Gynecologic Oncology 85, 89 –94 (2002) doi:10.1006/gyno.2001.6557, available online at http://www.idealibrary.com on

Phase II Trial of Topotecan and Cisplatin in Persistent or Recurrent Squamous and Nonsquamous Carcinomas of the Cervix J. Fiorica,* ,1 R. Holloway,† B. Ndubisi,‡ J. Orr,§ E. Grendys,* R. Boothby, ¶ S. DeCesare,㛳 J. LaPolla,** M. Hoffman,†† and J. Patel‡‡ *H. Lee Moffitt Cancer Center, Tampa, Florida; †Florida Hospital, Orlando, Florida; ‡University Medical Center, Jacksonville, Florida; §Patty Berg Cancer Center, Fort Myers, Florida; ¶M.D. Anderson Cancer Center, Orlando, Florida; 㛳University of Florida at Pensacola, Florida; **Bayfront Medical Center, St. Petersburg, Florida; ††Watson Clinic, Lakeland, Florida; and ‡‡GlaxoSmithKline, Jacksonville, Florida Received August 14, 2001; published online February 7, 2002

Key Words: cisplatin; topotecan; nonsquamous cell carcinoma of the cervix; platinum-based chemotherapy; recurrent; squamous cell carcinoma of the cervix; topotecan.

Objective. Cisplatin is a standard treatment in advanced, recurrent cervical cancer. Because topotecan is an established treatment in gynecologic malignancies such as ovarian cancer and exhibits nonoverlapping toxicity with cisplatin, a phase II trial was conducted to evaluate the tolerability and antitumor activity of a cisplatin/topotecan doublet in persistent or recurrent cervical cancer patients. Methods. Patients with bidimensionally measurable persistent or recurrent squamous cell and non squamous cell cervical cancer and adequate bone marrow were enrolled. Patients received 50 mg/m 2 of cisplatin intravenously over 1 h on Day 1 and 0.75 mg/m 2 of topotecan intravenously over 30 min on Days 1, 2, and 3 of 21-day cycles for six cycles or until disease progression. Tumor response and regimen toxicity were assessed using established Gynecologic Oncology Group criteria. Results. Thirty-two of 35 enrolled patients were evaluable for toxicity and tumor response. All but 2 evaluable patients had received previous radiotherapy. No patient received prior chemotherapy. The cisplatin/topotecan doublet was well tolerated, with 77 and 78% of courses given without interruption or delay and at full doses, respectively. As anticipated, the most common toxicity was hematologic, with grade 3/4 neutropenia and thrombocytopenia reported in 30 and 10% of cycles, respectively. The overall response rate was 28% (9/32), with 3 complete and 6 partial responses. The antitumor response in nonirradiated fields (30%) was similar to the response observed in previously irradiated fields (33%), suggesting good drug penetration. Median duration of response was 5 months (range, 2 to 15ⴙ months). An additional 9 (28%) patients achieved stable disease. Median survival was 10 months, with 3 patients in lasting remission. Conclusions. These results demonstrate that the cisplatin/topotecan combination is safe, well tolerated, and active in persistent or recurrent cervical cancer patients. A phase III, multicenter trial is under way (cisplatin/topotecan versus cisplatin) based on these favorable results to confirm the safety and efficacy profile in this patient population. © 2002 Elsevier Science (USA)

INTRODUCTION Carcinoma of the uterine cervix is a significant cause of death in women suffering from gynecologic malignancies in the United States, and an estimated 12,900 new cases will be diagnosed in 2001 [1]. Although cytologic screening of the cervix has contributed to a 45% decrease in mortality in the United States over the past 20 years, the annual mortality rate for those diagnosed exceeds 33% (4400 deaths) [1]. Nevertheless, the mortality rate continues to decline, as evidenced by a reduction in the estimated number of deaths in 2001 relative to 1999 (4800) [2]. Because of the success of cytologic screening in the United States, the majority of women are identified at an early disease stage for which they receive surgery or radiation therapy. However, women who are not diagnosed through screening typically present with more advanced disease. These patients receive radiation therapy, which has been associated with good (66 to 71%) 5-year survival [3, 4]. However, a high proportion of these patients have persistent disease despite irradiation or recurrent disease with locoregional and/or distant metastases. Additionally, for patients presenting with International Federation of Gynecology and Obstetrics (FIGO) tumor stage II and higher, localized treatments may fail or, alternatively, may not be feasible. An important option for these patients is systemic chemotherapy. Cisplatin represents the most active single agent in advanced stage cervical cancer, demonstrating response rates of approximately 20 to 30% with a median survival of 6 to 7 months [5, 6]. In an attempt to improve tumor responses with cisplatin, other active agents have been investigated in combination. One such agent is the topoisomerase I inhibitor topotecan (Hycamtin, GlaxoSmithKline, Brentford, Middlesex, UK). Impor-

