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Phase II study of weekly topotecan in patients with recurrent or persistent epithelial ovarian cancer
Gynecologic Oncology 95 (2004) 686 – 690 www.elsevier.com/locate/ygyno
Phase II study of weekly topotecan in patients with recurrent or persistent epithelial ovarian cancer Tally Levya,*, Moshe Inbarb, Joseph Menczera, Dan Grisaruc, Marek Glezermand, Tamar Safrab a Division of Gynecologic Oncology, Wolfson Medical Center, Holon, the Sackler Faculty of Medicine, Tel Aviv, Israel Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel c Department of Obstetrics and Gynecology, Tel Aviv Sourasky Medical Center, Tel Aviv, the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel d Department of Obstetrics and Gynecology, Wolfson Medical Center, Holon, Israel b
Received 9 June 2004 Available online 22 October 2004
Abstract Objective. To assess the toxicity and effectiveness of once-weekly administration of topotecan (HycamtinR; GlaxoSmithKline) for relapsed ovarian and primary peritoneal cancer. Methods. Twenty-three patients with recurrent or persistent epithelial ovarian cancer (EOC) and primary peritoneal carcinoma (PPC) previously exposed to at least one line of platinum-based chemotherapy were treated with IV weekly topotecan as a 30-min bolus at a starting dose of 4 mg/m2 administered weekly for 3 weeks in a 28-day cycle. Results. The patients’ median age was 62 years (42–83). Thirteen women (56.5%) were defined as having platinum-sensitive and 10 (43.5%) as having platinum-resistant disease. Altogether, 88 cycles were administered for a total of 264 weekly treatments, with a median of four courses (range 2–6). There were no treatment delays. The main bone marrow toxicity was grade II and III thrombocytopenia, necessitating dose reduction in four patients (17.4%) and treatment cessation in one patient. The most frequent nonhematologic toxicity was fatigue (nine patients, 39.1%). There were four complete responses (17.4%, three in the platinum-sensitive and one in the platinum-resistant patients) and seven (30.4%) partial responses, for an overall response rate of 47.8%. The ORR was similar in platinum-sensitive and platinum-resistant patients (47.8% and 52.2%, respectively). The median progression-free survival was 4.9 months with a mean survival time of 11.59 months. Two women sustained complete response lasting N6 months. Conclusion. Topotecan given as a weekly bolus is a highly active and well-tolerated treatment regimen for relapsed ovarian and primary peritoneal cancer and thus deserves further evaluation. D 2004 Elsevier Inc. All rights reserved. Keywords: Ovarian cancer; Primary peritoneal cancer; Topotecan; Chemotherapy
Introduction Ovarian cancer is the most common cause of death among women with gynecological malignancies. About 23,400 women are diagnosed with ovarian cancer each year in the United States and about 13,900 will die of their disease [1]. More than 75% of patients have advanced stage disease at the * Corresponding author. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wolfson Medical Center, Holon, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Fax: +972 3 5028503. E-mail address: [email protected] (T. Levy). 0090-8258/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2004.09.005
time of diagnosis and will require cytoreductive surgery followed by adjuvant chemotherapy. First-line therapy with a combination of paclitaxel and cisplatin results in an overall response rate of 73–77% [2,3] and a median survival of 35–38 months. Most patients, however, will recur and fewer than 30% survive for 5 years [4]. Response rates to salvage treatment are modest and the duration of response is relatively short. Thus, the aim of second-line treatment is essentially palliative, and the issues of quality of life and reduction of side effects are major concerns in this setting. Topotecan (HycamtinR; GlaxoSmithKline, Philadelphia, PA) is a topoisomerase I inhibitor that is currently indicated for the treatment of relapsed ovarian cancer after failure of
T. Levy et al. / Gynecologic Oncology 95 (2004) 686–690
initial platinum-based chemotherapy. Several phase II and III studies have demonstrated response rates of 13–33% to topotecan as a single-agent treatment [5–11]. Topotecan is approved by the FDA to be administrated as an intravenous (IV) infusion of 1.5 mg/m2 for 5 consecutive days of a 21day cycle. Although this regimen demonstrates significant antitumor activity, the associated morbidity of grade 3 and 4 myelosuppression [5–9] and fatigue [11] led to the investigation of other less toxic and more patient-convenient schedules. Recently, several preliminary studies showed improved activity and reduced toxicity using topotecan at a dose of 4 mg/m2 once a week [12–14]. In the present Phase II study, we report our experience with weekly topotecan in recurrent epithelial ovarian and primary peritoneal cancer.
