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Topotecan in small cell lung cancer
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Chemotherapy: New Agents, Combinations
Topotecan in small cell lung cancer Joan H. Schiller. University of Wisconsin Comprehensive. Cancer Center, Madison, W/, USA A plant alkaloid extract derived from the oriental tree, Cafnptothecan acuminata, Camptothecin is a potent inhibitor of the nuclear enzyme DNA topoisomerase I. Topoisomerases are nuclear enzymes essential for DNA replication and RNA synthesis, as they help relieve torsional “strain” created by unwinding of DNA during transcription and translation. One of two types of topoisomerases, topoisomerase I (top0 I) relaxes supercoiled DNA by creating single-stranded breaks through which another DNA strand can pass during DNA replication. Camptothecan and three semi-synthetic derivatives (irinotecan or CPT-11,9-aminocamptothecin and topotecan) stabilize a covalent DNA-top0 I complex to yield enzyme-linked DNA single-strand breaks by reversibly inhibiting the religation step of topo I, thus increasing the number of covalent topo-I DNA adducts or cleavable complexes in the cell. These compounds have been found to be active against a number of tumor models in vitro and in animal xenografts, raising considerable interest in their clinical anti-tumor activity [i-3]. In addition to significant antitumor activity in cisplatin-refractory ovarian cancer, topotecan has been shown to have significant clinical activity in small cell lung cancer (SCLC). The Eastern Cooperative Oncology Group conducted a phase II trial of topotecan in which forty-eight patients with previously untreated, extensive-stage small cell lung cancer received 2.0 mg/m2 of topotecan daily for 5 days [4]. The first 13 patients were treated without colony-stimulating-factor support; the next 35 patients received 5 mcglkg of granulocyte-colonystimulating factor for IO to 14 days starting on day 6. Cycles were repeated every 3 weeks for a maximum of 4 cycles. Nineteen of the 48 patients had a partial response for an objective response rate of 39%. The median response duration was 4.8 months. After median follow-up of 18.2 months, the overall median survival was 10.0 months; 1 -year survival rate was 39%. The most common toxicity was hematologic. Ninety-two percent of patients treated without G-CSF developed grade 3 or 4 neutropenia, compared to 29% receiving G-CSF. The incidence of neutropenic fevers was 11% and 8% in the groups with and without G-CSF, respectively, and 1 patient in each group died of infection. Thrombocytopenia and anemia were relatively mild (incidence of grade 3 and 4 thrombocytopenia and anemia of 38% and 27%, respectively). Nonhematologic toxicity was otherwise mild. Other investigators have explored the role of topotecan in previously treated patients with SCLC. The European Organization for Research and Treatment of Cancer (EORTC) studied patients who had either failed first-line treatment 53 months from chemotherapy discontinuation (“refractory” patients) or who had responded to first-line therapy and progressed ~3 months after their chemotherapy was stopped (“sensitive” patients) [5]. One hundred one patients were entered onto the study; 86 were evaluable for response. Patients receive 1.5 mg/m2 for 5 consecutive days every 3 weeks until disease progression or toxicity. The overall response rate was 23%; however, 39% of the “sensitive” group responded whereas only 7% of the “refractory” group responded. The median survival of the “refractory” patients was 4.7 months
in Small Cell Lung Cancer
while the median survival of the “sensitive” patients was 6.9 months. A similar trial was conducted by Eckardt, et al. in 99 patients with SCLC who had failed one prior chemotherapy regimen [6]. Forty-seven patients were “refractory” to their prior therapy and 52 were “sensitive,” using definitions very similar to those used in the EORTC study. Results were analyzed by “intent-to-treat,” and revealed a 2% response rate in “refractory” patients and a 15% response rate in “sensitive” patients. The observed response rates were significantly lower than in the EORTC trial, perhaps due to differences in the intent-totreat analysis in the U.S. study versus the number of patients that were unevaluable for response in the EORTC trial. However, the median survival was similar; 21 weeks and 28 weeks in the “refractory” and “sensitive” groups, respectively. M.D. Anderson Cancer Center also conducted a Phase II trial of topotecan, but restricted their patient population to patients who had failed to respond to etoposide containing frontline therapy, or who had progressed during or within 3 months of the first dose of etoposide containing front-line or secondline therapy [7]. Three of 28 (11%) evaluable patients achieved a partial remission; one of these three had failed