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To whom correspondence and reprint requests should be addressed at Gynecologic Oncology Program, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612-9497. Fax: 813-903-3538. E-mail: [email protected]. 89

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tantly, topotecan is an established treatment in recurrent ovarian cancer, with response rates of 13 to 33% reported [7–11]. Topotecan and cisplatin have nonoverlapping toxicities; the dose-limiting toxicity associated with topotecan is noncumulative myelosuppression, whereas cisplatin is associated with dose-limiting, cumulative nephrotoxicity and neurotoxicity. Finally, in vitro findings have suggested that the two agents may have synergistic activity mediated through topotecan inhibition of DNA repair [12–14]. Additionally, the feasibility and antitumor activity of topotecan have been studied in recurrent squamous cell carcinoma of the cervix by the Gynecologic Oncology Group (GOG) [15]. In that study, topotecan (1.5 mg/m 2/day ⫻ 5 days) was active in patients with cervical cancer, with an overall response rate of 12.5% [15]. The single-agent activity of topotecan in cervical carcinoma was also the subject of a report by Noda et al. [16], in which 4 of 22 (18%) evaluable patients achieved a partial tumor response. The dose-limiting toxicity was myelosuppression. The tolerability of the cisplatin/topotecan combination has been established in phase I, dose-finding studies [17, 18]. Based on dose-limiting hematologic toxicities (e.g., neutropenia, thrombocytopenia), the recommended doses for follow-up in phase II studies were 0.75 to 1.0 mg/m 2/day of topotecan (⫻5 days) and 50 mg/m 2 of cisplatin on Day 1 (without granulocyte colony-stimulating factor [G-CSF] support) or 75 mg/m 2 of cisplatin (with G-CSF support). Evidence of antitumor activity for the combination was observed in these early clinical studies, thereby providing the rationale for follow-up study in the phase II setting [17–19]. In 1998, the Florida Society of Gynecologic Oncology initiated a phase II study of topotecan and cisplatin in patients with persistent or recurrent squamous and nonsquamous carcinoma of the cervix. At the time of study enrollment, the majority of cervical cancer patients received radiation therapy. There was some concern that topotecan in combination with cisplatin may result in additive hematologic toxicity in this patient population. Because of the associated hematologic toxicity with the 5-day regimen, we investigated a 3-day topotecan regimen with the hypothesis that this regimen would be associated with reduced myelosuppression in previously irradiated patients. The results and conclusions of this study are herein reported. PATIENTS AND METHODS Eligibility Patients with persistent or recurrent histologically confirmed squamous or nonsquamous cell carcinoma of the cervix were enrolled. Eligible patients demonstrated bidimensionally measurable disease by medical imaging techniques or physical examination; GOG performance status ⱕ3; adequate bone marrow function, defined as absolute neutrophil count (ANC) ⱖ1500 cells/mm 3, platelet count ⱖ100,000/mm 3, and hemo-