Patients and methods We conducted this open nonrandomized double-center trial on 23 patients who were treated with weekly topotecan for recurrent or persistent epithelial ovarian or primary peritoneal carcinoma between 2003 and 2004. The study was approved by the Institutional Review Boards and the Israeli Ministry of Health. Eligibility criteria included histological confirmation of epithelial ovarian cancer (EOC) or primary peritoneal carcinoma (PPC), previous exposure to at least one line of platinum-based chemotherapy, and measurable (bidimensional measurable disease by clinical examination or by computer tomography [CT]) or assessable disease (defined as elevated serum CA-125 level only to z75 with no measurable lesions). Additional requirements included an Eastern Cooperative Oncology group (ECOG) performance status of V2 and a life expectancy of at least 3 months. Pretreatment laboratory requirements included leukocytes z3000/AL, platelets z100,000/AL, granulocytes z1500/AL, and serum creatinine V1.5 mg%. Patients were categorized as platinum-sensitive if they had a treatment-free interval of N6 months after the end of first-line combination chemotherapy. Platinum-resistant was defined as (1) progressive disease during first-line combination chemotherapy (refractory disease), (2) demonstration of less than a partial response on primary therapy, or (3) initial response and subsequent development of recurrent disease within 6 months after the discontinuation of firstline treatment.
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patients with an objective response (complete [CR] or partial [PR] and in those with stable disease [SD]), until evidence of disease progression or unacceptable toxicity was observed. The dose was reduced by 25% for any grade III and IV toxicity according to the National Cancer Institute toxicity criteria. The patients had a complete blood count before each treatment. Physical examination, toxicity evaluation, chemistry, and CA-125 levels were determined at the end of each 4-week treatment cycle. CT scan was obtained in all patients every three treatment cycles. Information on the status of the patient was obtained every 2 months after she had completed the treatment protocol. Evaluation of response A CR was defined as the complete disappearance of all measurable disease or, in its absence, a normalization of the CA-125 level by two consecutive samples for at least 4 weeks. A PR was defined as a z50% reduction in the product obtained from the measurement of each bidimensional lesion or a drop in the CA-125 by at least 50% over two samples for at least 4 weeks. Disease progression was defined as a z25% increase in the product from any lesion documented within 8 weeks of study entry, the appearance of any new lesion within 8 weeks of study entry, or any increase in the CA-125 levels from baseline. SD was defined as disease status not meeting any of the above criteria. Duration of treatment was dependent upon response. All the patients were offered at least four courses of topotecan unless there had been progression of disease. Thereafter, the patients who had completed treatment were followed with bimonthly clinical examinations and serum CA-125 measurements. Time-to-progression (TTP) was defined as the time between the first day of topotecan treatment to the time of the first objective evidence of disease progression, death, or the date of analysis. Overall survival was calculated from the first day of topotecan treatment to death or the date of analysis. Statistics Time-to-progression and survival were plotted by the Kaplan–Meier method.
Results Treatment plan The patients received 4 mg/m2 topotecan as a starting dose on days 1, 8, and 15 out of a 28-day cycle. The drug was administered by an IV infusion given in 250 mL normal saline over 30 min in an outpatient setting. Treatment with weekly topotecan was continued in
A total of 23 patients were treated with weekly topotecan for recurrent or persistent EOC and PPC. Their characteristics are outlined in Table 1. The median age was 62 years (range 42–83) with a median ECOG performance status of 1 (range 0–2). Most patients (78.3%) had FIGO stage III–IV disease. The median
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T. Levy et al. / Gynecologic Oncology 95 (2004) 686–690
Table 1 Selected patient characteristics (n = 23) Characteristics Age, years Median Range Patients with measurable disease Patients with assessable disease ECOG performance status 0 1 2 FIGO stage Ic IIc IIIa IIIc IV Epithelial ovarian cancer Primary peritoneal carcinomatosis Platinum sensitive Platinum resistant Prior number of regimens Median Mean (FSEa) Range a
Number of cases
%
62 42–83 18 5
78.3 21.7
11 8 4
47.8 34.8 17.4
4 1 1 13 4 19 4 13 10
17.4 4.35 4.35 56.5 17.4 82.6 17.4 56.5 43.5
1 1.74 F 0.22 1–5
SE = standard error.
