- Email: [email protected]
Weekly topotecan in heavily pretreated patients with recurrent epithelial ovarian carcinoma
Gynecologic Oncology 98 (2005) 242 – 248 www.elsevier.com/locate/ygyno
Weekly topotecan in heavily pretreated patients with recurrent epithelial ovarian carcinoma David M. O’Malley*, Masoud Azodi, Anita Makkenchery, Jacob Tangir, Jessica McAlpine, Michael Kelly, Peter Schwartz, Thomas Rutherford Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, PO Box 208063, New Haven, CT 06520, USA Received 20 December 2004
Abstract Objective. To investigate weekly topotecan in heavily pretreated patients with recurrent ovarian cancer. Methods. The records of patients with recurrent epithelial ovarian cancer who were treated with weekly topotecan after failure of 1 prior regimen were reviewed. Patients received topotecan (median starting dose ¨2.5 mg/m2) on days 1, 8, and 15 of a 28-day cycle. Antitumor response was assessed after 2 cycles by serial CA-125 levels. Results. Thirty-five heavily pretreated patients received a mean of 5 cycles of topotecan (range, 1 – 13 cycles). Thirty-two patients had definable platinum sensitivity (16 sensitive, 8 resistant, 8 refractory). Median age was 56 years. A total of 177 cycles (534 weeks) of topotecan was administered. Hematologic toxicity was generally mild, and no grade 4 toxicities were observed. Grade 3 hematologic toxicity, including leukopenia, neutropenia, thrombocytopenia, and anemia, was observed in 2, 2, 1, and 0 patients, respectively. No patients experienced grade 3 or 4 nonhematologic toxicity. Based on serial CA-125 measurements, there were 1 (3%) complete and 5 (15%) partial responses, with 1 of the partial responses in a patient with platinum-refractory disease. Stable disease was reported in 13 (38%) patients, including 5 patients with platinum-resistant/refractory disease. Conclusion. Weekly topotecan demonstrates activity and is well tolerated compared with historical data with the standard 5-day schedule. Higher doses may be warranted because of the high tolerability shown for weekly topotecan. Weekly topotecan may be an appropriate treatment option for patients with recurrent ovarian cancer, especially heavily pretreated patients who might require dosing schedules with improved tolerability. D 2005 Elsevier Inc. All rights reserved. Keywords: Alternate treatment regimens; Ovarian cancer; Retrospective analysis; Topotecan
Introduction Ovarian cancer is the fourth leading cause of cancerrelated deaths in women, with 22,220 new cases and 16,210 associated deaths predicted to occur in 2005 [1]. Although ovarian cancer typically responds to first-line platinumbased therapy, most patients experience disease relapse and eventually succumb to their disease [2,3]. In this setting, quality of survival is an important issue, disease stabiliza-
* Corresponding author. Fax: +1 203 785 6782. E-mail address: [email protected] (D.M. O’Malley). 0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.04.032
tion is considered a treatment benefit [4], and therapies with noncumulative toxicities are favored even if their overall response rates are relatively low [5]. With advances in chemotherapy and patient care, ovarian cancer is increasingly viewed as a chronic disease, with many patients progressing through a variety of chemotherapy regimens [5,6]. Unfortunately, many of the aggressive chemotherapy agents used in early treatment are associated with cumulative toxicities [5,6]. Accordingly, patients may become predisposed to adverse events and poorer quality of life with each additional regimen [5,7]. In addition, the rate and duration of response progressively decrease with each successive line of therapy.
