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A Phase II Study of Topotecan in Patients with Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study
Gynecologic Oncology 81, 213–215 (2001) doi:10.1006/gyno.2000.6024, available online at http://www.idealibrary.com on
A Phase II Study of Topotecan in Patients with Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study 1 Laila I. Muderspach, M.D.,* ,2 John A. Blessing, Ph.D.,† Charles Levenback, M.D.,‡ and James L. Moore, Jr., M.D.§ *Division of Gynecologic Oncology, University of Southern California, Los Angeles, California 90033; †Gynecologic Oncology Group, Cancer Research Scientist VI, Roswell Park Cancer Institute, Buffalo, New York; ‡Department of Gynecologic Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030; and §Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Mississippi Medical Center, Jackson, Mississippi 39216 Received January 24, 2000; published online April 4, 2001
Objective. The toxicity and activity of intravenous topotecan were assessed in a multicenter Phase II study (GOG 76-U) in patients with advanced, recurrent, or persistent squamous cell carcinoma of the uterine cervix. Methods. Intravenous topotecan was administered at 1.5 mg/m 2 per day for 5 consecutive days every 4 weeks in patients without prior chemotherapy, aside from chemosensitizing agents used in conjunction with radiotherapy. The study required histologic confirmation of primary diagnosis, adequate performance status, and measurable disease to assess response. A two-stage design for accrual was used to allow for early termination of the study should inadequate response or excessive toxicity be an issue. Modifications of dose were based on hematologic toxicity. Treatment was continued until progression of disease was documented or adverse effects prohibited further therapy. Results. A total of 49 patients were entered on study; of these 5 were never treated, and 1 was not evaluable for response. More than 88% (38 of 43 patients) had received prior radiotherapy. A median of two courses were administered per patient with a range of 1 to 14 cycles. Grade 4 neutropenia occurred in 68% and grade 4 thrombocytopenia in 18% of patients. Nonhematologic toxic effects were infrequent and not dose-limiting. The overall response rate (complete and partial) was 18.6%. The median progressionfree survival was 2.4 months.
Conclusions. Topotecan administered at this dose and schedule demonstrated moderate activity albeit at a cost of substantial hematologic toxicity in patients with advanced, recurrent, and persistent squamous cell carcinoma of the cervix. © 2001 Academic Press Key Words: topotecan; cervical cancer; squamous carcinoma of the uterine cervix.
INTRODUCTION
1
Cervical cancer remains a significant worldwide problem for women, particularly those outside the United States. However, even in the United States where screening and treatment of precursor lesions have made an impact on this disease, advanced cervical cancer is a problem [1]. Unfortunately, treatment of advanced disease with chemotherapeutic agents still yields limited success rates. Therefore, the Gynecologic Oncology Group (GOG) has pursued continued identification of new active drugs that might lead to improved remission rates. Currently, cisplatin remains the single agent with most activity in the treatment of advanced cervical cancer [2]. However, other alternatives and combinations that might augment cisplatin’s efficacy are necessary. Because of interest in camptothecins and their mechanism of action [3], as well as intriguing feasibility and response information including moderate response rates in squamous cancer of the lung [4] as well as ovarian cancer, the GOG evaluated topotecan in this Phase II trial. Topotecan (9-dimethylaminomethyl-10-hydroxycamptothecin) is a water-soluble semisynthetic camptothecin analogue that inhibits the intranuclear enzyme topoisomerase 1 [5]. Topotecan binds to topoisomerase 1, creating an enzyme–DNA complex that blocks DNA replication, leading to strand breaks and cell death [6]. Other work suggests that topotecan may be S phase specific and activity is related to anchorage status or cell attachment [7]. The optimal dosing schedule for topotecan administration remains unclear. However, previous Phase I/II studies have investigated prolonged administration or repeated dosing regimens because of reversible side effects and toxicity. Most
