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© 2003 American Society for Clinical Oncology Topotecan Is an Active Agent in the First-Line Treatment of Metastatic or Recurrent Endometrial Carcinoma: Eastern Cooperative Oncology Group Study E3E93
From the Weill Medical College of Cornell University, New York, and Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY; Dana-Farber Cancer Institute, Boston, MA; Rush Presbyterian-St Luke’s Medical Center, Chicago, IL; Bergan Mercy Medical Center, Omaha, NE; and University of Wisconsin, Madison, WI. Address reprint requests to Scott Wadler, MD, Department of Oncology, Division of Hematology-Oncology, Weill Medical College of Cornell University, 525 E 68th St, STARR 353, New York, NY 10021; email: scw2004{at}med.cornell.edu.
Purpose: To determine the clinical activity and the toxicity profile of the topoisomerase-I inhibitor, topotecan, in women with recurrent or advanced endometrial carcinoma. Patients and Methods: A prospective, phase II clinical trial was initiated by the Eastern Cooperative Oncology Group (ECOG). Patients had histologically confirmed advanced or recurrent endometrial carcinoma, measurable disease, no prior cytotoxic therapy, an ECOG performance status of 0 to 2, and evidence of disease progression while on progestins or after radiation therapy. Topotecan was administered at 1.5 mg/m2 (or 1.2 mg/m2 for patients with prior pelvic radiation) intravenously daily for 5 days every 3 weeks. Results: A total of 44 patients were enrolled; 42 were eligible. The study was suspended because of unexpected toxicities, primarily sepsis and bleeding. After toxicity review, the study was reopened using lower doses of topotecan (1.0 mg/m2 or 0.8 mg/m2 for patients with prior radiation therapy). In addition, prophylactic use of growth factors was allowed after the first cycle, and patients with performance status of 2 were excluded. The major toxicities were hematologic and gastrointestinal. Among the 40 assessable patients, there were three (7.5%) complete responders and five partial responders (12.5%), for an overall response rate of 20%. The median duration of response was 8.0 months and of overall survival was 6.5 months. Conclusion: Topotecan is an active agent for the treatment of advanced endometrial carcinoma. At the doses and schedules initially used, toxicities were unacceptable; however, at the modified doses, toxicities were acceptable and clinical activity was preserved.
CARCINOMA OF the endometrium is the most common gynecologic cancer and the second leading cause of cancer deaths involving gynecologic tumors in the United States.1 Despite a decrease in the death rate from endometrial cancer since the 1930s, it still accounts for 6% of all cancers in women and 2% of all cancer deaths.1 One explanation for the decreased mortality has been the widespread recognition of the classical presenting sign, postmenopausal bleeding, resulting in a high rate of early detection and thus cure. Nevertheless, for patients with endometrial carcinoma that is beyond the scope of definitive surgical resection, the prognosis remains poor. Patients with recurrent or metastatic endometrial carcinoma often receive hormonal therapy with progestins. Although progestins offer effective palliation in the minority of women with well-differentiated tumors or tumors expressing high levels of the progesterone receptor, for the majority of patients, hormonal therapy offers only modest benefits, albeit with minimal toxicities.2 For patients whose cancer is refractory to hormonal therapy, treatment with cytotoxic agents has been attempted. Although agents such as doxorubicin, cisplatin, carboplatin, ifosfamide, and paclitaxel have demonstrated modest efficacy, newer agents are clearly needed. Topotecan is a semisynthetic, water soluble camptothecin analog that inhibits topoisomerase I activity.3,4 Topoisomerase I binds supercoiled DNA covalently, creating a transient single-strand break, which allows passage of the second strand of DNA, followed by resealing of the lesion. Topotecan inhibits the religation step, leading to permanent strand breaks and apoptosis.5 A phase I clinical trial of topotecan using a schedule of once daily for 5 days (daily x 5) every 3 weeks demonstrated the tolerability of a dosing level of 1.5 mg/m2.6 At this dose level, the predominant toxicity was neutropenia. After phase II trials demonstrated clinical efficacy for topotecan in women with relapsed ovarian cancer, the United States Food and Drug Administration granted approval for treatment for this indication. On the basis of these promising results, we undertook a phase II trial of topotecan as first-line therapy in women with advanced or recurrent endometrial carcinoma.
Administrative This prospective, multi-institutional trial was initiated in April 1995. The aims of the trial were to determine the response rates, overall survival, and toxicities of topotecan therapy in women with endometrial carcinoma. The trial was approved by the institutional review boards of each participating institution and in accordance with an assurance filed with and approved by the United States Department of Health and Human Services.