to respond to front-line cisplatin and etoposide. The overall median duration of survival was 20 weeks. Interestingly, topotecan has been reported to have activity on SCLC brain metastases [8]. Topotecan was administered to 16 patients with asymptomatic SCLC brain metastases. Four of 16 had a complete response and 6 of 16 had a partial response, with a CNS response rate of 63%. Responses were observed both systemically, as well as in the brain. These data suggest that topotecan has significant activity in small cell lung cancer as a first line agent, or in patients who have relapsed more than 3 months from their prior therapy. The activity of this agent warrants additional investigation to determine the optimal method of combining this agent with other cytotoxic drugs for SCLC. References [I] Chabner, B.A. 1992. Camptothecins. J Clin Oncol 10: 34. [2] Liu, L. 1989. DNA topoisomerase poisons as antitumor drugs, Ann. Rev. Biochem. 58: 351375. [3] Rowinsky, E.K., L.B. Grochow, C.B. Hendricks, D.S. Ettinger, A.A. Forastiere. L.A. Hurowitz, W.P. McGuire, SE. Sartorius, B.G. Lubejko, S.H. Kaufmann. and R.C. Donehower. 1992. Phase I and pharmacologic study of topotecan: A novel topoisomerase I inhibitor. J Clin Oncol 10: 647-656. [4] Schiller, J.H., K. Kim, P. Hutson, R. DeVore, J. Glick, J. Stewart, and D. Johnson. 1998. Phase II study of topotecan in patients with extensive-stage small cell carcinoma of the lung: an Eastern Cooperative Oncology Group Trial (E1592). J Clin Oncol 14: 234%2352. [5] Ardizzoni, A., H. Hansen, J. Wanders, P. Dombernowsky, T. Gamucci, S. Kaplan, P. Postmus, I. Hudson, G. Giaccone, and J. Verweij. 1996. Topotecan (T), a new active agent in the second-line treatment of “refractory” and “sensitive” small-ceil lung cancer (SCLC). Ann Oncol 7 (Suppl 5): 106. (61 Eckardt, J., R. Gralla, MC. Palmer, D. Gandara, J. Laplante, A. Sandler, S.Z. Fields, D. Fitts, and C. Broom. 1996. Topotecan (T) as second-line theraov in oatients with small cell luna cancer fSCLC): a phase II study. Ann Oncol7 (Suppl5): 107. ’ [7j Perez-Soler, FL, B.S. Glisson, J.S. Lee, F.V. Fossella, W.K. Murphy, D.M. Shin, and W.K. Hong. 1996. Treatment of patients with small-cell lung cancer refractory to etoside and cisplatin with the topoisomerase I poison topotecan. J Clin Oncol 14 (10): 2785-2790. [8] Managold, C., J.V. Pawel, W. Scheithauer, J. Lan, B. Schaefer, R. Pastovic, and H.J. Staab. 1996. Response of SCLC brain metastases on topotecan (SK&F 104864) therapy. Ann Oncol7 (Suppl5): 106.
Chemotherapy: New Agents, Combinations
Topotecan in small cell lung cancer Joan H. Schiller. University of Wisconsin Comprehensive. Cancer Center, Madison, W/, USA A plant alkaloid extract derived from the oriental tree, Cafnptothecan acuminata, Camptothecin is a potent inhibitor of the nuclear enzyme DNA topoisomerase I. Topoisomerases are nuclear enzymes essential for DNA replication and RNA synthesis, as they help relieve torsional “strain” created by unwinding of DNA during transcription and translation. One of two types of topoisomerases, topoisomerase I (top0 I) relaxes supercoiled DNA by creating single-stranded breaks through which another DNA strand can pass during DNA replication. Camptothecan and three semi-synthetic derivatives (irinotecan or CPT-11,9-aminocamptothecin and topotecan) stabilize a covalent DNA-top0 I complex to yield enzyme-linked DNA single-strand breaks by reversibly inhibiting the religation step of topo I, thus increasing the number of covalent topo-I DNA adducts or cleavable complexes in the cell. These compounds have been found to be active against a number of tumor models in vitro and in animal xenografts, raising considerable interest in their clinical anti-tumor activity [i-3]. In addition to significant antitumor activity in cisplatin-refractory ovarian cancer, topotecan has been shown to have significant clinical activity in small cell lung cancer (SCLC). The Eastern Cooperative Oncology Group conducted a phase II trial of topotecan in which forty-eight patients with previously untreated, extensive-stage small cell lung cancer received 2.0 mg/m2 of topotecan daily for 5 days [4]. The first 13 patients were treated without colony-stimulating-factor support; the next 35 patients received 5 mcglkg of granulocyte-colonystimulating factor for IO to 14 days starting on day 6. Cycles were repeated every 3 weeks for a maximum of 4 cycles. Nineteen of the 48 patients had a partial response for an objective response rate of 39%. The median response duration was 4.8 months. After median follow-up of 18.2 months, the overall median survival was 10.0 months; 1 -year survival rate was 39%. The most common toxicity was hematologic. Ninety-two percent of patients treated without G-CSF developed grade 3 or 4 neutropenia, compared to 29% receiving G-CSF. The incidence of neutropenic fevers was 11% and 8% in the groups