This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517). The following Gynecologic Oncology Group institutions participated in this study: University of Southern California Medical Center at Los Angeles, University of Mississippi Medical Center, Indiana University Medical Center, Bowman Gray School of Medicine of Wake Forest University, The Albany Medical College of Union University, University of California Medical Center at Irvine, Eastern Virginia Medical School, The Johns Hopkins Oncology Center, University of Texas M.D. Anderson Cancer Center, and University of Toronto/Sunnybrook Regional Cancer Center. 2 To whom correspondence should be addressed at Division of Gynecologic Oncology, 1441 Eastlake Avenue No. 7417, Los Angeles, CA 90033. Fax: (323) 226-2734. E-mail: [email protected]. Address reprint requests to GOG Administrative Office, Suite 1945, 1234 Market Street, Philadelphia, PA 19107. 213
0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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TABLE 1 Patient Characteristics (N ⴝ 43) Characteristic Age (years) Median Range GOG performance status 0 1 2 Site of measurable disease Pelvis Extrapelvic Prior radiotherapy Tumor grade 1 2 3
Number of patients (%)
44.0 23–74 15 (34.9) 19 (44.2) 9 (20.9) 23 (53.5) 20 (46.5) 38 (88.4) 4 (9.3) 23 (53.5) 16 (37.2)
published clinical experience used a 5-day regimen with a 30-min topotecan infusion. This regimen has demonstrated activity in patients with other squamous cancers and with previously treated epithelial ovarian cancer [8 –10]. MATERIAL AND METHODS Between January 1994 and December 1995, 49 women with advanced, recurrent, or persistent squamous cell carcinoma of the cervix were enrolled into this GOG study using topotecan. Five patients were never treated and one was evaluable only for toxicity; thus, 43 patients were evaluable for response. In all women the diagnosis of recurrence was confirmed by histologic review by the GOG pathology committee. All patients had measurable disease by physical or radiologic examination. In addition, patients must have failed primary surgical and/or radiation therapy, not received prior chemotherapy, and not be candidates for curative therapy. Patients who had received agents for chemosensitization with concomitant radiation were not excluded. In addition, eligibility requirements included: GOG performance status of 0 –2, WBC ⱖ 3000/l [with absolute neutrophil count (ANC) ⱖ 1500/l], platelets ⱖ 100,000/l, creatinine ⱕ 2.0 mg/dl, bilirubin ⱕ 1.5 ⫻ normal, and serum glutamic– oxaloacetic transaminase (AST, SGOT) along with alkaline phosphatase ⱕ 3X normal. Written informed consent was obtained from all women prior to entry on study fulfilling all institutional, state, and federal regulations. According to GOG 76 Phase II trial statistics, the target sample size was 48 patients, which is a larger than normal sample size to accurately assess the true response rate within ⫹10%. There was two-step enrollment, which allowed for interim analysis after 20 patients to determine if at least two responses were present to resume the study; otherwise the study would have been closed.
Topotecan was provided by the Cancer Therapy Evaluation Program of the National Cancer Institute (Bethesda, MD) in collaboration with SmithKline Beecham (Collegeville, PA). Patients were treated with an intravenous dose of 1.5 mg/m 2 over 30 min daily for 5 consecutive days based on information from ovarian cancer studies. Dose modifications and delays were made to manage toxicity; however, there was no dose modification made for prior radiation or renal function. This study was conducted before information about toxicity related to renal function was available. Hematopoietic colony-stimulating factors were not prophylactically administered. Treatment was continued until there was progression of disease or adverse effects preventing further therapy. A dose level reduction to 1.0 mg/m 2 was made for any grade 4 hematologic toxicity. A maximum delay of 14 days was allowed for recovery of the ANC ⱖ 1500/l and platelets ⱖ 100,000/l. A dose level escalation to 2.0 mg/m 2 was allowed for hematologic toxicity less than grade 2 since this was a Phase II study. Toxicity was reported according to the GOG common toxicity criteria. Response was defined according to GOG criteria. Complete response (CR) was defined by the disappearance of all measurable disease for at least 4 weeks; partial response (PR) required a 50% reduction in the product of the transverse diameters of each measurable lesion for at least 4 weeks. Increasing disease required a 50% increase in the product of transverse diameters of any lesion or the appearance of new lesions within 8 weeks of entry. All other patients were categorized as having stable disease. RESULTS The patients’ characteristics are listed in Table 1. The median age was 44 years (range, 23–74 years). The majority of patients had prior radiation treatment (38/43, 88.4%). The TABLE 2 Adverse Effects (N ⴝ 44) Adverse effect Hematologic Neutropenia, grade 4 Thrombocytopenia, grade 4 Anemia, grades 3 and 4 Nonhematologic (grades 3 and 4) a Gastrointestinal Neurologic Cardiovascular Fever Vaginal bleeding Dyspnea Deep vein thrombosis Alkaline phosphatase Bilirubin Death a
Recorded as possibly drug-related toxicity.
