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Original article: Teniposide in advanced breast cancer. A phase II trial in patients with no prior chemotherapy
Annals of Oncology 3: 377-378, 1992. C 1992 Kluwer Academic Publishers. Primed in the Netherlands.
Original article Teniposide in advanced breast cancer. A phase II trial in patients with no prior chemotherapy
1
Department of Oncology, Herlev Hospital, University of Copenhagen; Internal Medicine C, Bispebjerg Hospital, Copenhagen, Denmark
2
Summary. The objective response rates were determined using teniposide as first-line chemotherapy for patients with recurrent breast cancer. Twenty-seven evaluable patients with advanced disease received teniposide 70 mg/m2 i.v. days 1-5 every 3 weeks. A total of 211 courses were given. Responses included one complete (4%) and 9 partial responses (33%) with a median duration of response of 9 months (range 2-31
months). The main toxicity was myelosuppression. The results show that teniposide has at least modest activity in patients with advanced breast cancer treated previously with endocrine therapy.
Introduction
Unless rapid disease progression or unacceptable toxicity occurred, patients were considered evaluable for response if they had completed two courses of therapy. Evaluation of response and toxic side effects were done according to WHO criteria [4|.
Teniposide (VM-26) is a semi-synthetic podophyllotoxin derivative with substantial antitumor activity in acute leukemias, malignant lymphomas, small cell lung cancer, and testicular cancer [1-3]. In most other solid tumors the efficacy is either low or has not yet been tested properly. We report a phase II study of teniposide in patients with advanced breast cancer unexposed to prior chemotherapy.
Patients and methods Patients with histologically proven, progressive, metastatic breast cancer, aged >60 years, with a performance status (WHO grading) <2, and adequate kidney (s-creatinine <1.2 mg/dl) and liver (s-bilirubin <1.5 mg/dl) function were included. Additional criteria were measurable or unidimensionally measurable disease |4|, no prior chemotherapy, a WBC count of >3.0x 1071, and a platelet count of >100xl071 unless bone marrow involvement was documented. Patients with either CNS metastases, secondary malignancies or radiotherapy to indicator lesions were not eligible. Informed consent was obtained from all patients, and the study was approved by the regional scientific ethical committee. Teniposide was dissolved in 500 ml saline and administered intravenously over 30 min at a dose of 70 mg/m2 on day 1-5 every 3 weeks. Dose modifications were made according to WBC and platelets counts. Subsequent cycles of teniposide were postponed by 1 week if toxicity persisted at the day of scheduled retreatment. If the nadir WBC count was <1.0xl07l or nadir platelet count was <50x 1071, the next dose was reduced to 67%. Reductions were made in the daily dose and not in the number of treatment days. If nadir WBC count was >2.0x 1071 and platelet count > 100 x 1071 in the previous course, the dose was escalated by 25%. On the day of retreatment the dose was reduced to 75% if WBC count was between 2.5 and 3.0 x 1071 and/or platelet count between 75 and 100x 1071. Treatment was postponed if WBC count was <2.5 x 1071 and/or platelet count was <75 x 1071.