number of prior chemotherapy regimens was 1 (range 1– 5), with a mean of 1.74 [F0.22 SE; 95% confidence interval (CI) of 1.26–2.2]. Thirteen (56.5%) had platinumsensitive disease and 10 (43.5%) were platinum resistant. Eighteen (78.3%) had a measurable disease while the remaining 5 (21.7%) were assessable by elevated CA-125 levels only. Overall, 88 cycles were administered for a total of 264 weekly treatments and a median of four courses (range 2–6). The median duration of follow-up
Fig. 1. Kaplan–Meier probability curve of time to progression.
was 6.8 months (range: 2–13.07 months; 95% CI of 3.69– 9.53). There were four (17.4%) complete responders (CR) and seven (30.4%) partial responses (PR) for an overall response rate (ORR) of 47.8% (11 patients; 95% CI of 26%–69%). Eleven (47.8%) patients had SD and one (4.8%) patient progressed while on treatment. Fig. 1 depicts TTP. The median TTP after weekly topotecan therapy was 4.9 months (range 1.4–13.07 months with 95% CI of 3.71–6.09, SE F 0.61). Twenty of the 23 patients (86.9%) patients are still alive and three have died of their disease for a median overall survival of 11.59 months (95% CI 10.12–13.05, SE F 0.75). Of the 20 living patients, two are in sustained remission lasting more than 6 months and 18 are alive with disease, seven patients remain on weekly topotecan treatment, one with PR and 6 with SD. The women were also stratified as platinum sensitive or platinum resistant. The ORR for patients with platinumsensitive and platinum-resistant disease was 47.8% and 52.2%, respectively ( P = 0.54). Of the four CRs, three had platinum-sensitive and one had platinum-resistant disease. Fig. 2 shows TTP according to the primary response to platinum treatment. The TTP was 5.9 months in the platinum-sensitive and 4.67 months in the platinum-resistant patients ( P = 0.86). Topotecan toxicity was assessed in all 23 patients. One patient (4.3%) had grade III neutropenia and one had grade III anemia. Grade III thrombocytopenia needing dose reduction was observed in four patients (17.4%). One of them was taken off protocol after two treatment cycles because of prolonged grade II thrombocytopenia. Other side effects that did not require dose alteration included grade II nausea in two (8.7%), grade II neuropathy in two, and grade I–II fatigue in nine (39.1%) patients.
Fig. 2. Kaplan–Meier probability curve of time to progression in platinumsensitive and platinum-resistant patients.
T. Levy et al. / Gynecologic Oncology 95 (2004) 686–690
Discussion Insofar as recurrent EOC is an incurable disease, the main treatment goal is to achieve long-term remission with a reasonable quality of life. Currently, the FDA-approved treatment for recurrent EOC is topotecan administered as a daily dose of 1.5 mg/m2 for 5 consecutive days every 21 days. Although good response rates have been observed with this regimen, its toxicity often results in treatment interruption and dose reduction. ten Bokkel Huinik et al. [6] showed 79% grade IV neutropenia, followed by 25% thrombocytopenia. Kudelka et al. [7] reported that 61% of patients required dose reduction because of myelosuppression and that 25% suffered from neutropenic fever. Two other second-line studies also showed that the incidence of grade IV neutropenia was 33% [10] and 57% [15] of cycles. Fatigue is the most common nonhematological toxicity in the 5-day treatment schedule, reported in 22–34% of topotecan-treated patients [6,11]. Moreover, it was found to be the most prominent cause for removing responding patients from therapy [11]. Recently, in a dose-escalating study conducted on patients with recurrent EOC, Homesley et al. [12] evaluated weekly administration of topotecan. On the one hand, a weekly dose below 2 mg/m2 was not associated with antitumor activity. On the other hand, the maximal tolerated weekly dose was 4 mg/m2. Although myelosuppression was rarely dose limiting, nausea, vomiting, and fatigue led to patient refusal to continue treatment on higher doses. In the current study, our starting