globin ⱖ8.0 g/dL; and adequate renal (serum creatinine ⱕ2 mg/dL) and hepatic function (bilirubin ⱕ1.5⫻ institutional normal, aspartate aminotransferase and alkaline phosphatase ⱕ3⫻ institutional normal). Patients must have failed local therapeutic measures or have been considered incurable with local therapeutic measures. Exclusion criteria included prior chemotherapy; concomitant malignancies or previous malignancies other than cervical cancer within the past 5 years (except for squamous or basal cell carcinoma of the skin); treatment with an investigational drug within 30 days or 5 half-lives prior to study entry; and pregnancy. All patients provided written informed consent. Study Design Patients received 50 mg/m 2 of cisplatin in 500 mL of 3% NaCl given intravenously (IV) over 1 h on Day 1 and 0.75 mg/m 2 of topotecan given IV over 30 min on Days 1, 2, and 3. Patients were premedicated with granisetron (2 mg oral [PO] or 1 mg IV, Days 1 to 3) 30 min before and dexamethasone (20 mg IV or PO) 45 min before chemotherapy. Additionally, patients were administered 1 liter (500 mL/hour) of 5% dextrose in water, 1/2 normal saline with 20 mEq/L KCl and 8 mEq/L MgSO 4 and 12.5 g mannitol over 15 min prior to cisplatin. Chemotherapy was continued every 21 days for six courses or until disease progression or toxicity prohibited further therapy. Patients with continued response or stable disease after six courses were permitted to continue on study. Hematologic support with G-CSF (filgrastim; Neupogen; Amgen, Inc., Thousand Oaks, CA; 5 ␮g/kg/day subcutaneous [SC]) was administered in those patients who failed to reach target ANC (1500 cells/mm 3) before the next treatment course. G-CSF was also used in patients who developed febrile neutropenia. Once initiated, G-CSF was continued in each subsequent treatment course at 5 ␮g/kg/day SC starting 24 to 48 h after the completion of chemotherapy and continuing until ANC ⱖ10,000 cells/mm 3. The use of G-CSF was not permitted within 24 h of initiation of a subsequent cycle. If patients continued to demonstrate hematologic toxicity after the use of G-CSF, one dose-level reduction of topotecan to 0.5 mg/m 2 administered on Days 1, 2, and 3 was allowed. Because of potential additive hematologic toxicity in patients previously treated with radiation, a one-dose-level reduction was permitted if nadir ANC was 1000 to 1500 cells/mm 3 or nadir platelet counts were 25,000 to 49,000/mm 3. Further, a two-dose-level reduction in topotecan to 0.5 mg/m 2 on Days 1 and 2 was permitted in patients with nadir ANC ⱕ500 cells/mm 3 or nadir platelet counts ⬍50,000/mm 3. No dose modifications for cisplatin were permitted. Patient Assessments The safety and tolerability of cisplatin and topotecan were evaluated by changes in hematologic and other clinical laboratory assessments, by physical examination, and by the fre-

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quency and severity of adverse events. Complete blood count and platelet counts were monitored at baseline and then weekly. Chemistry panels were assessed prior to study entry and at each chemotherapy treatment. All patients who received at least one infusion of topotecan and cisplatin with follow-up were included in the analysis of drug tolerability. Toxicity was graded using standard GOG toxicity criteria. All serious (grade 3/4) or unexpected toxicities were reported to the principal investigator. Grade 3 or 4 nausea or vomiting was managed initially by supportive care under the direction of the oncologist. If nausea and vomiting persisted, cisplatin was discontinued. Grade 2 hepatic toxicity required a one-dose-level reduction of topotecan, whereas grade 3 or 4 hepatic toxicity required notification of the principal investigator. Grade 3 neurologic toxicity required discontinuation of cisplatin therapy for the current course. Patients were discontinued from all therapy for grade 4 neurologic toxicity and for grade 3/4 hearing loss or paresthesia. Patients who received at least one course of therapy with follow-up were considered evaluable for response. Tumor response was assessed every three courses by chest X ray or other imaging techniques and prior to each course by physical examination. Pelvic examinations were performed prior to each course of therapy. Objective response was recorded for all measurable lesions. For such lesions, the measurement of the largest perpendicular diameters was used. Changes in the product of the diameters served as a guide to response. Complete response was defined as the disappearance of all gross evidence of disease for at least 4 weeks, whereas partial response involved a 50% reduction in the product obtained from measurement of each lesion for at least 4 weeks. Increasing disease or progressive disease was defined as a 50% increase in the product of any lesions documented within 2 months of study entry or the appearance of any new lesion within 8 weeks of study entry. Stable disease included disease not meeting any of the above criteria. Other objective parameters studied included overall survival and progression-free interval. Statistics To facilitate the prompt discovery of an inactive regimen, yet provide an adequate number of patients to estimate antitumor activity, patients were accrued by stages with monthly accrual stops to access activity. Gynecologic Oncology Group guidelines for phase II studies were used to determine the continuation of patient accrual and the target accrual number. The Kaplan–Meier method was used to estimate the overall patient survival and progression-free interval. RESULTS Patients A total of 35 patients were enrolled in the trial between August 1997 and April 2000. Thirty-two patients were evalu-