Number (%)
30 (68.2) 8 (18.2) 6 (13.6) 4 (9.1) 2 (4.5) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3)
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TOPOTECAN IN SQUAMOUS CERVICAL CANCER
TABLE 3 Clinical Response Response
Number (%)
Complete response Partial response Stable disease Increasing disease
3 (7.0) 5 (11.6) 14 (32.6) 21 (48.8)
median GOG performance status was 1. Table 2 summarizes the adverse effects and reports of all grade 3 or 4 events. Hematologic toxicity was common, with 68% of patients experiencing grade 4 neutropenia and 18% experiencing grade 4 thrombocytopenia. However, hematologic toxicity was not cumulative and patients could receive further cycles of chemotherapy after the initial dose was reduced according to the protocol. One death from septic complications was considered potentially due to treatment. This patient never completed the 5 days of topotecan and was admitted with sepsis and died from complications related to overwhelming infection and disease. Of the 43 patients evaluable for response, there were 3 complete responders (7.0%) and 5 partial responders (11.6%). Of those with complete response, all had prior radiation and 2 of 3 had disease within the radiation field. Only one patient had a partial response within the radiation field. The overall response rate (CR ⫹ PR) was 18.6% (95% confidence interval: 8.4 –33.4%). The clinical response information is summarized in Table 3. The median progression-free interval was 2.4 months (range, 0.4 –25.9⫹ months). The median overall survival was 6.4 months (range, 0.4 – 42.3⫹ months). DISCUSSION Since cervical cancer is a significant global problem, identification of new drugs and methods of treatment is needed. In addition, an active drug with a mechanism of action different from that of cisplatin, currently the most active drug, might be of interest for combination therapy. A prior Phase III GOG study with three arms (cisplatin alone, cisplatin plus mitolactol, cisplatin plus ifosfamide) demonstrated a higher response rate with combination regimens, however, at the cost of increased toxicity and without survival benefit [11]. In the present GOG Phase II trial, topotecan administration was feasible with acceptable toxicity. Hematologic toxicity was common but generally managed with a delay in treatment, dose reduction, or use of colony-stimulating factors. The inci-
dence of grade 4 neutropenia and thrombocytopenia in this trial was similar to the experience reported with previously treated patients with epithelial ovarian cancer. However, in patients with prior radiation and borderline renal function, it may be helpful to start at a dose of 1.25 mg/m 2 rather than 1.5 mg/m 2. In this study, single-agent topotecan, a semisynthetic, watersoluble camptothecin derivative that inhibits topoisomerase activity, exhibited moderate activity in patients with advanced, recurrent, or persistent squamous cell carcinoma of the cervix. Of clinical interest, two of three patients with complete response had regression of disease within the radiation field. Potential future roles for topotecan may include combination with cisplatin or use as a radiation sensitizing agent. Because of the pharmacokinetics of topotecan, future studies may consider other schedules for administration such as continuous infusion and oral administration. REFERENCES 1. NIH consensus statement on cervical cancer. NIH 14(1):1–23, 1996 2. Bonomi P, Blessing JSA, Stehman FB, et al.: Randomized trial of three cisplatin dose schedules in squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 3:1079 –1085, 1985 3. Muggia FM, Dimery I, Arbuck SG: Camptothecin and its analogs: an overview of their potential in cancer therapeutics. Ann NY Acad Sci 903:21323, 1996 4. Schiller JH: Topotecan in small cell lung cancer. Semin Oncol 24 (6, Suppl 20):S34 –S41, 1997 5. Rowinsky EK, Grochow LB, Hendricks CB, et al.: Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 10:647– 656, 1992 6. Hsiang YH, Liu LF: Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 48:1722–1726, 1988 7. Whiteacre CM, Berger NA: Factors affecting topotecan-induced programmed cell death: adhesion protects cells from apoptosis and impairs cleavage of poly(ADP-ribose) polymerase. Cancer Res 57:2157–2163, 1997 8. Saltz L, Sirott M, Young C, et al.: Phase I clinical and pharmacology study of topotecan given daily for 5 consecutive days to patients with advanced solid tumors, with attempt at dose intensification using recombinant granulocyte colony-stimulating factor. J Natl Can Inst 85:1499 –1507, 1993 9. Kudelka AP, Tresukosol D, Edwards CL, et al.: Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 14:1552–1557, 1996 10. Creemers GJ, Bolis G, Gore M, et al.: Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study. J Clin Oncol 14:3056 –3061, 1996 11. Omura GA, Blessing JA, Vaccarello L, et al.: Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 15:165–171, 1997