ONK, Rigshospitalet, University of Copenhagen; 3Department of
Key words: breast cancer, chemotherapy, teniposide
Results Twenty-nine patients entered the study. Two patients were ineligible due to prior treatment with chemotherapy. Characteristics of evaluable patients are given in Table 1. The median number of treatment courses with teniposide was 7 (range, 1-19). Dose reductions and escalations were performed in 12 and 3 patients, respectively. Table I. Characteristics of evaluable patients. Total no. of patients No. of evaluable patients Median age in years (range) Performance status 0-1 2-3
Previous treatment (no. of patients) Adjuvant endocrine Endocrine for advanced disease Radiotherapy Sites of metastases Lung Liver Bone
Soft tissue Number of metastatic sites 1 2 >3
29 27
71 (63-79) 21 6 7 20 3 5 4 14 19 15 10 2
Downloaded from https://academic.oup.com/annonc/article-abstract/3/5/377/224138 by University of Western Sydney Library user on 14 January 2019
D. Nielsen,1 J. Boas,1 S. A. Engelholm,2 O. Paaske Hansen3 & P. Dombernowsky1
378
Discussion Previous trials have shown minor activity in heavily pretreated patients with metastatic breast cancer using daily or weekly schedules of teniposide [5, 6]. More recent studies using a day 1—5 every 3 weeks schedule have demonstrated an overall response rate of 8% PR's in 52 patients previously treated with chemotherapy [2, 3, 7]. Accordingly, a 7% response rate was found using etoposide (VP-16) to 383 heavily pretreated patients [8]. The low activity of the two epipodophyllotoxins have been observed at dose levels creating moderate to severe hematologic toxicity. However, valuable treatment effects have been overlooked when teniposide was used as second-line - or later treatment in lung cancer [9J. Only one phase II trial of the epipodophyllotoxin derivatives in previously untreated patients with breast cancer has been reported [10]. Treatment with etoposide 230 mg/m2 day 1-3 every 4 weeks was used. A response rate of 15% (3 PR's among 20 patients) was observed, but the toxic side effects, especially hematologic, were mild as no dose reductions were necessary. In our study we observed a response rate of 37% (95% confidence limits 19%-58%) and a median response duration of 9 months. We accepted, however,
a correspondingly more pronounced hematologic toxicity. A wide variation in the WBC and platelet nadirs was registered. Other authors have reported a similar toxicity [11]. We did not find any factors (performance status, tumor burden, or age) which predicted the hematological toxicity. Although the patient population in this study was highly selected according to age and sites of metastatic disease (soft tissue predominant) these results suggest that teniposide has at least modest activity in previously endocrine treated, elderly patients with advanced breast cancer.
References 1. Cox EB, Vogel CL, Carpenter JT Jr, Raney M. Phase II evaluation of teniposide (VM-26) in metastatic breast carcinoma. A Southeastern Cancer Study Group trial. Invest New Drugs 1988; 6: 37-40. 2. European Organization for Research on the Treatment of Cancer, Cooperative Group for Leukemias and Hematosarcomas. Clinical screening of epipodophyllotoxin VM-26 in malignant lymphomas and solid tumors. Br Med J 1972; 2: 744-8. 3. O'Dwyer P, Alonso MT, Leyland-Jones B, Marsoni S. Teniposide: a review of 12 years of experience. Cancer Treat Rep 1984; 68: 1455-66. 4. WHO Handbook for reporting Results of Cancer Treatment. Geneva: WHO; 1979. 5. Spremulli E, Schultz JJ, Speckhart VJ, Wampler GL. Phase II study of VM-26 in adult malignancies. Cancer Treat Rep 1980; 64: 147-9. 6. Tirelli U, Frenchin G, Crivellan D et al. Phase II study of VM-26 in extensively pretreated breast cancer. Am J Clin Oncol 1984; 7:451-2. 7. Boas J, Rasmussen D, Hansen OP, Engelholm SA, Dombernowsky P. Phase II study of teniposide in advanced breast cancer. Cancer Chemother Pharmacol 1990; 25:463-4. 