dose was 4 mg/m2 and it was well tolerated: no patient withdrew from the study due to intolerable toxicity and only 4 patients (17.4%) needed dose reduction for thrombocytopenia. One patient had grade III neutropenia, one had grade III anemia, and three grade III thrombocytopenia. Thus, the level of myelosuppression among our patients was fairly low compared to the standard schedule of topotecan in EOC. The main nonhematological side effect was grade I–II fatigue in 39.1% of patients, but no dose reduction, treatment delay, or discontinuation were requested or required. The weekly topotecan regimen we followed resulted in excellent response rates. We achieved 17.4% CR and 30.4% PR for an ORR of 47.8%. Additionally, 11 patients (47.8%) had SD for a clinical benefit (CR + PR + SD) of 95.6%. Prior studies using the standard regimen of topotecan showed ORRs ranging from 13% to 33% [5–11]. In their Phase III study, ten Bokkel Huinink et al. [6] comparing topotecan with paclitaxel reported 20.5% ORR and 30% SD in their 112 topotecan-treated patients. The lower ORRs usually appeared in patients with platinum-resistant disease. McGuire et al. [11] found 33% RR and additional 48% stable disease when topotecan was administered as first-line salvage therapy in platinum-sensitive EOC. Similarly, Bolis et al. [15] showed a 31.4% ORR and a 37.1% SD rate in platinum-sensitive patients. Morris et al. [14] in an ongoing study observed similar high ORRs with the weekly top-
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otecan regimen in platinum-sensitive patients. Their group reported a 32% PR and 45% SD with less than 2% grade III–IV toxicity. Although high ORRs have been achieved, their duration is short-lived. The median TTP in our study was 4.9 months (Fig. 1), which is consistent with that of 2.8, 3.96, and 5.36 months reported in other (large-scale) studies [5,6,16] using the 5-day topotecan regimen. The treatmentfree interval also has a bearing on TTP. McGuire et al. [11] observed a prolonged TTP of 9.6 months in platinumsensitive patients. In the present study, patients with platinum-sensitive disease had longer TTP compared to platinum-resistant patients (Fig. 2) although it did not reach statistical significance (5.9 vs. 4.67 months, respectively, P = 0.86). Furthermore, three of our four CRs had platinum-sensitive disease. In conclusion, our data indicate that weekly IV topotecan at a starting dose of 4 mg/m2 demonstrates impressive activity in patients with persistent or recurrent ovarian cancer. Our results are based on a small group of patients with a relatively short follow-up period. However, the encouraging high ORR with a very low rate of side effects warrants further investigation and comparison of this weekly protocol to the standard 5-day topotecan schedule for the treatment of recurrent ovarian cancer.
Acknowledgments Esther Eshkol is thanked for the editorial assistance and Dr. Mona Boaz for the statistical analysis.
References [1] Greenlee RT, Hill-Harmon MB, Murray T, Thum M. Cancer statistics, 2001. CA Cancer J Clin 2001;51:15 – 36. [2] McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1 – 6. [3] Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, et al. Randomized intergroup trial of cisplatin–paclitaxel versus cisplatin–cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000;92: 699 – 708. [4] McGuire WP, Ozols RF. Chemotherapy of advanced ovarian cancer. Semin Oncol 1998;25:340 – 8. [5] Creemers GJ, Bolis G, Gore M, Scarfone G, Lacave AJ, Guastalla JP, 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 1996;12:3056 – 61. [6] ten Bokkel Huinink W, Gore M, Carmichael J, Gordon A, Malfetano J, Hudson I, et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial. J Clin Oncol 1997;15:2183 – 93. [7] Kudelka AP, Tresukosol D, Edwards CL, Freedman RS, Levenback C, Chantarawiroj P, et al. Phase II study of intravenous topotecan as a 5day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 1996;14:1552 – 7. [8] Swisher EM, Mutch DG, Rader JS, Elbendary A, Herzog TJ.