TABLE 1 Patient Characteristics Characteristic

Patients

Patients enrolled Patients evaluable Age, years Median Range Performance status, n (%) 0 1 2 3 Prior radiation therapy, n (%) Disease site, n (%) Local Distant Lung Liver Periaortic Intraabdominal Bone Inguinal lymph node Supraclavicular Both

35 32 50 28–77 14 (44) 12 (38) 4 (13) 2 (6) 30 (94) 9 (28) 20 (63) 9 4 2 2 1 1 1 3 (9)

able for toxicity and tumor response. Three patients were unevaluable: 1 did not receive treatment and 2 were discontinued after completing the first course with no follow-up. Of the evaluable patients, 21 had squamous carcinoma and 11 had nonsquamous carcinoma (adenocarcinoma and adenosquamous carcinoma). Patient characteristics are described in Table 1. All but 2 evaluable patients had received prior radiation therapy; no patient had received chemotherapy. The majority (20 of 32 patients) of patients had distant metastatic sites involving primarily the lungs (9/20 [45%]) and liver (4/20 [20%]). A total of 160 cycles of chemotherapy were administered during the study period. The median number of courses administered was 5, with a range of 1 to 10 cycles per patient. Safety and Tolerability The cisplatin/topotecan doublet was generally well tolerated, with 77 and 78% of courses administered without interruption or delay and at full dose, respectively. There were 37 delays in treatment in 17 patients and 35 dose reductions in 12 patients. The majority of delays and dose adjustments were attributed to neutrophil nadirs and failure in hematologic recovery prior to initiating the next course of treatment. The most frequent grade 3/4 hematologic toxicities are summarized in Table 2. Grade 3/4 neutropenia and thrombocytopenia were observed in 30 and 10% of courses, respectively. Only 1 case of grade 4 thrombocytopenia and 1 case of febrile neutropenia were reported. G-CSF was administered in 64 (40%) courses in 19 patients.

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TABLE 2 Summary of Hematologic and Nonhematologic Toxicities Events (% of cycles) a Adverse event Hematologic Neutropenia Thrombocytopenia Anemia Nonhematologic Infection Nausea/vomiting Constipation Weakness Pain a

Grade 3

Grade 4

31 (19) 15 (9) 4 (3)

17 (11) 1 (⬍1) 1 (⬍1)

4 (3) 1 (⬍1) 1 (⬍1) 1 (⬍1) 1 (⬍1)

0 1 (⬍1) 0 0 1 (⬍1)

FIG. 1.

N ⫽ 16 cycles.

There was a low occurrence of severe nonhematologic toxicity (Table 2). Two patients each experienced grade 3/4 nausea/vomiting and pain and 1 patient experienced grade 3 muscle weakness. No patient experienced grade 3/4 neurologic toxicity or hearing loss.

Kaplan–Meier curve showing overall patient survival.

radiated field. The median duration of response for all patients was 5 months, with a range of 2 to 15⫹ months. The median overall survival for patients was 10⫹ months (range, 1 to 41⫹ months) (Fig. 1). Three patients are alive in remission at 41, 37, and 17 months. Two other patients are alive on chemotherapy at 13 and 15 months. As shown in Fig. 2, the median progression-free interval was 5 months (range, 1 to 41⫹ months). DISCUSSION

Antitumor Response Thirty-two patients were evaluable for tumor response based on the availability of measurable disease at study entry and follow-up assessments. Greater than 50% of patients benefited from therapy (arrested tumor progression). The overall response rate (complete plus partial responses) was 28% (9/32), with 3 complete and 6 partial responses (Table 3). Two of the 3 complete responses were seen in patients with disease recurrence at distant sites (lung and periaortic lymph nodes). Of the 6 patients who achieved partial responses, 4 had distant metastases and 2 were localized. An additional 9 (28%) patients achieved stable disease. The response rate in previously irradiated fields was 33%. Of the nonsquamous patients 1 had a CR, 2 had a PR, and 2 had SD within the radiated field. Two nonsquamous patients had SD and 3 had PD outside the

Current management of persistent or recurrent carcinoma of the cervix involves systemic chemotherapy with cisplatin. Although cisplatin is currently the most active agent in cervical cancer and has been associated with tumor response rates ranging from approximately 20 to 30% [5, 6], there is nevertheless significant room for improvement in clinical outcomes (i.e., median survival of 6 to 7 months). Topotecan is a novel topoisomerase I inhibitor with established activity in recurrent gynecologic malignancies and a different mechanism of action than cisplatin. Furthermore, the two agents exhibit disparate and generally nonoverlapping toxicity profiles: the dose-limiting toxicity associated with topotecan is noncumulative my-

TABLE 3 Tumor Response Summary by Disease Site Patients, n (%)

Response

Irradiated field (n ⫽ 9)

Other sites (n ⫽ 20)

Both (n ⫽ 3)

Overall response Complete response Partial response Stable disease Progressive disease

3 (33) 1 (11) 2 (22) 2 (22) 4 (44)

6 (30) 2 (10) 4 (20) 6 (30) 8 (40)

— — 1 (33) 2 (66)

FIG. 2.