A Phase II Study of Topotecan in Patients with Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study 1 Laila I. Muderspach, M.D.,* ,2 John A. Blessing, Ph.D.,† Charles Levenback, M.D.,‡ and James L. Moore, Jr., M.D.§ *Division of Gynecologic Oncology, University of Southern California, Los Angeles, California 90033; †Gynecologic Oncology Group, Cancer Research Scientist VI, Roswell Park Cancer Institute, Buffalo, New York; ‡Department of Gynecologic Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030; and §Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Mississippi Medical Center, Jackson, Mississippi 39216 Received January 24, 2000; published online April 4, 2001
Objective. The toxicity and activity of intravenous topotecan were assessed in a multicenter Phase II study (GOG 76-U) in patients with advanced, recurrent, or persistent squamous cell carcinoma of the uterine cervix. Methods. Intravenous topotecan was administered at 1.5 mg/m 2 per day for 5 consecutive days every 4 weeks in patients without prior chemotherapy, aside from chemosensitizing agents used in conjunction with radiotherapy. The study required histologic confirmation of primary diagnosis, adequate performance status, and measurable disease to assess response. A two-stage design for accrual was used to allow for early termination of the study should inadequate response or excessive toxicity be an issue. Modifications of dose were based on hematologic toxicity. Treatment was continued until progression of disease was documented or adverse effects prohibited further therapy. Results. A total of 49 patients were entered on study; of these 5 were never treated, and 1 was not evaluable for response. More than 88% (38 of 43 patients) had received prior radiotherapy. A median of two courses were administered per patient with a range of 1 to 14 cycles. Grade 4 neutropenia occurred in 68% and grade 4 thrombocytopenia in 18% of patients. Nonhematologic toxic effects were infrequent and not dose-limiting. The overall response rate (complete and partial) was 18.6%. The median progressionfree survival was 2.4 months.
Conclusions. Topotecan administered at this dose and schedule demonstrated moderate activity albeit at a cost of substantial hematologic toxicity in patients with advanced, recurrent, and persistent squamous cell carcinoma of the cervix. © 2001 Academic Press Key Words: topotecan; cervical cancer; squamous carcinoma of the uterine cervix.
INTRODUCTION
1
Cervical cancer remains a significant worldwide problem for women, particularly those outside the United States. However, even in the United States where screening and treatment of precursor lesions have made an impact on this disease, advanced cervical cancer is a problem [1]. Unfortunately, treatment of advanced disease with chemotherapeutic agents still yields limited success rates. Therefore, the Gynecologic Oncology Group (GOG) has pursued continued identification of new active drugs that might lead to improved remission rates. Currently, cisplatin remains the single agent with most activity in the treatment of advanced cervical cancer [2]. However, other alternatives and combinations that might augment cisplatin’s efficacy are necessary. Because of interest in camptothecins and their mechanism of action [3], as well as intriguing feasibility and response information including moderate response rates in squamous cancer of the lung [4] as well as ovarian cancer, the GOG evaluated topotecan in this Phase II trial. Topotecan (9-dimethylaminomethyl-10-hydroxycamptothecin) is a water-soluble semisynthetic camptothecin analogue that inhibits the intranuclear enzyme topoisomerase 1 [5]. Topotecan binds to topoisomerase 1, creating an enzyme–DNA complex that blocks DNA replication, leading to strand breaks and cell death [6]. Other work suggests that topotecan may be S phase specific and activity is related to anchorage status or cell attachment [7]. The optimal dosing schedule for topotecan administration remains unclear. However, previous Phase I/II studies have investigated prolonged administration or repeated dosing regimens because of reversible side effects and toxicity. Most
This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517). The following Gynecologic Oncology Group institutions participated in this study: University of Southern California Medical Center at Los Angeles, University of Mississippi Medical Center, Indiana University Medical Center, Bowman Gray School of Medicine of Wake Forest University, The Albany Medical College of Union University, University of California Medical Center at Irvine, Eastern Virginia Medical School, The Johns Hopkins Oncology Center, University of Texas M.D. Anderson Cancer Center, and University of Toronto/Sunnybrook Regional Cancer Center. 2 To whom correspondence should be addressed at Division of Gynecologic Oncology, 1441 Eastlake Avenue No. 7417, Los Angeles, CA 90033. Fax: (323) 226-2734. E-mail: [email protected]. Address reprint requests to GOG Administrative Office, Suite 1945, 1234 Market Street, Philadelphia, PA 19107. 213
0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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MUDERSPACH ET AL.