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T. Levy et al. / Gynecologic Oncology 95 (2004) 686–690 Topotecan in platinum-and paclitaxel resistant ovarian cancer. Gynecol Oncol 1997;66:480 – 6. Hoskins P, Eisenhauer E, Beare S, Roy M, Drouin P, Stuart G, et al. Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group study. J Clin Oncol 1998; 16:2233 – 7. Bookman MA, Malmstrom H, Bolis G, Gordon A, Lissoni A, Krebs JB, et al. 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. 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. Homesley HD, Hall DJ, Martin DA, Lewandowski GS, Vaccarello L, Nahhas WA, et al. A dose-escalating study of weekly bolus topotecan
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in previously treated ovarian cancer patients. Gynecol Oncol 2001; 83:394 – 9. Morris RT, Munkarah A, Field J, Baker VV, Drake R, Malone J. Phase II trial of weekly topotecan in patients with potentially platinum sensitive relapsed ovarian and peritoneal cancer. Proc Am Soc Clin Oncol 2002;21:173 [abstract 2512]. Morris RT, Alvarez RD, Andrews S, Malone J, Bryant C, Munkarah A. Topotecan weekly bolus chemotherapy for potentially chemosensitive relapsed ovarian and peritoneal cancer—an update. Proc Am Soc Clin Oncol 2003;22:459 [abstract 1846]. Bolis G, Scarfone G, Tateo S, Mangili G, Villa A, Parazzini F. Response and toxicity to topotecan in sensitive ovarian cancer cases with small residual disease after first-line treatment with carboplatinum and paclitaxel. Gynecol Oncol 2001;80:13 – 5. Gore M, Oza A, Rustin G, Malfetano J, Calvert H, Clarke-Pearson D, et al. A randomised trial of oral versus intravenous topotecan in patients with relapsed epithelial ovarian cancer. Eur J Cancer 2002;38:57 – 63.
Phase II study of weekly topotecan in patients with recurrent or persistent epithelial ovarian cancer Tally Levya,*, Moshe Inbarb, Joseph Menczera, Dan Grisaruc, Marek Glezermand, Tamar Safrab a Division of Gynecologic Oncology, Wolfson Medical Center, Holon, the Sackler Faculty of Medicine, Tel Aviv, Israel Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel c Department of Obstetrics and Gynecology, Tel Aviv Sourasky Medical Center, Tel Aviv, the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel d Department of Obstetrics and Gynecology, Wolfson Medical Center, Holon, Israel b
Received 9 June 2004 Available online 22 October 2004
Abstract Objective. To assess the toxicity and effectiveness of once-weekly administration of topotecan (HycamtinR; GlaxoSmithKline) for relapsed ovarian and primary peritoneal cancer. Methods. Twenty-three patients with recurrent or persistent epithelial ovarian cancer (EOC) and primary peritoneal carcinoma (PPC) previously exposed to at least one line of platinum-based chemotherapy were treated with IV weekly topotecan as a 30-min bolus at a starting dose of 4 mg/m2 administered weekly for 3 weeks in a 28-day cycle. Results. The patients’ median age was 62 years (42–83). Thirteen women (56.5%) were defined as having platinum-sensitive and 10 (43.5%) as having platinum-resistant disease. Altogether, 88 cycles were administered for a total of 264 weekly treatments, with a median of four courses (range 2–6). There were no treatment delays. The main bone marrow toxicity was grade II and III thrombocytopenia, necessitating dose reduction in four patients (17.4%) and treatment cessation in one patient. The most frequent nonhematologic toxicity was fatigue (nine patients, 39.1%). There were four complete responses (17.4%, three in the platinum-sensitive and one in the platinum-resistant patients) and seven (30.4%) partial responses, for an overall response rate of 47.8%. The ORR was similar in platinum-sensitive and platinum-resistant patients (47.8% and 52.2%, respectively). The median progression-free survival was 4.9 months with a mean survival time of 11.59 months. Two women sustained complete response lasting N6 months. Conclusion. Topotecan given as a weekly bolus is a highly active and well-tolerated treatment regimen for relapsed ovarian and primary peritoneal cancer and thus deserves further evaluation. D 2004 Elsevier Inc. All rights reserved. Keywords: Ovarian cancer; Primary peritoneal cancer; Topotecan; Chemotherapy
Introduction Ovarian cancer is the most common cause of death among women with gynecological malignancies. About 23,400 women are diagnosed with ovarian cancer each year in the United States and about 13,900 will die of their disease [1]. More than 75% of patients have advanced stage disease at the * Corresponding author. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wolfson Medical Center, Holon, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Fax: +972 3 5028503. E-mail address: [email protected] (T. Levy). 0090-8258/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2004.09.005
