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PHASE II STUDY OF TOPOTECAN IN EXTENSIVE STAGE SMALL CELL LUNG CANCER. J. H. Schiller, M.D.; K. Kim, Ph.D.; and D. Johnson, M.D. for the Eastern Cooperative Oncology Group, University of Wisconsin, Madison, WI; Dana-Faber Cancer Center, Boston, MA; Vanderbilt University, Nashville, TN.

Small cell carcinoma of the lung (SCLC) is a disease which is extremely sensitive to chemo- therapy. Etoposide, a topoisomerase II inhibitor, is among the most active single agents, with a 45% response rate as a single agent (1). Poly-chemotherapy regimens which include etoposide can be expected to induce responses in 70% to 90% of cases (2).

Despite the high response rates, however, median survival for patients with SCLC is only 9 to 12 months, and over 90% of patients will die of the disease. Identification of new, more active drugs is clearly crucial. Current recommendations regarding drug development for SCLC have indicated it is safe and ethical to test new agents in this group of patients, when appropriate safeguards are in place, particularly when the new agents: (1) have novel or unknown mechanisms of activity and which show clinical activity in other solid tumors, (2) show specific activity for small cell lung cancer in preclinical drug screens, or (3) are analogs of active drugs, and are being developed primarily because of a different toxicity profile (3,4).

Topotecan falls into the first group of agents. Topotecan is a water-soluble analog of camptothecan, a plant alkaloid extract derived from the oriental tree Camptothecun acumiruztu. Camptothecan is a potent inhibitor of DNA topoisomerase I, the enzyme that relaxes supercoiled DNA by creating single-stranded breaks through which another DNA strand can pass. Due to clinical toxicities observed with the parent compound, two semi-synthetic derivatives have been developed which are currently in clinical trials: CPT- 11 and topotecan. These agents stabilize a covalent DNA-topoisomerase I complex to yield enzyme linked DNA single strand breaks, resulting in breaks that cannot be relegated. They have been found to be active against a number of tumor models in vitro and in animal xenografts (5, 6).

CPT- 11 has been evaluated in 16 patients with refractory or relapsed SCLC, all of whom had received prior treatment with etoposide, a topoisomerase II inhibitor (7). Seven patients (47%) responded, with a median duration of response of 58 days. Responses to topotecan have also been observed in nonsmall cell lung carcinoma, esophageal cancer, adenocarcinoma of unknown primary, and platin-refractory ovarian carcinoma in Phase I trials (6,8)

Based upon the activity of etoposide, a topoisomerase II inhibitor; the preclinical and clinical activity of topoisomerase I inhibitors; and the need for identification of new, more active agents in this disease, the Eastern Cooperative Oncology Group (ECOG) is conducting a Phase II trial of topotecan in extensive-stage SCLC. The trial design is similar to that used by ECOG in other Phase II trials eval- uating other new agents for SCLC, with a cross-over to standard therapy with cisplatin and etoposide for nonresponding patients (9). The objective of the trial is to determine the response rate and survival of extensive-stage SCLC patients treated with topotecan.

All patients are required to have measurable or evaluable, previously untreated extensive-stage SCLC. Patients must have adequate bone marrow (WBC 2 4000/mm3, platelet count 2 100,000/mm3) hepatic (bilirubin I 1.5 mg%), and renal (creatinine I 1.5 mg%) function and an ECOG performance status of 0, 1, or 2. Patients with brain metastasis, a second primary cancer, or active infection were excluded.

Patients received 2.0 mg/m2 of topotecan intravenously as a 30 minute infusion daily for 5 days every 3 weeks.

Patients who had a partial or complete response to topotecan continued for a total of 4 to 6 cycles (minimum of 4 cycles, plus 2 cycles past a complete response). Patients who developed progressive disease after 1 cycle of topotecan, or stable disease following 2 cycles, were taken off topotecan, and were switched to salvage therapy with intravenous cisplatin and etoposide every 2 1 days for 6 to 8 cycles. Patients achieving a complete response were allowed prophylactic whole brain irradiation.

Thirty-eight of a planned 44 patients have been entered thus far. According to the two-stage design, the study had been temporarily suspended after the initial 13 patients for response verification. Data from these 13 patients are available for analysis.

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The median age of patients was 59 years with a range of 43-86. The sex ratio was 7 male, and 6 female. Only 4 patients had an ECOG performance status of 2. Fifty-four percent of patients lost more that 5% of body weight during the 6 months prior to entry on study. Six partial responses (45%) were observed. The median time to treatment failure was 4.3 months; however, the median survival has not been reached after a median follow-up of more than 6 months.

Fifteen percent and 77% of patients have experienced grade 3 and 4 neutropenia, respectively; 15% and 23% experienced grade 3 and 4 thrombocytopenia. One patient died of neutropenic fevers. Because of the high incidence of neutropenia, additional patients will receive granulocyte-colony- stimulating factor. Other toxicities included nausea and vomiting, and rash.

We conclude that topotecan is an active drug in small cell lung cancer. Additional trials are warranted to determine the optimal method of combining topotecan with other active cytotoxic drugs, including topoisomerase II inhibitors, for this disease.

References:

1. Comis RL: Principles and Practice of Oncology Updates 1: 1-18, 1987 2. Ihde D: N Engl J Med 327: 1434-1441, 1992 3. Moore T and Kom E: J Nat1 Cancer Inst 84: 150-154, 1992 4. Ettinger D: J Clin Oncol8: 374-377, 1990 5. Chabner B: J Clin Oncol 10: 3-4, 1992 6. Rowinsky E, et al: J Clin Oncol 10: 647-656, 1992 7. Masuda N, et al: CPT-11: J Clin Oncol 10: 1225-1229, 1992 8. Saltz L, et al: J Nat1 Cancer Inst 85: 1499-1507, 1993 9. Ettinger D, et al.: Proc ASCO 9: 224, 1990