Kaplan–Meier curve summarizing the progression-free interval.

TOPOTECAN/CISPLATIN IN CERVICAL CANCER

elosuppression, whereas cumulative renal and neural toxicity limit the dose of cisplatin. The novel mechanism of action of topotecan, limited overlap in toxicity with platinum-based therapy, and synergy with cisplatin in in vitro tumor cell lines suggest that topotecan may compliment cisplatin-based therapy in patients with advanced cervical cancer. The feasibility of cisplatin and topotecan in combination therapy has been evaluated in patients with solid tumors [17, 18], including gynecologic malignancies [20]. Based on doselimiting myelosuppression seen in early pharmacokinetic studies, the recommended doses for follow-up in phase II studies were topotecan (0.75 to 1.0 mg/m 2/day ⫻ 5 days) and cisplatin (50 mg/m 2) on Day 1 [12, 13, 19]. We elected to evaluate the antitumor activity and tolerability of lower total dose levels of topotecan (0.75 mg/m 2/day ⫻ 3 days) and cisplatin (50 mg/ m 2). Our decision to use lower dose levels of the two agents was based on in vitro evidence of synergy with the agents in a variety of solid tumor cell lines, including ovarian systems, and on pharmacokinetic and clinical experience [12, 13, 19]. Additionally, it has yet to be clearly demonstrated that cisplatin doses ⬎50 mg/m 2 lead to improved outcomes compared with cisplatin doses of 50 mg/m 2 [5]. The toxicity and potential antitumor activity of combination cisplatin and topotecan are highly sequence dependent. A higher occurrence of myelosuppression has been observed in patients receiving cisplatin on Day 1 than on Day 5 [19]. Although unproven, the sequence-dependent myelotoxicity has been attributed to cisplatin-induced reductions in the renal clearance of topotecan [19]. However, the results of other studies have suggested that the pharmacokinetics of topotecan are unaltered by the coadministration of cisplatin [21, 22] and that cisplatin has a greater effect on the pharmacodynamic properties of topotecan. Irrespective of the mechanism underlying sequence dependence, the cisplatin/topotecan doublet was generally well tolerated in the present study, with delays and dose adjustments limited to approximately 22% of courses. Treatment delays were generally ⬍7 days in duration, in part attributable to the noncumulative nature of myelotoxicity with topotecan and to G-CSF support. Grade 3/4 neutropenia was limited to 30% of cycles and there was a low occurrence of grade 4 thrombocytopenia. The 3-day regimen of topotecan used in this study was better tolerated than the 5-day regimen, with a lower incidence of severe myelotoxicity [8 –10]. Only one case of febrile neutropenia was observed during the study and no patient died as a consequence of hematologic sequelae. The level of febrile neutropenia or neutropenic infection was comparable with that of other studies of the cisplatin/topotecan combination [20]. Because of the low incidence of complicated neutropenia and noncumulative myelotoxicity, routine G-CSF treatment may not be necessary in these patients. Nonhematologic toxicity was minimal with this regimen. Cisplatin was well tolerated, with little dose-limiting nonhematologic toxicity, including no serious cases of nephrotoxicity, neurotoxicity, or hepatotoxicity. Additionally, there was a