with and without G-CSF, respectively, and 1 patient in each group died of infection. Thrombocytopenia and anemia were relatively mild (incidence of grade 3 and 4 thrombocytopenia and anemia of 38% and 27%, respectively). Nonhematologic toxicity was otherwise mild. Other investigators have explored the role of topotecan in previously treated patients with SCLC. The European Organization for Research and Treatment of Cancer (EORTC) studied patients who had either failed first-line treatment 53 months from chemotherapy discontinuation (“refractory” patients) or who had responded to first-line therapy and progressed ~3 months after their chemotherapy was stopped (“sensitive” patients) [5]. One hundred one patients were entered onto the study; 86 were evaluable for response. Patients receive 1.5 mg/m2 for 5 consecutive days every 3 weeks until disease progression or toxicity. The overall response rate was 23%; however, 39% of the “sensitive” group responded whereas only 7% of the “refractory” group responded. The median survival of the “refractory” patients was 4.7 months
in Small Cell Lung Cancer
while the median survival of the “sensitive” patients was 6.9 months. A similar trial was conducted by Eckardt, et al. in 99 patients with SCLC who had failed one prior chemotherapy regimen [6]. Forty-seven patients were “refractory” to their prior therapy and 52 were “sensitive,” using definitions very similar to those used in the EORTC study. Results were analyzed by “intent-to-treat,” and revealed a 2% response rate in “refractory” patients and a 15% response rate in “sensitive” patients. The observed response rates were significantly lower than in the EORTC trial, perhaps due to differences in the intent-totreat analysis in the U.S. study versus the number of patients that were unevaluable for response in the EORTC trial. However, the median survival was similar; 21 weeks and 28 weeks in the “refractory” and “sensitive” groups, respectively. M.D. Anderson Cancer Center also conducted a Phase II trial of topotecan, but restricted their patient population to patients who had failed to respond to etoposide containing frontline therapy, or who had progressed during or within 3 months of the first dose of etoposide containing front-line or secondline therapy [7]. Three of 28 (11%) evaluable patients achieved a partial remission; one of these three had failed to respond to front-line cisplatin and etoposide. The overall median duration of survival was 20 weeks. Interestingly, topotecan has been reported to have activity on SCLC brain metastases [8]. Topotecan was administered to 16 patients with asymptomatic SCLC brain metastases. Four of 16 had a complete response and 6 of 16 had a partial response, with a CNS response rate of 63%. Responses were observed both systemically, as well as in the brain. These data suggest that topotecan has significant activity in small cell lung cancer as a first line agent, or in patients who have relapsed more than 3 months from their prior therapy. The activity of this agent warrants additional investigation to determine the optimal method of combining this agent with other cytotoxic drugs for SCLC. References [I] Chabner, B.A. 1992. Camptothecins. J Clin Oncol 10: 34. [2] Liu, L. 1989. DNA topoisomerase poisons as antitumor drugs, Ann. Rev. Biochem. 58: 351375. [3] Rowinsky, E.K., L.B. Grochow, C.B. Hendricks, D.S. Ettinger, A.A. Forastiere. L.A. Hurowitz, W.P. McGuire, SE. Sartorius, B.G. Lubejko, S.H. Kaufmann. and R.C. Donehower. 1992. Phase I and pharmacologic study of topotecan: A novel topoisomerase I inhibitor. J Clin Oncol 10: 647-656. [4] Schiller, J.H., K. Kim, P. Hutson, R. DeVore, J. Glick, J. Stewart, and D. Johnson. 1998. Phase II study of topotecan in patients with extensive-stage small cell carcinoma of the lung: an Eastern Cooperative Oncology Group Trial (E1592). J Clin Oncol 14: 234%2352. [5] Ardizzoni, A., H. Hansen, J. Wanders, P. Dombernowsky, T. Gamucci, S. Kaplan, P. Postmus, I. Hudson, G. Giaccone, and J. Verweij. 1996. Topotecan (T), a new active agent in the second-line treatment of “refractory” and “sensitive” small-ceil lung cancer (SCLC). Ann Oncol 7 (Suppl 5): 106. (61 Eckardt, J., R. Gralla, MC. Palmer, D. Gandara, J. Laplante, A. Sandler, S.Z. Fields, D. Fitts, and C. Broom. 1996. Topotecan (T) as second-line theraov in oatients with small cell luna cancer fSCLC): a phase II study. Ann Oncol7 (Suppl5): 107. ’ [7j Perez-Soler, FL, B.S. Glisson, J.S. Lee, F.V. Fossella, W.K. Murphy, D.M. Shin, and W.K. Hong. 1996. Treatment of patients with small-cell lung cancer refractory to etoside and cisplatin with the topoisomerase I poison topotecan. J Clin Oncol 14 (10): 2785-2790. [8] Managold, C., J.V. Pawel, W. Scheithauer, J. Lan, B. Schaefer, R. Pastovic, and H.J. Staab. 1996. Response of SCLC brain metastases on topotecan (SK&F 104864) therapy. Ann Oncol7 (Suppl5): 106.