8. Sledge Jr GW. Etoposide in the management of metastatic breast cancer. Cancer 1991; 67: 266-70. 9. Bork E, Hansen M, Dombernowsky P, Hansen SW, Pedersen AG, Hansen HH. Teniposide (VM-26), an overlooked highly active agent in small-cell lung cancer. Results of a phase II trial in untreated patients. J Clin Oncol 1986; 4: 524-7. 10. Wander H-E, Rauschning W, Meyer D, Achterrath W, Nagel G-A. Phase II study with etoposide in previously untreated advanced breast cancer. Cancer Chemother Pharmacol 1989; 24:261-3. 11. Bork E, Ersbell J, Dombernowsky P, Bergman B, Hansen M, Hansen HH. Teniposide and etoposide in previously untreated small-cell lung cancer A randomized study. J Clin Oncol 1991; 9: 1627-31. Received 18 November 1991; accepted 14 January 1992. Correspondence to: Done Nielsen, M.D. Department of Oncology Herlev Hospital University of Copenhagen Herlev Ringvej 2730 Herlev, Denmark
Downloaded from https://academic.oup.com/annonc/article-abstract/3/5/377/224138 by University of Western Sydney Library user on 14 January 2019
In one patient with a supraclavicular lymph node a complete response (CR) (3.7%, 95% confidence limits 0.1%-18.0%) was observed. The duration of her response was 7 months. Partial response (PR) was registered in 9 patients (33.3%, 95% confidence limits 16.5%-54.0%) with a median duration of 10 months (range, 2-31 months). Furthermore, 11 patients had no change (NC) with a median duration of 6 months (range, 1-13 months). After discontinuation of teniposide 4 patients received chemotherapy, among these one CR, one PR, and two NC were reported. Eight patients received endocrine therapy, 6 NC and 2 PD were observed. However, among these 6 patients had received antiestrogen for metastatic disease and 2 adjuvant endocrine therapy, respectively. Hematologic toxicity was dominant. The median WBC and platelet nadirs were 1.8 x 109/l (range, 0.34.1) and 116 x 1071 (range, 4-266), respectively. WBC nadirs below 3.0, 2.0, and 1.0 x 109/I were registered in 77%, 65% and 12%, respectively. In 42% the platelet counts were below 100xl0 9 /l and in 15% below 50 x 109/l. One patient experienced leukopenia (WBC 1.0 x 109/l) and fever and two developed septicaemia (WBC 0.3 and 0.6 x 109/l), resulting in one toxic death. Bleeding due to thrombocytopenia was observed in one patient with a platelet count of 4 x 109/l. Alopecia was observed in all patients, while none developed WHO grade III—IV nausea or vomiting.
Original article Teniposide in advanced breast cancer. A phase II trial in patients with no prior chemotherapy
1
Department of Oncology, Herlev Hospital, University of Copenhagen; Internal Medicine C, Bispebjerg Hospital, Copenhagen, Denmark
2
Summary. The objective response rates were determined using teniposide as first-line chemotherapy for patients with recurrent breast cancer. Twenty-seven evaluable patients with advanced disease received teniposide 70 mg/m2 i.v. days 1-5 every 3 weeks. A total of 211 courses were given. Responses included one complete (4%) and 9 partial responses (33%) with a median duration of response of 9 months (range 2-31
months). The main toxicity was myelosuppression. The results show that teniposide has at least modest activity in patients with advanced breast cancer treated previously with endocrine therapy.
Introduction
Unless rapid disease progression or unacceptable toxicity occurred, patients were considered evaluable for response if they had completed two courses of therapy. Evaluation of response and toxic side effects were done according to WHO criteria [4|.
Teniposide (VM-26) is a semi-synthetic podophyllotoxin derivative with substantial antitumor activity in acute leukemias, malignant lymphomas, small cell lung cancer, and testicular cancer [1-3]. In most other solid tumors the efficacy is either low or has not yet been tested properly. We report a phase II study of teniposide in patients with advanced breast cancer unexposed to prior chemotherapy.