D.M. O’Malley et al. / Gynecologic Oncology 98 (2005) 242 – 248
Topotecan (HYCAMTIN\; GlaxoSmithKline, Philadelphia, PA) is a topoisomerase I inhibitor that has demonstrated antitumor activity in relapsed epithelial ovarian cancer (EOC). The US Food and Drug Administrationapproved dose and schedule for topotecan are 1.5 mg/m2/ day via 30-min intravenous (IV) infusion on days 1 through 5 of a 21-day cycle. Overall response rates for this regimen in the second-line EOC setting range from 19% to 33% for platinum-sensitive disease [8,9] and 12 –18% for platinumresistant disease [8,10]. Additionally, stable disease (SD) is reported in up to 46% of patients receiving topotecan therapy [10,11]. After relapse, ovarian cancer is considered a chronic disease condition, and patients typically receive multiple rounds of treatment to manage their disease, with the response rate and duration of response typically decreasing with each successive round of chemotherapy [5]. Topotecan is associated with few nonhematologic toxicities and a manageable, noncumulative, reversible hematologic toxicity profile. Nonetheless, hematologic toxicity limits the use of topotecan, particularly in patients with advanced age, poorer performance status, or comorbidities. Tolerability to topotecan therapy may also be reduced in heavily pretreated patients who have experienced cumulative toxicities from prior chemotherapy regimens. Treatment delays, dose reductions, and the administration of growth factors are often employed to manage myelosuppression in these patients [12 – 14]. Indeed, there appears to be a positive correlation between the number of prior myelosuppressive chemotherapy agents and the requirement for growth factor support [14]. The chronic course and the palliative goals in the treatment of recurrent ovarian cancer require alternative dosing and scheduling strategies for heavily pretreated patients who are susceptible to myelosuppression. Lowdose topotecan, continuous IV infusions (CIV), and weekly administration have all been investigated as alternative regimens in patients with relapsed ovarian cancer [15]. Although only preliminary results have been reported, weekly topotecan appears to be a promising alternative regimen. Weekly topotecan is associated with reduced myelosuppression compared with the standard regimen and is associated with antitumor efficacy [15 – 18]. In this retrospective analysis, we report on the use of weekly topotecan in our clinical experience in heavily pretreated patients with relapsed ovarian cancer.
Materials and methods Patient population and treatment We retrospectively examined medical records of patients with recurrent ovarian cancer who were treated with weekly topotecan at the Yale University School of Medicine/YaleNew Haven Hospital (New Haven, CT) between January 2001 and December 2003. Eligible patients had received 1
243
prior regimen, 1 of which must have contained a platinum agent. Patients who had received 4 weeks of topotecan infusions were eligible for the analysis. These criteria were chosen because patients who had just initiated therapy would not have provided an accurate reflection of the efficacy of therapy and would not have provided insight into whether the associated toxicity was cumulative or noncumulative in nature. Patients with either platinum-sensitive (relapse >6 months after primary therapy), platinumresistant (relapse during or 6 months after primary therapy), or platinum-refractory disease (progressive disease while on platinum therapy) were eligible. Patients received topotecan on days 1, 8, and 15 of a 28-day cycle (or a small variation of this schedule). Hematologic toxicity was managed by dose delays, reductions and adjustments, and growth factor and/or blood product support. Dose escalation was also permitted. Patients were treated until progression or until complete clinical response. Institutional Review Board/Human Investigative Committee approval was obtained. Patient assessment All patients who received 1 cycle of weekly topotecan were considered evaluable for safety. Hematologic and nonhematologic toxicities were assessed by clinical reports and laboratory assessments, including hemoglobin, leukocyte, neutrophil, and platelet nadir measurements. Toxicity was evaluated according to National Cancer Institute Common Toxicity Criteria. Dose escalation, reduction, and treatment delays were noted, as well as growth factor support, including granulocyte colony-stimulating factor (G-CSF), erythropoietin, and blood product support. Antitumor response was assessed after two 28-day cycles by serial cancer antigen 125 (CA-125) levels. Response rates are reported based on best response. Response rates were based on a modification of the Rustin CA-125 criteria [19] or Response Evaluation Criteria in Solid Tumors (RECIST) in the cases for which CA-125 levels were not a tumor marker. In the clinical practice setting, patients who are being treated for ovarian cancer that has relapsed multiple times are often managed according to their symptoms, with the intention of maximizing quality of life. Therefore, response evaluations are often performed less frequently than in the clinical trial setting. Moreover, CA125 evaluations during chemotherapy are often performed only when a response or disease progression is suspected, and the scans necessary for evaluating measurable disease are often forgone because of cost and scheduling issues for the patient. Response definitions must therefore factor in the limited disease evaluation data that are available in this setting. For patients who had no follow-up scans for measurable disease, CA-125 levels were used as surrogate criteria for disease response. If follow-up CA-125 assessments were available, these were used to confirm responses. Complete response (CR) was defined as normalization of
244
D.M. O’Malley et al. / Gynecologic Oncology 98 (2005) 242 – 248
CA-125 levels (to <35 U/ml) with no clinical or radiologic evidence of disease. Partial response (PR) was defined as a 50% reduction in CA-125 levels. Progressive disease was defined as at least a doubling in CA-125 levels or clinical or radiologic evidence of progressive disease. Patients who did not fit these criteria were considered to have SD.