time of diagnosis and will require cytoreductive surgery followed by adjuvant chemotherapy. First-line therapy with a combination of paclitaxel and cisplatin results in an overall response rate of 73–77% [2,3] and a median survival of 35–38 months. Most patients, however, will recur and fewer than 30% survive for 5 years [4]. Response rates to salvage treatment are modest and the duration of response is relatively short. Thus, the aim of second-line treatment is essentially palliative, and the issues of quality of life and reduction of side effects are major concerns in this setting. Topotecan (HycamtinR; GlaxoSmithKline, Philadelphia, PA) is a topoisomerase I inhibitor that is currently indicated for the treatment of relapsed ovarian cancer after failure of
T. Levy et al. / Gynecologic Oncology 95 (2004) 686–690
initial platinum-based chemotherapy. Several phase II and III studies have demonstrated response rates of 13–33% to topotecan as a single-agent treatment [5–11]. Topotecan is approved by the FDA to be administrated as an intravenous (IV) infusion of 1.5 mg/m2 for 5 consecutive days of a 21day cycle. Although this regimen demonstrates significant antitumor activity, the associated morbidity of grade 3 and 4 myelosuppression [5–9] and fatigue [11] led to the investigation of other less toxic and more patient-convenient schedules. Recently, several preliminary studies showed improved activity and reduced toxicity using topotecan at a dose of 4 mg/m2 once a week [12–14]. In the present Phase II study, we report our experience with weekly topotecan in recurrent epithelial ovarian and primary peritoneal cancer.
Patients and methods We conducted this open nonrandomized double-center trial on 23 patients who were treated with weekly topotecan for recurrent or persistent epithelial ovarian or primary peritoneal carcinoma between 2003 and 2004. The study was approved by the Institutional Review Boards and the Israeli Ministry of Health. Eligibility criteria included histological confirmation of epithelial ovarian cancer (EOC) or primary peritoneal carcinoma (PPC), previous exposure to at least one line of platinum-based chemotherapy, and measurable (bidimensional measurable disease by clinical examination or by computer tomography [CT]) or assessable disease (defined as elevated serum CA-125 level only to z75 with no measurable lesions). Additional requirements included an Eastern Cooperative Oncology group (ECOG) performance status of V2 and a life expectancy of at least 3 months. Pretreatment laboratory requirements included leukocytes z3000/AL, platelets z100,000/AL, granulocytes z1500/AL, and serum creatinine V1.5 mg%. Patients were categorized as platinum-sensitive if they had a treatment-free interval of N6 months after the end of first-line combination chemotherapy. Platinum-resistant was defined as (1) progressive disease during first-line combination chemotherapy (refractory disease), (2) demonstration of less than a partial response on primary therapy, or (3) initial response and subsequent development of recurrent disease within 6 months after the discontinuation of firstline treatment.
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patients with an objective response (complete [CR] or partial [PR] and in those with stable disease [SD]), until evidence of disease progression or unacceptable toxicity was observed. The dose was reduced by 25% for any grade III and IV toxicity according to the National Cancer Institute toxicity criteria. The patients had a complete blood count before each treatment. Physical examination, toxicity evaluation, chemistry, and CA-125 levels were determined at the end of each 4-week treatment cycle. CT scan was obtained in all patients every three treatment cycles. Information on the status of the patient was obtained every 2 months after she had completed the treatment protocol. Evaluation of response A CR was defined as the complete disappearance of all measurable disease or, in its absence, a normalization of the CA-125 level by two consecutive samples for at least 4 weeks. A PR was defined as a z50% reduction in the product obtained from the measurement of each bidimensional lesion or a drop in the CA-125 by at least 50% over two samples for at least 4 weeks. Disease progression was defined as a z25% increase in the product from any lesion documented within 8 weeks of study entry, the appearance of any new lesion within 8 weeks of study entry, or any increase in the CA-125 levels from baseline. SD was defined as disease status not meeting any of the above criteria. Duration of treatment was dependent upon response. All the patients were offered at least four courses of topotecan unless there had been progression of disease. Thereafter, the patients who had completed treatment were followed with bimonthly clinical examinations and serum CA-125 measurements. Time-to-progression (TTP) was defined as the time between the first day of topotecan treatment to the time of the first objective evidence of disease progression, death, or the date of analysis. Overall survival was calculated from the first day of topotecan treatment to death or the date of analysis. Statistics Time-to-progression and survival were plotted by the Kaplan–Meier method.