Patients and methods Patients with histologically proven, progressive, metastatic breast cancer, aged >60 years, with a performance status (WHO grading) <2, and adequate kidney (s-creatinine <1.2 mg/dl) and liver (s-bilirubin <1.5 mg/dl) function were included. Additional criteria were measurable or unidimensionally measurable disease |4|, no prior chemotherapy, a WBC count of >3.0x 1071, and a platelet count of >100xl071 unless bone marrow involvement was documented. Patients with either CNS metastases, secondary malignancies or radiotherapy to indicator lesions were not eligible. Informed consent was obtained from all patients, and the study was approved by the regional scientific ethical committee. Teniposide was dissolved in 500 ml saline and administered intravenously over 30 min at a dose of 70 mg/m2 on day 1-5 every 3 weeks. Dose modifications were made according to WBC and platelets counts. Subsequent cycles of teniposide were postponed by 1 week if toxicity persisted at the day of scheduled retreatment. If the nadir WBC count was <1.0xl07l or nadir platelet count was <50x 1071, the next dose was reduced to 67%. Reductions were made in the daily dose and not in the number of treatment days. If nadir WBC count was >2.0x 1071 and platelet count > 100 x 1071 in the previous course, the dose was escalated by 25%. On the day of retreatment the dose was reduced to 75% if WBC count was between 2.5 and 3.0 x 1071 and/or platelet count between 75 and 100x 1071. Treatment was postponed if WBC count was <2.5 x 1071 and/or platelet count was <75 x 1071.
ONK, Rigshospitalet, University of Copenhagen; 3Department of
Key words: breast cancer, chemotherapy, teniposide
Results Twenty-nine patients entered the study. Two patients were ineligible due to prior treatment with chemotherapy. Characteristics of evaluable patients are given in Table 1. The median number of treatment courses with teniposide was 7 (range, 1-19). Dose reductions and escalations were performed in 12 and 3 patients, respectively. Table I. Characteristics of evaluable patients. Total no. of patients No. of evaluable patients Median age in years (range) Performance status 0-1 2-3
Previous treatment (no. of patients) Adjuvant endocrine Endocrine for advanced disease Radiotherapy Sites of metastases Lung Liver Bone
Soft tissue Number of metastatic sites 1 2 >3
29 27
71 (63-79) 21 6 7 20 3 5 4 14 19 15 10 2
Downloaded from https://academic.oup.com/annonc/article-abstract/3/5/377/224138 by University of Western Sydney Library user on 14 January 2019
D. Nielsen,1 J. Boas,1 S. A. Engelholm,2 O. Paaske Hansen3 & P. Dombernowsky1
378
Discussion Previous trials have shown minor activity in heavily pretreated patients with metastatic breast cancer using daily or weekly schedules of teniposide [5, 6]. More recent studies using a day 1—5 every 3 weeks schedule have demonstrated an overall response rate of 8% PR's in 52 patients previously treated with chemotherapy [2, 3, 7]. Accordingly, a 7% response rate was found using etoposide (VP-16) to 383 heavily pretreated patients [8]. The low activity of the two epipodophyllotoxins have been observed at dose levels creating moderate to severe hematologic toxicity. However, valuable treatment effects have been overlooked when teniposide was used as second-line - or later treatment in lung cancer [9J. Only one phase II trial of the epipodophyllotoxin derivatives in previously untreated patients with breast cancer has been reported [10]. Treatment with etoposide 230 mg/m2 day 1-3 every 4 weeks was used. A response rate of 15% (3 PR's among 20 patients) was observed, but the toxic side effects, especially hematologic, were mild as no dose reductions were necessary. In our study we observed a response rate of 37% (95% confidence limits 19%-58%) and a median response duration of 9 months. We accepted, however,
a correspondingly more pronounced hematologic toxicity. A wide variation in the WBC and platelet nadirs was registered. Other authors have reported a similar toxicity [11]. We did not find any factors (performance status, tumor burden, or age) which predicted the hematological toxicity. Although the patient population in this study was highly selected according to age and sites of metastatic disease (soft tissue predominant) these results suggest that teniposide has at least modest activity in previously endocrine treated, elderly patients with advanced breast cancer.