Table 2 Incidence of hematologic toxicity Patients, n (%) (N = 35)
Anemia Leukopenia Neutropenia Thrombocytopenia
Grade 1
Grade 2
Grade 3
Grade 4
10 (29) 2 (6) 0 1 (3)
11 (31) 2 (6) 4 (11) 0
0 2 (6) 2 (6) 1 (3)
0 0 0 0
Results Safety and tolerability Patients Thirty-five pretreated patients who had received weekly topotecan therapy for recurrent epithelial ovarian cancer were evaluated. A summary of patient and baseline disease characteristics is provided in Table 1. Median age of this patient population was 56 years (range, 37 – 82 years). Thirty-three (94%) patients had been diagnosed with stage III disease, with ¨60% diagnosed with stage IIIC/IV disease. Nearly 50% of the patients had received 3 prior chemotherapy regimens and approximately two thirds of the patients had received 2 prior chemotherapy regimens. All patients had received prior platinum therapy and approximately half of the patients had platinum-sensitive disease. Mean (Tstandard deviation) baseline CA-125 at level at study entry was 263 T 433 U/ml. Table 1 Patient demographics and baseline disease characteristics Characteristic
Patients (N = 35)
Median age, years (range) Stage, n (%) IC IIC III IIIA IIIB IIIC IV Unknown Prior treatment regimens, n (%) 1 2 3 4 Platinum status, n (%) Sensitive Resistant/refractory Unknowna Baseline CA-125 level, U/ml Mean T standard deviation Median Range Measurable disease, n (%) Yes No
56 (37 – 82) 1 (3) 1 (3) 11 (31) 1 (3) 1 (3) 14 (40) 5 (14) 1 (3) 13 (37) 5 (14) 7 (20) 10 (29) 16 (46) 16 (46) 3 (9) 263 T 433 99 11 – 2231 6 (17) 29 (83)
CA-125 = Cancer antigen 125. a Patients had an allergic reaction to carboplatin; therefore, chemosensitivity could not be determined.
All 35 patients were evaluable for safety and tolerability. A total of 534 weekly infusions was administered (median, 12 weekly infusions) for a median of 4 cycles of therapy (total of 177 cycles). The median starting dose of topotecan was 2.5 mg/m2, with 21 patients starting at this dose. Eleven patients started at doses >2.5 mg/m2 (range, 3– 5 mg/m2) and 3 patients started at doses <2.5 mg/m2 (range, 1.5– 2 mg/m2). Two patients had dose escalations and 3 patients had dose reductions after the first cycle; 1 of these patients underwent a second dose reduction after the third treatment cycle. Although all 35 patients had received prior treatment, no patients experienced any grade 4 hematologic toxicities (Table 2). Grade 3 neutropenia and grade 3 leukopenia were each reported in 2 (6%) patients. Seven patients experienced treatment delays because of grade 2 or 3 neutropenia or leukopenia, with a median delay of 1 week (range, 1– 3 weeks). Grades 1 and 2 anemia were the most common hematologic toxicity, with 21 (60%) patients experiencing mild to moderate anemia. Fifteen of these patients received erythropoietin, with 5 patients requiring transfusions. Grade 1/2 thrombocytopenia was less common, occurring in <10% of patients. In this patient population, weekly topotecan was also associated with a favorable nonhematologic toxicity profile. No grade 3 or 4 nonhematologic toxicities were reported and only 7 patients reported grade 1 or 2 nonhematologic toxicities. Nonhematologic toxicities included fatigue (n = 3), neuropathy (n = 3), small bowel obstruction (n = 1), nausea (n = 2), abdominal pain (n = 1), and renal toxicity (n = 1). Antitumor activity Patients were followed with clinical examination and serial CA-125 levels, which is the standard protocol at our institution. Computed tomography (CT) scans were only obtained if indicated by clinical history or when disease status was not evaluable by serial CA-125 measurement or clinical exam. Thirty-four of the 35 patients were evaluable for response. Twenty-eight of the 34 (82%) patients were evaluable for response by serial CA-125 assessment. Six patients (18%) did not have elevated CA-125, yet had clinically or radiologically measurable disease. The overall response rate for 34 evaluable patients was 21%, with 1
D.M. O’Malley et al. / Gynecologic Oncology 98 (2005) 242 – 248 Table 3 Best responses to weekly topotecan therapy Parameter
Patients, n (%) (N = 34) Sensitive Resistant/refractory Unknowna Total
Complete response 1 Partial response 3 Stable disease 6 Progressive disease 6 Total 16
(3) (9) (18) (18) (47)
0 1 5 9 15
(3) (15) (26) (44)
0 1 (3) 2 (6) 0 3 (9)
1 5 13 15 34
(3) (15) (38) (44) (100)
a These patients had a reaction to carboplatin that prevented platinum sensitivity assessment.