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very low incidence of grade 3/4 nausea and vomiting. The favorable toxicity profile of topotecan and cisplatin used in this study suggests that there may be room for dose intensification if cisplatin is administered on Day 3 or if the duration of treatment is increased from 3 to 5 days with G-CSF therapy. In our study population of women, most of whom were previously treated with radiation and exhibited a high proportion of distant metastases (63%), the cisplatin/topotecan doublet was active, with 33% of patients achieving responses in previously irradiated fields and 30% achieving tumor responses at other sites. One of the challenges that we anticipated to delivering therapeutic drug levels to previously irradiated tumors involved a reduction in the blood supply to the tumor. In our study, all but 2 patients had received prior radiation therapy. These data suggest that therapeutic levels of cisplatin/ topotecan were achieved at the tumor site. Additionally, 4 of the 32 evaluable patients received ⱕ2 courses of treatment and thus were on therapy for ⬍6 weeks. Because the median time to response associated with topotecan therapy has been estimated to be 9 weeks [15], it is possible that the response rate in this study was underreported. The antitumor response rates and survival that we observed compare favorably with cisplatin used as single-agent therapy, in which overall tumor response ranges from approximately 20 to 30% and median survival is 6 to 7 months [5, 6]. The median survival in this study was 10 months, with three patients remaining in lasting remission. The response rates observed in this trial also compared favorably with that achieved with gemcitabine. Although gemcitabine as single-agent therapy for advanced recurrent squamous cell carcinoma of the cervix was inactive [23], gemcitabine in combination with cisplatin produced response rates of 30% in previously irradiated fields [24]. However, a study by Burnett et al. [24] was smaller than the current study, and all women were of GOG performance status 0 or 1. Also, 94% of patients in the current study were previously irradiated compared with 59% of patients in the Burnett study. In addition, only one patient in the Burnett study achieved a prolonged tumor response compared with three patients in the current study who achieved prolonged tumor responses. Based on tolerability and activity observations in this study of previously treated patients with advanced disease, we recommend further evaluation of the cisplatin/topotecan doublet for the systemic treatment of advanced disease or potentially used in conjunction with radiation therapy in the management of regional disease. Topotecan has proven to be a potent radiosensitizer in tumor cell lines [25, 26], and may prove valuable in combined-modality therapy with radiation for cervical cancer. A large, multicenter, phase III study is currently underway to compare the antitumor activity and overall survival of patients treated with topotecan plus cisplatin with cisplatin as single-agent therapy. The results of this trial are eagerly anticipated.

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ACKNOWLEDGMENTS The authors thank the members of the Florida Gynecologic Oncology Group, study nurses and coordinators, patients, and administrative assistants for their assistance and participation. The authors also acknowledge the unrestricted grant from GlaxoSmithKline to conduct this important trial.

REFERENCES 1. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001;51:15–36. 2. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999;49:8 –31, 1. 3. Brewster WR, Monk BJ, Ziogas A, Anton-Culver H, Yamada SD, Berman ML. Intent-to-treat analysis of stage Ib and IIa cervical cancer in the United States: radiotherapy or surgery 1988 –1995. Obstet Gynecol 2001; 97:248 –54. 4. Hong JH, Tsai CS, Wang CC, Lai CH, Chen WC, Lee SP, Chang TC, Tseng CJ. Comparison of clinical behaviors and responses to radiation between squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas of the cervix. Changgeng Yi Xue Za Zhi 2000;23:396 – 404. 5. Bonomi P, Blessing JA, Stehman FB, DiSaia PJ, Walton L, Major FJ. Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 1985;3:1079 – 85. 6. Alberts DS, Garcia D, Mason-Liddil N. Cisplatin in advanced cancer of the cervix: an update. Semin Oncol 1991;18(suppl 3):11–24. 7. McGuire WP, Blessing JA, Bookman MA, Lentz SS, Dunton CJ. Topotecan has substantial antitumor activity as first-line salvage therapy in platinum-sensitive epithelial ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2000;18:1062–7. 8. ten Bokkel Huinink W, Carmichael J, Armstrong D, Gordon A, Malfetano J. Efficacy and safety of topotecan in the treatment of advanced ovarian carcinoma. Semin Oncol 1997;24(suppl 5):S5-19 –S5-25. 9. Bookman MA, Malmstrom H, Bolis G, Gordon A, Lissoni A, Krebs JB, Fields SZ. Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol 1998;16:3345–52. 10. Kudelka AP, Tresukosol D, Edwards CL, Freedman RS, Levenback C, Chantarawiroj P, Gonzalez de Leon C, Kim EE, Madden T, Wallin B, Hord M, Verschraegen C, Raber M, Kavanagh JJ. Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 1996;14:1552–7. 11. Swisher EM, Mutch DG, Rader JS, Elbendary A, Herzog TJ. Topotecan in platinum- and paclitaxel-resistant ovarian cancer. Gynecol Oncol 1997; 66:480 – 6, doi:10.1006/gyno.1977.4787. 12. Romanelli S, Perego P, Pratesi G, Carenini N, Tortoreto M, Zunino F. In vitro and in vivo interaction between cisplatin and topotecan in ovarian carcinoma systems. Cancer Chemother Pharmacol 1998;41:385–90. 13. Ma J, Maliepaard M, Nooter K, Boersma AW, Verweij J, Stoter G, Schellens JH. Synergistic cytotoxicity of cisplatin and topotecan or SN-38 in a panel of eight solid-tumor cell lines in vitro. Cancer Chemother Pharmacol 1998;41:307–16.