Results Treatment plan The patients received 4 mg/m2 topotecan as a starting dose on days 1, 8, and 15 out of a 28-day cycle. The drug was administered by an IV infusion given in 250 mL normal saline over 30 min in an outpatient setting. Treatment with weekly topotecan was continued in
A total of 23 patients were treated with weekly topotecan for recurrent or persistent EOC and PPC. Their characteristics are outlined in Table 1. The median age was 62 years (range 42–83) with a median ECOG performance status of 1 (range 0–2). Most patients (78.3%) had FIGO stage III–IV disease. The median
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Table 1 Selected patient characteristics (n = 23) Characteristics Age, years Median Range Patients with measurable disease Patients with assessable disease ECOG performance status 0 1 2 FIGO stage Ic IIc IIIa IIIc IV Epithelial ovarian cancer Primary peritoneal carcinomatosis Platinum sensitive Platinum resistant Prior number of regimens Median Mean (FSEa) Range a
Number of cases
%
62 42–83 18 5
78.3 21.7
11 8 4
47.8 34.8 17.4
4 1 1 13 4 19 4 13 10
17.4 4.35 4.35 56.5 17.4 82.6 17.4 56.5 43.5
1 1.74 F 0.22 1–5
SE = standard error.
number of prior chemotherapy regimens was 1 (range 1– 5), with a mean of 1.74 [F0.22 SE; 95% confidence interval (CI) of 1.26–2.2]. Thirteen (56.5%) had platinumsensitive disease and 10 (43.5%) were platinum resistant. Eighteen (78.3%) had a measurable disease while the remaining 5 (21.7%) were assessable by elevated CA-125 levels only. Overall, 88 cycles were administered for a total of 264 weekly treatments and a median of four courses (range 2–6). The median duration of follow-up
Fig. 1. Kaplan–Meier probability curve of time to progression.
was 6.8 months (range: 2–13.07 months; 95% CI of 3.69– 9.53). There were four (17.4%) complete responders (CR) and seven (30.4%) partial responses (PR) for an overall response rate (ORR) of 47.8% (11 patients; 95% CI of 26%–69%). Eleven (47.8%) patients had SD and one (4.8%) patient progressed while on treatment. Fig. 1 depicts TTP. The median TTP after weekly topotecan therapy was 4.9 months (range 1.4–13.07 months with 95% CI of 3.71–6.09, SE F 0.61). Twenty of the 23 patients (86.9%) patients are still alive and three have died of their disease for a median overall survival of 11.59 months (95% CI 10.12–13.05, SE F 0.75). Of the 20 living patients, two are in sustained remission lasting more than 6 months and 18 are alive with disease, seven patients remain on weekly topotecan treatment, one with PR and 6 with SD. The women were also stratified as platinum sensitive or platinum resistant. The ORR for patients with platinumsensitive and platinum-resistant disease was 47.8% and 52.2%, respectively ( P = 0.54). Of the four CRs, three had platinum-sensitive and one had platinum-resistant disease. Fig. 2 shows TTP according to the primary response to platinum treatment. The TTP was 5.9 months in the platinum-sensitive and 4.67 months in the platinum-resistant patients ( P = 0.86). Topotecan toxicity was assessed in all 23 patients. One patient (4.3%) had grade III neutropenia and one had grade III anemia. Grade III thrombocytopenia needing dose reduction was observed in four patients (17.4%). One of them was taken off protocol after two treatment cycles because of prolonged grade II thrombocytopenia. Other side effects that did not require dose alteration included grade II nausea in two (8.7%), grade II neuropathy in two, and grade I–II fatigue in nine (39.1%) patients.
Fig. 2. Kaplan–Meier probability curve of time to progression in platinumsensitive and platinum-resistant patients.