TABLE 1 Patient Characteristics (N ⴝ 43) Characteristic Age (years) Median Range GOG performance status 0 1 2 Site of measurable disease Pelvis Extrapelvic Prior radiotherapy Tumor grade 1 2 3
Number of patients (%)
44.0 23–74 15 (34.9) 19 (44.2) 9 (20.9) 23 (53.5) 20 (46.5) 38 (88.4) 4 (9.3) 23 (53.5) 16 (37.2)
published clinical experience used a 5-day regimen with a 30-min topotecan infusion. This regimen has demonstrated activity in patients with other squamous cancers and with previously treated epithelial ovarian cancer [8 –10]. MATERIAL AND METHODS Between January 1994 and December 1995, 49 women with advanced, recurrent, or persistent squamous cell carcinoma of the cervix were enrolled into this GOG study using topotecan. Five patients were never treated and one was evaluable only for toxicity; thus, 43 patients were evaluable for response. In all women the diagnosis of recurrence was confirmed by histologic review by the GOG pathology committee. All patients had measurable disease by physical or radiologic examination. In addition, patients must have failed primary surgical and/or radiation therapy, not received prior chemotherapy, and not be candidates for curative therapy. Patients who had received agents for chemosensitization with concomitant radiation were not excluded. In addition, eligibility requirements included: GOG performance status of 0 –2, WBC ⱖ 3000/l [with absolute neutrophil count (ANC) ⱖ 1500/l], platelets ⱖ 100,000/l, creatinine ⱕ 2.0 mg/dl, bilirubin ⱕ 1.5 ⫻ normal, and serum glutamic– oxaloacetic transaminase (AST, SGOT) along with alkaline phosphatase ⱕ 3X normal. Written informed consent was obtained from all women prior to entry on study fulfilling all institutional, state, and federal regulations. According to GOG 76 Phase II trial statistics, the target sample size was 48 patients, which is a larger than normal sample size to accurately assess the true response rate within ⫹10%. There was two-step enrollment, which allowed for interim analysis after 20 patients to determine if at least two responses were present to resume the study; otherwise the study would have been closed.
Topotecan was provided by the Cancer Therapy Evaluation Program of the National Cancer Institute (Bethesda, MD) in collaboration with SmithKline Beecham (Collegeville, PA). Patients were treated with an intravenous dose of 1.5 mg/m 2 over 30 min daily for 5 consecutive days based on information from ovarian cancer studies. Dose modifications and delays were made to manage toxicity; however, there was no dose modification made for prior radiation or renal function. This study was conducted before information about toxicity related to renal function was available. Hematopoietic colony-stimulating factors were not prophylactically administered. Treatment was continued until there was progression of disease or adverse effects preventing further therapy. A dose level reduction to 1.0 mg/m 2 was made for any grade 4 hematologic toxicity. A maximum delay of 14 days was allowed for recovery of the ANC ⱖ 1500/l and platelets ⱖ 100,000/l. A dose level escalation to 2.0 mg/m 2 was allowed for hematologic toxicity less than grade 2 since this was a Phase II study. Toxicity was reported according to the GOG common toxicity criteria. Response was defined according to GOG criteria. Complete response (CR) was defined by the disappearance of all measurable disease for at least 4 weeks; partial response (PR) required a 50% reduction in the product of the transverse diameters of each measurable lesion for at least 4 weeks. Increasing disease required a 50% increase in the product of transverse diameters of any lesion or the appearance of new lesions within 8 weeks of entry. All other patients were categorized as having stable disease. RESULTS The patients’ characteristics are listed in Table 1. The median age was 44 years (range, 23–74 years). The majority of patients had prior radiation treatment (38/43, 88.4%). The TABLE 2 Adverse Effects (N ⴝ 44) Adverse effect Hematologic Neutropenia, grade 4 Thrombocytopenia, grade 4 Anemia, grades 3 and 4 Nonhematologic (grades 3 and 4) a Gastrointestinal Neurologic Cardiovascular Fever Vaginal bleeding Dyspnea Deep vein thrombosis Alkaline phosphatase Bilirubin Death a
Recorded as possibly drug-related toxicity.