14. Chou TC, Motzer RJ, Tong Y, Bosl GJ. Computerized quantitation of synergism and antagonism of Taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. J Natl Cancer Inst 1994;86:1517–24. 15. Bookman MA, Blessing JA, Hanjani P, Herzog TJ, Andersen WA. Topotecan in squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol 2000;77:446 –9, doi: 10.1006/gyno.2000.5807. 16. Noda K, Sasaki H, Yamamoto K, Yamamoto T, Nishimura R, Sugiyama T, Nakajima H: Phase II trial of topotecan for cervical cancer of the uterus (abstract). Proc Am Soc Clin Oncol 1996;15:280. [Abstract 754] 17. Miller AA, Hargis JB, Lilenbaum RC, Fields SZ, Rosner GL, Schilsky RL. Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a Cancer and Leukemia Group B study. J Clin Oncol 1994;12: 2743–50. 18. Raymond E, Burris HA, Rowinsky EK, Eckardt JR, Rodriguez G, Smith L, Weiss G, Von Hoff DD. Phase I study of daily times five topotecan and single injection of cisplatin in patients with previously untreated nonsmall-cell lung carcinoma. Ann Oncol 1997;8:1003– 8. 19. Rowinsky EK, Kaufmann SH, Baker SD, Grochow LB, Chen T-L, Peereboom D, Bowling MK, Sartorius SE, Ettinger DS, Forastiere AA, Donehower RC. Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence. J Clin Oncol 1996;14:3074 – 84. 20. Hoskins P, Eisenhauer E, Vergote I, Dubuc-Lissoir J, Fisher B, Grimshaw R, Oza A, Plante M, Stuart G, Vermorken J. Phase II feasibility study of sequential couplets of cisplatin/topotecan followed by paclitaxel/cisplatin as primary treatment for advanced epithelial ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group study. J Clin Oncol 2000;18:4038 – 44. 21. de Jonge MJ, Loos WJ, Gelderblom H, Planting AS, van der Burg ME, Sparreboom A, Brouwer E, van Beurden V, Mantel MA, Doyle E, Hearn S, Ross G, Verweij J. Phase I pharmacologic study of oral topotecan and intravenous cisplatin: sequence-dependent hematologic side effects. J Clin Oncol 2000;18:2104 –15. 22. Gelderblom AJ, Loos WJ, de Jonge MJA, Sparreboom A, Planting AST, van der Burg MEL, Brouwer E, Verheij C, Ouwens L, Hearn S, Verweij J. Phase I and pharmacological study of increased dose oral topotecan in combination with intravenous cisplatin. Ann Oncol 2000;11:1205–7. 23. Schilder RJ, Blessing JA, Morgan M, Mangan CE, Rader JS. Evaluation of gemcitabine in patients with squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol 2000;76:204-7, doi:10.1006/gyno.1999.5657. 24. Burnett AF, Roman LD, Garcia AA, Muderspach LI, Brader KR, Morrow CP. A phase II study of gemcitabine and cisplatin in patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix. Gynecol Oncol 2000;76:63– 6, doi:10.1006/gyno.1999.5671. 25. Miyamoto S, Huang TT, Wuerzberger-Davis S, Bornmann WG, Pink JJ, Tagliarino C, Kinsella TJ, Boothman DA. Cellular and molecular responses to topoisomerase I poisons. Exploiting synergy for improved radiotherapy. Ann N Y Acad Sci 2000;922:274 –92. 26. Chastagner P, Merlin JL, Marchal C, Hoffstetter S, Barberi-Heyob M, Vassal G, Duprez A. In vivo potentiation of radiation response by topotecan in human rhabdomyosarcoma xenografted into nude mice. Clin Cancer Res 2000;6:3327–33.