References 1. Cox EB, Vogel CL, Carpenter JT Jr, Raney M. Phase II evaluation of teniposide (VM-26) in metastatic breast carcinoma. A Southeastern Cancer Study Group trial. Invest New Drugs 1988; 6: 37-40. 2. European Organization for Research on the Treatment of Cancer, Cooperative Group for Leukemias and Hematosarcomas. Clinical screening of epipodophyllotoxin VM-26 in malignant lymphomas and solid tumors. Br Med J 1972; 2: 744-8. 3. O'Dwyer P, Alonso MT, Leyland-Jones B, Marsoni S. Teniposide: a review of 12 years of experience. Cancer Treat Rep 1984; 68: 1455-66. 4. WHO Handbook for reporting Results of Cancer Treatment. Geneva: WHO; 1979. 5. Spremulli E, Schultz JJ, Speckhart VJ, Wampler GL. Phase II study of VM-26 in adult malignancies. Cancer Treat Rep 1980; 64: 147-9. 6. Tirelli U, Frenchin G, Crivellan D et al. Phase II study of VM-26 in extensively pretreated breast cancer. Am J Clin Oncol 1984; 7:451-2. 7. Boas J, Rasmussen D, Hansen OP, Engelholm SA, Dombernowsky P. Phase II study of teniposide in advanced breast cancer. Cancer Chemother Pharmacol 1990; 25:463-4. 8. Sledge Jr GW. Etoposide in the management of metastatic breast cancer. Cancer 1991; 67: 266-70. 9. Bork E, Hansen M, Dombernowsky P, Hansen SW, Pedersen AG, Hansen HH. Teniposide (VM-26), an overlooked highly active agent in small-cell lung cancer. Results of a phase II trial in untreated patients. J Clin Oncol 1986; 4: 524-7. 10. Wander H-E, Rauschning W, Meyer D, Achterrath W, Nagel G-A. Phase II study with etoposide in previously untreated advanced breast cancer. Cancer Chemother Pharmacol 1989; 24:261-3. 11. Bork E, Ersbell J, Dombernowsky P, Bergman B, Hansen M, Hansen HH. Teniposide and etoposide in previously untreated small-cell lung cancer A randomized study. J Clin Oncol 1991; 9: 1627-31. Received 18 November 1991; accepted 14 January 1992. Correspondence to: Done Nielsen, M.D. Department of Oncology Herlev Hospital University of Copenhagen Herlev Ringvej 2730 Herlev, Denmark
Downloaded from https://academic.oup.com/annonc/article-abstract/3/5/377/224138 by University of Western Sydney Library user on 14 January 2019
In one patient with a supraclavicular lymph node a complete response (CR) (3.7%, 95% confidence limits 0.1%-18.0%) was observed. The duration of her response was 7 months. Partial response (PR) was registered in 9 patients (33.3%, 95% confidence limits 16.5%-54.0%) with a median duration of 10 months (range, 2-31 months). Furthermore, 11 patients had no change (NC) with a median duration of 6 months (range, 1-13 months). After discontinuation of teniposide 4 patients received chemotherapy, among these one CR, one PR, and two NC were reported. Eight patients received endocrine therapy, 6 NC and 2 PD were observed. However, among these 6 patients had received antiestrogen for metastatic disease and 2 adjuvant endocrine therapy, respectively. Hematologic toxicity was dominant. The median WBC and platelet nadirs were 1.8 x 109/l (range, 0.34.1) and 116 x 1071 (range, 4-266), respectively. WBC nadirs below 3.0, 2.0, and 1.0 x 109/I were registered in 77%, 65% and 12%, respectively. In 42% the platelet counts were below 100xl0 9 /l and in 15% below 50 x 109/l. One patient experienced leukopenia (WBC 1.0 x 109/l) and fever and two developed septicaemia (WBC 0.3 and 0.6 x 109/l), resulting in one toxic death. Bleeding due to thrombocytopenia was observed in one patient with a platelet count of 4 x 109/l. Alopecia was observed in all patients, while none developed WHO grade III—IV nausea or vomiting.