Eligibility
Study Design
Statistical Analysis
Demographic Characteristics As shown in Table 1  , 44 patients were enrolled. Two patients were ineligible because of wrong histology and absence of progressive disease after radiation treatment. Among the 42 eligible patients, two were unassessable because they never received treatment (one refused and one died before receiving therapy). Among the 40 assessable patients, median age was 67.7 years, most patients were white, and 87.5% had a performance status of 0 to 1. The median time from diagnosis to study entry was 12.0 months (range, 0.5 to 83 months). Most patients (67.5%) had an associated chronic disease, and 75.0% were taking medications chronically. Almost all patients (97.5%) were postmenopausal (natural or surgery-induced), with menopausal status unknown for the remaining patient. Progesterone receptor status was only analyzed for 15% of the patients and was positive in 10%. As expected, 85% of patients had grade 2/3 tumors.
Toxicities As shown in Table 2 , the primary toxicities were hematologic. Among the first 28 eligible patients, there were five lethal toxicities, including gastrointestinal hemorrhage (n = 2) and sepsis (n = 3) with or without pneumonia or pulmonary embolus. Four of these occurred in the first cycle. Furthermore, there were five cases of grade 3 or higher hepatotoxicity and three cases of grade 3 or higher neurotoxicity. On the basis of a review of the toxicities, the protocol was amended to reduce the starting dose of topotecan to 1.0 mg/m2 (0.8 mg/m2 in patients with prior pelvic radiation therapy), to exclude patients with a performance status of more than 1, and to allow the use of hematopoietic growth factors for patients who developed hematologic toxicity after the first cycle. After restarting the study, 12 additional patients were accrued for a total of 40 patients. Among these patients, there were no grade 4/5 toxicities, except for one patient with grade 4 granulocytopenia. With the exception of hematologic toxicities, there were only two grade 3 toxicities among these patients, including infection and nausea, and no evidence of hepatotoxicity or neurotoxicity observed with the higher doses.
Response to Treatment As shown in Table 3 , among the 40 eligible patients, there were three complete responses (7.5%; 90% CI, 2.3% to 20.4%) and five partial responses (12.5%; 90% CI, 5.2% to 25.1%), for an overall response rate of 20% (90% CI, 10.4% to 33.3%). The median duration of response was 8.0 months. The response rates for the patients enrolled before study suspension was 20.7% (90% CI, 6.8% to 27.8%), with two complete and four partial responses. The response rate for those registered after the suspension was 18.2% (90% CI, 1.2% to 18.9%), with one complete and one partial response. The median overall survival for all eligible patients was 6.5 months, and the median progression-free survival was 3.2 months.
This is the first study to demonstrate clinical activity for topotecan in the first-line setting in patients with advanced or recurrent endometrial carcinoma. Of interest is the relatively high complete response rate (7.5%) and the relatively favorable duration of response (8.0 months), indicating that topotecan may have durable clinical benefits. This confirms the activity observed in other trials using topotecan in women with endometrial carcinoma. A trial by the Gynecologic Oncology Group using a daily x 5 schedule in patients who had received prior therapy demonstrated a response rate of 10%.9 An early phase I/II trial using bolus topotecan administered weekly demonstrated a partial response rate of 23% in previously treated patients.10 A small phase II study combined topotecan on a daily times five schedule with cisplatin administered day 5 in previously untreated patients with advanced or recurrent endometrial cancer.11 Among eight assessable patients, two achieved a complete response. Finally, in patients with serous tumors of the endometrium, topotecan administered on a daily x 5 schedule was highly active.12
Given the limited armamentarium in treating advanced endometrial carcinoma,13 identification of a novel active agent is an important finding. Only a handful of agents have demonstrated reproducible response rates One concern in the current trial was the high incidence of lethal toxicities at the 1.5 mg/m2 dose level. In the original phase I trial, which tested the daily x 5 schedule,6 grade 3 and 4 neutropenia occurred in most courses at doses of 1.5 mg/m2; however, neutropenia was brief and rarely associated with fevers or treatment delays. Thrombocytopenia, skin rash, diarrhea, and vomiting occurred infrequently and were modest in severity. In that phase I trial, renal elimination accounted for 38.7% of drug disposition. Given that endometrial carcinoma tends to occur in the seventh decade and is associated with comorbid disease, including diabetes and hypertension, which may predispose to a higher incidence of subclinical renal dysfunction, it is not surprising that women in this patient population may have a higher incidence of complications, as was observed among the first cohort of patients treated in our trial. Clinical guidelines for patients with topotecan-associated