Number (%)
30 (68.2) 8 (18.2) 6 (13.6) 4 (9.1) 2 (4.5) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3)
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TOPOTECAN IN SQUAMOUS CERVICAL CANCER
TABLE 3 Clinical Response Response
Number (%)
Complete response Partial response Stable disease Increasing disease
3 (7.0) 5 (11.6) 14 (32.6) 21 (48.8)
median GOG performance status was 1. Table 2 summarizes the adverse effects and reports of all grade 3 or 4 events. Hematologic toxicity was common, with 68% of patients experiencing grade 4 neutropenia and 18% experiencing grade 4 thrombocytopenia. However, hematologic toxicity was not cumulative and patients could receive further cycles of chemotherapy after the initial dose was reduced according to the protocol. One death from septic complications was considered potentially due to treatment. This patient never completed the 5 days of topotecan and was admitted with sepsis and died from complications related to overwhelming infection and disease. Of the 43 patients evaluable for response, there were 3 complete responders (7.0%) and 5 partial responders (11.6%). Of those with complete response, all had prior radiation and 2 of 3 had disease within the radiation field. Only one patient had a partial response within the radiation field. The overall response rate (CR ⫹ PR) was 18.6% (95% confidence interval: 8.4 –33.4%). The clinical response information is summarized in Table 3. The median progression-free interval was 2.4 months (range, 0.4 –25.9⫹ months). The median overall survival was 6.4 months (range, 0.4 – 42.3⫹ months). DISCUSSION Since cervical cancer is a significant global problem, identification of new drugs and methods of treatment is needed. In addition, an active drug with a mechanism of action different from that of cisplatin, currently the most active drug, might be of interest for combination therapy. A prior Phase III GOG study with three arms (cisplatin alone, cisplatin plus mitolactol, cisplatin plus ifosfamide) demonstrated a higher response rate with combination regimens, however, at the cost of increased toxicity and without survival benefit [11]. In the present GOG Phase II trial, topotecan administration was feasible with acceptable toxicity. Hematologic toxicity was common but generally managed with a delay in treatment, dose reduction, or use of colony-stimulating factors. The inci-
dence of grade 4 neutropenia and thrombocytopenia in this trial was similar to the experience reported with previously treated patients with epithelial ovarian cancer. However, in patients with prior radiation and borderline renal function, it may be helpful to start at a dose of 1.25 mg/m 2 rather than 1.5 mg/m 2. In this study, single-agent topotecan, a semisynthetic, watersoluble camptothecin derivative that inhibits topoisomerase activity, exhibited moderate activity in patients with advanced, recurrent, or persistent squamous cell carcinoma of the cervix. Of clinical interest, two of three patients with complete response had regression of disease within the radiation field. Potential future roles for topotecan may include combination with cisplatin or use as a radiation sensitizing agent. Because of the pharmacokinetics of topotecan, future studies may consider other schedules for administration such as continuous infusion and oral administration. REFERENCES 1. NIH consensus statement on cervical cancer. NIH 14(1):1–23, 1996 2. Bonomi P, Blessing JSA, Stehman FB, et al.: Randomized trial of three cisplatin dose schedules in squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 3:1079 –1085, 1985 3. Muggia FM, Dimery I, Arbuck SG: Camptothecin and its analogs: an overview of their potential in cancer therapeutics. Ann NY Acad Sci 903:21323, 1996 4. Schiller JH: Topotecan in small cell lung cancer. Semin Oncol 24 (6, Suppl 20):S34 –S41, 1997 5. Rowinsky EK, Grochow LB, Hendricks CB, et al.: Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 10:647– 656, 1992 6. Hsiang YH, Liu LF: Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 48:1722–1726, 1988 7. Whiteacre CM, Berger NA: Factors affecting topotecan-induced programmed cell death: adhesion protects cells from apoptosis and impairs cleavage of poly(ADP-ribose) polymerase. Cancer Res 57:2157–2163, 1997 8. Saltz L, Sirott M, Young C, et al.: Phase I clinical and pharmacology study of topotecan given daily for 5 consecutive days to patients with advanced solid tumors, with attempt at dose intensification using recombinant granulocyte colony-stimulating factor. J Natl Can Inst 85:1499 –1507, 1993 9. Kudelka AP, Tresukosol D, Edwards CL, et al.: Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 14:1552–1557, 1996 10. Creemers GJ, Bolis G, Gore M, et al.: Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study. J Clin Oncol 14:3056 –3061, 1996 11. Omura GA, Blessing JA, Vaccarello L, et al.: Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 15:165–171, 1997