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Discussion Insofar as recurrent EOC is an incurable disease, the main treatment goal is to achieve long-term remission with a reasonable quality of life. Currently, the FDA-approved treatment for recurrent EOC is topotecan administered as a daily dose of 1.5 mg/m2 for 5 consecutive days every 21 days. Although good response rates have been observed with this regimen, its toxicity often results in treatment interruption and dose reduction. ten Bokkel Huinik et al. [6] showed 79% grade IV neutropenia, followed by 25% thrombocytopenia. Kudelka et al. [7] reported that 61% of patients required dose reduction because of myelosuppression and that 25% suffered from neutropenic fever. Two other second-line studies also showed that the incidence of grade IV neutropenia was 33% [10] and 57% [15] of cycles. Fatigue is the most common nonhematological toxicity in the 5-day treatment schedule, reported in 22–34% of topotecan-treated patients [6,11]. Moreover, it was found to be the most prominent cause for removing responding patients from therapy [11]. Recently, in a dose-escalating study conducted on patients with recurrent EOC, Homesley et al. [12] evaluated weekly administration of topotecan. On the one hand, a weekly dose below 2 mg/m2 was not associated with antitumor activity. On the other hand, the maximal tolerated weekly dose was 4 mg/m2. Although myelosuppression was rarely dose limiting, nausea, vomiting, and fatigue led to patient refusal to continue treatment on higher doses. In the current study, our starting dose was 4 mg/m2 and it was well tolerated: no patient withdrew from the study due to intolerable toxicity and only 4 patients (17.4%) needed dose reduction for thrombocytopenia. One patient had grade III neutropenia, one had grade III anemia, and three grade III thrombocytopenia. Thus, the level of myelosuppression among our patients was fairly low compared to the standard schedule of topotecan in EOC. The main nonhematological side effect was grade I–II fatigue in 39.1% of patients, but no dose reduction, treatment delay, or discontinuation were requested or required. The weekly topotecan regimen we followed resulted in excellent response rates. We achieved 17.4% CR and 30.4% PR for an ORR of 47.8%. Additionally, 11 patients (47.8%) had SD for a clinical benefit (CR + PR + SD) of 95.6%. Prior studies using the standard regimen of topotecan showed ORRs ranging from 13% to 33% [5–11]. In their Phase III study, ten Bokkel Huinink et al. [6] comparing topotecan with paclitaxel reported 20.5% ORR and 30% SD in their 112 topotecan-treated patients. The lower ORRs usually appeared in patients with platinum-resistant disease. McGuire et al. [11] found 33% RR and additional 48% stable disease when topotecan was administered as first-line salvage therapy in platinum-sensitive EOC. Similarly, Bolis et al. [15] showed a 31.4% ORR and a 37.1% SD rate in platinum-sensitive patients. Morris et al. [14] in an ongoing study observed similar high ORRs with the weekly top-
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otecan regimen in platinum-sensitive patients. Their group reported a 32% PR and 45% SD with less than 2% grade III–IV toxicity. Although high ORRs have been achieved, their duration is short-lived. The median TTP in our study was 4.9 months (Fig. 1), which is consistent with that of 2.8, 3.96, and 5.36 months reported in other (large-scale) studies [5,6,16] using the 5-day topotecan regimen. The treatmentfree interval also has a bearing on TTP. McGuire et al. [11] observed a prolonged TTP of 9.6 months in platinumsensitive patients. In the present study, patients with platinum-sensitive disease had longer TTP compared to platinum-resistant patients (Fig. 2) although it did not reach statistical significance (5.9 vs. 4.67 months, respectively, P = 0.86). Furthermore, three of our four CRs had platinum-sensitive disease. In conclusion, our data indicate that weekly IV topotecan at a starting dose of 4 mg/m2 demonstrates impressive activity in patients with persistent or recurrent ovarian cancer. Our results are based on a small group of patients with a relatively short follow-up period. However, the encouraging high ORR with a very low rate of side effects warrants further investigation and comparison of this weekly protocol to the standard 5-day topotecan schedule for the treatment of recurrent ovarian cancer.
Acknowledgments Esther Eshkol is thanked for the editorial assistance and Dr. Mona Boaz for the statistical analysis.
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