neutropenia suggest dose reduction and use of hematopoietic growth factors,22 as used in our study. This resulted in nearly complete abrogation of severe toxicities. Fortunately, dose reduction has not been associated with loss of therapeutic benefit,22 and in our study, the comparable response rates in the cohort of patients treated after dose reduction and those treated before the dose reduction support this observation. A second concern in our trial was the higher than expected incidence of hepatic and neurotoxicity. Neurotoxicity is a relatively uncommon side effect from topotecan therapy. In one trial, however, which used a higher dose of topotecan on a 3-day schedule with hematopoietic growth factor support, neurotoxicity was the dose-limiting toxicity.23 Two of four patients (68 and 73 years of age) at the highest dose level, 4.25 mg/m2, experienced severe, nonfocal neurotoxicity that required discontinuation of therapy; at the next lowest dose, 3.75 mg/m2, neurotoxicity was dose-limiting. A subsequent study using 2 mg/m2 failed to demonstrate significant neurotoxicity.24 In other studies in which neurotoxicity has been observed with topotecan, it has usually been used in combination with other neurotoxic agents, such as paclitaxel, cisplatin, or both.25–27 In contrast, hepatotoxicity is seen rarely in patients treated with topotecan. A recent meta-analysis of studies using topotecan in patients with ovarian cancer failed to identify hepatotoxicity as an important side effect of treatment.28 Although the 1.0 mg/m2 dose level was efficacious and well tolerated in our study, further studies with topotecan using an alternative schedule of administration are worth pursuing given the clinical activity of the daily x 5 schedule used by us. Weekly topotecan is an active and well-tolerated regimen (reviewed in Rowinsky29). Prolonged infusional topotecan has been shown to be tolerable30 and has demonstrated clinical activity in heavily pretreated patients with ovarian cancer.31 Furthermore, detailed pharmacodynamic studies support the use of such a schedule of prolonged administration of topotecan.31–33 Oral topotecan may mimic the pharmacokinetics of the prolonged infusion, with greater patient acceptance. In a randomized trial in women with previously treated ovarian cancer,34 however, there were comparable response rates, but a slightly lower survival and a higher incidence of gastrointestinal toxicities for the oral formulation. Nevertheless, the convenience of orally administered therapy must be considered in the palliative setting. In summary, topotecan has clinical activity in women with advanced or recurrent endometrial carcinoma who have not received prior cytotoxic therapy. The initial schedule and dosages used, 1.5 mg/m2, had unacceptable toxicities. The lower dosages, 1.0 mg/m2 for women without prior pelvic irradiation or 0.8 mg/m2 for women with prior pelvic irradiation with the use of prophylactic hematopoietic growth factors, are well tolerated and active. This regimen should be used in women who are fully ambulatory. Other schedules of administration of topotecan in women with endometrial cancer should be explored.
This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair) and supported in part by Public Health Service grants CA23318, CA66636, CA21115, CA14958, CA13650, and CA49883 from the National Cancer Institute, National Institutes of Health (Bethesda, MD), and the Department of Health and Human Services (Washington, DC). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
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22. Armstrong D, O’Reilly S: Clinical guidelines for managing topotecan-related hematologic toxicity. Oncologist 3:4–10, 1998 23. Brown JV 3rd, Peters WA 3rd, Rettenmaier MA, et al: A phase I trial of a 3-day topotecan Q 21 days for recurrent epithelial cancers of the ovary, fallopian tube, and peritoneum. Gynecol Oncol 79:495–498, 2000[CrossRef][Medline] 24. Brown JV, Peters WA, Rettenmaier MA, et al: Three-consecutive-day topotecan is an active regimen for recurrent epithelial ovarian cancer. Gynecol Oncol 88:136–140, 2003[CrossRef][Medline]
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31. Hochster H, Wadler S, Runowicz C, et al: Activity and pharmacodynamics of 21-day topotecan infusion in patients with ovarian cancer previously treated with platinum-based chemotherapy: New York Gynecologic Oncology Group. J Clin Oncol 17:2553–2561, 1999 32. Hochster H, Liebes L, Speyer J, et al: Effect of prolonged topotecan infusion on topoisomerase 1 levels: A phase I and pharmacodynamic study. Clin Cancer Res 3:1245–1252, 1997[Abstract] 33. Liebes L, Potmesil M, Kim T, et al: Pharmacodynamics of topoisomerase I inhibition: Western blot determination of topoisomerase I and cleavable complex in patients with upper gastrointestinal malignancies treated with topotecan. Clin Cancer Res 4:545–557, 1998[Abstract] 34. Gore M, Oza A, Rustin G, et al: A randomised trial of oral versus intravenous topotecan in patients with relapsed epithelial ovarian cancer. Eur J Cancer 38:57–63, 2002[Medline] Submitted December 16, 2002; accepted March 21, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
4,000/mL, platelet count 
1.5 mg/dL, and serum creatinine 
