nine patients with metastatic prostate cancer that had progressed following orchiectomy were treated with intravenous epirubicin 90 mg/m2 every 28 days. Their median age was 71 years (range 49-78) and the median Zubrod scale (WHO score) was 1. Two patients had soft tissue lesions, 20 had bone metastases and 7 had both. Tumour response was assessed according to the National Prostatic Cancer Project criteria. Of 29 patients, 11 (38%) achieved a partial remission. The median duration of response was 6 months and the median survival time of all patients was 9 months (range 2-27). It seemed that treatment with epirubicin was not associated with an increase in survival. Toxicity was moderate and consisted of alopecia and mild nausea/ vomiting. There was no significant haematological toxicity and no clinical cardiotoxicity. It was concluded that epirubicin was active in hormone-resistant metastatic prostate cancer in approximately 33% of the patients.
No effective treatment exists after hormonal failure in advanced prostate cancer. Chemotherapy is advocated by some, but must still be considered experimental. Subjective improvement may be achieved but objective partial responses occur in only 20 to 30% of patients, without measurable impact on survival. Combination chemotherapy does not appear to be superior to single agents. Doxorubicin can be regarded as one of the single drugs with reported activity. Because of the better therapeutic index of epirubicin, it appeared worthwhile to assess this drug. Tolerance of therapy and decreased cardiotoxicity are particularly important in these patients, who are usually elderly and often have concomitant cardiovascular disease.
Patients and Methods Eligibility criteria included metastatic prostate carcinoma that progressed following orchiectomy, age less than 80 years, performance status (WHO score) 0-2, normal radioisotope left ventricular ejection fraction and adequate general condition. Treatment consisted of intravenous epirubicin 90 mg/m2 every 4 weeks. Treatment was withheld in the case of >grade 1 haematological toxicity on the scheduled day of treatment. Accepted for publication 19 November 1991
Response in patients with bone metastases was assessed according to the criteria of the National Prostatic Cancer Project, i.e. partial response in the case of >SO% reduction in areas of increased uptake on radioisotope bone scans, with >50% decrease in acid phosphatase and no new sites of disease. In patients with soft tissue lesions the WHO criteria were used, i.e. partial response in the case of a 50% reduction in the sum of the products of the largest perpendicular diameters of measurable lesions for at least 4 weeks. Patients with both soft tissue and bone metastases who showed a response in soft tissue without progression in bone metastases were classified as a partial response. The duration of partial response and of survival was measured from the start of treatment. A total of 29 patients entered the phase I1 study and all were fully evaluable. Their median age was 71 years (range 49-78). Their median performance status was grade 1 (range 0-3). Twenty patients had only bone metastases, 2 only soft tissue lesions, and 7 had both. Results There were no complete responses. Eleven patients (38%) achieved a partial response. Of 9 patients with soft tissue lesions 5 (55%) responded, while of
641
642
BRITISH JOURNAL OF UROLOGY
rate of 16% or improvement in 84% of 25 patients was reported (Torti et al., 1983), or good symptomatic improvement in 10 of 21 patients (50%) (Robinson et al., 1983).However, Fossg et al. (1987) found no objective responses with weekly doxorubicin in 21 patients. Epirubicin in a low-dose weekly schedule of 12 mg/m2 has been assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Urological Group. There was a 12% response rate with 42% stabilisation in 33 evaluable patients with soft tissue, liver or lung metastases as indicator lesions (Jones et al., 1987). The difficulty in measuring response in patients with osteoblastic bone metastases is well recognised. The response rate in the present study might be regarded as inflated because we modified the criteria developed by the NPCP and qualified a 50% reduction instead of normalisation of the tumour marker in patients with bone metastases as a partial response. With strict criteria, however, the overall response rate was 28%. Thus epirubicin can produce responses with acceptable toxicity in patients with metastatic symptomatic prostate cancer refractory to hormonal manipulation. The Discussion optimal administration schedule and comparison The response in this trial is within the confidence with other treatment options in these patients limits of that reported with doxorubicin and other require comparative studies. single agents (Jones et al., 1986). Doxorubicin has been assessed in several phase I1 and I11 studies as References a single agent and in combination chemotherapy. Fossi, S. D., Urnes, T.and Kaalhus, 0.(1987). Weekly low-dose Response rates ranged between 0 and 50%. In adriamycin in hormone-resistant cancer of the prostate. particular, a weekly “low-dose’’ schedule has Scand. J . Urol. Nephrol., 21, 13-16. aroused interest. In 2 studies an objective response Jones, W. G., Fossi,S. D., Bono, A. V. e t d (1986). Mitomycin-
20 patients with only bone metastases 6 (30%) achieved partial remission. All responders experienced clear subjective improvement. Three of the 6 responders with only bone metastases had normal acid phosphatase. The median duration of response was 6 months (range 3-19). Transient relief of symptoms was observed in 14 patients (48%). It was remarkable that obvious symptomatic relief occurred in 3 patients who did not show any objective response. Bone pain-a major symptom in 26 patients-diminished in 13 cases (50%). The symptoms of general malaise, present in 5 patients, disappeared in 3 cases. In general, the WHO performance scale improved in approximately onethird of patients. With the exception of alopecia, toxicity was moderate and all patients were ambulatory. The median number of cycles was 6 (range 1-1 2). There was no significant haematological toxicity. Nausea/vomiting was grade 1-2 only. There was no clinical cardiotoxicity. All patients have now died. Their median survival was 9 months (range 2-27) (Fig.).
entered died
29 29
C in the treatment of metastatic prostate cancer: report on an EORTC phase I1 study. World J . Urol., 4, 182-185. Jones, W. G., Fossi, S. D., Bono, A. V. et d (1987). European Organisation for Research and Treatment of Cancer (EORTC) phase I1 study of low-dose weekly epirubicin in metastatic prostate cancer. Cancer Treat. Rep., 71, 1317. Robinson, M. R. G., Chandrysekran, S., Newling, D. W. W. et d (1983).Low-dose doxorubicin in the management of advanced carcinoma of the prostate. Br. J . Urol.,55,747-748. Torti, F. M., Aston, D., Lum, B. L. et d (1983). Weekly doxorubicin in endocrinerefractory carcinomaof the prostate. J . Clin. Oncol., 1,477-482.
The Authors K. P. J. Delaere, MD, PhD, Urologist, De Wever Hosuital. H. Leliefeld, MD, PhD, Urologist,-LaurentiusHospital. F. Peulen, MD, PhD, Urologist, Laurentius Hospital. E. W. Stapper, MD, Urological Resident, De Wever Hospital. J. Smeets, Statistician, Farmitalia Carlo Erba. J. Wils, MD, PhD, Oncologist, Laurentius Hospital. 0
3
6
9
12
15
18 21
Months
Fig. Survival of all patients.
24 2 7 30
Requests for reprints to: K. P. J. Delaere, Department of Urology, De Wever Hospital, P.O. Box 4446,6401 CX Heerlen, The Netherlands.