(3%) patient achieving a CR, 5 (15%) patients achieving a PR (Table 3), and 13 (38%) patients achieving SD. One (6%) of the 16 patients with platinum-sensitive disease achieved a CR and 3 (19%) achieved a PR. An additional 6 (38%) patients experienced SD. Five of the 15 patients with platinum-resistant or -refractory disease experienced SD, and 1 achieved a PR. One of the 3 patients whose disease chemosensitivity was unknown achieved a PR, and the other 2 patients experienced SD. Among the 23 patients who were treated with weekly topotecan at doses 2.5 mg/m2, 12 (52%) experienced clinical benefit (CR, PR, or SD). Among the 11 patients who were treated with weekly topotecan >2.5 mg/m2, 7 (64%) experienced clinical benefit. One patient received 6 cycles of topotecan therapy after neoadjuvant chemotherapy (carboplatin/paclitaxel) followed by an optimal tumor debulking. She had a normal CA-125 level and no measurable disease at the initiation of therapy; therefore, she was not evaluable for tumor response. At the completion of her 6 cycles of topotecan therapy, she had normal CA125 and no clinical evidence of disease by CT scan for 20 weeks when she presented with new onset of ascites. The patient who achieved a CR received 12 cycles of therapy. Following therapy she had no evidence of disease on CT scan and a normal CA-125. Twelve months after completing therapy, she is alive without evidence of disease. The median response duration was 28 weeks (range, 16 –44 weeks) for patients who achieved a PR. Median duration of SD was 20 weeks (range, 12– 52 weeks). At the time of this analysis, median follow-up was 19.2 months, and 2 patients had died (survival of 4 months and 10.5 months after the initiation of weekly topotecan). Median overall survival had not been reached.
Discussion Topotecan is currently approved for the treatment of patients with relapsed ovarian cancer. However, the standard regimen for topotecan (1.5 mg/m2 on days 1– 5 of a 21-day cycle) often is not well tolerated by patients with advanced age, comorbidities, poor performance status, or a susceptibility to myelosuppression because of prior treatment. Therefore, alternative regimens for this active agent have
245
been explored. Alternative dosing schedules have included a 21-day, 24-h CIV infusion; 3-day bolus IV infusion; and several weekly regimens [15]. Alternate regimens that decrease the number of treatment days and reduce the need for blood factor or hematopoietic growth factor support could also increase the convenience of therapy. However, although reducing the number of treatment days from the standard 5-day regimen to 3 days or one 24-h infusion per 21-day cycle has resulted in more favorable hematologic toxicity profiles, such regimens have demonstrated limited activity, especially in patients with platinum-resistant or platinum-refractory disease [20 – 24]. In contrast, there is increasing evidence that weekly bolus infusions of topotecan are active in this setting. Topotecan targets topoisomerase I activity during the Sphase of the cell cycle. In early studies, it was thought that the cytotoxicity of topotecan was solely dependent on the duration of exposure [17]. As a result, it was thought that an intermittent regimen would not be effective. However, intermittent schedules with several other schedule-dependent cytotoxic agents (e.g., paclitaxel and gemcitabine) have demonstrated activity in relapsed ovarian cancer with a weekly regimen [25 – 28]. In addition, preclinical studies in a non-small cell lung cancer cell model indicate that prolonged exposure to topotecan may not provide superior cytotoxic activity because of topoisomerase I modulation [29]. On prolonged exposure, topoisomerase I levels decreased but also appeared to return to baseline levels after 1 week, suggesting that a weekly regimen may target cells when they are most vulnerable to topotecan therapy. More importantly, preclinical studies with topotecan in human colon carcinoma xenografts, B16 melanoma, and Lewis lung carcinoma murine models have shown that topotecan administered in schedules equivalent to a weekly schedule in humans is associated with antitumor activity, delays in tumor growth, and improved survival [15,17,30]. Results from the preclinical studies and other observations prompted investigators to study weekly administration of topotecan in patients. An early phase I study determined that a weekly 24-h CIV regimen was feasible in patients with solid tumors [31]. Subsequently, Hoskins et al. [32] compared the standard topotecan dosing regimen with a weekly 24-h CIV regimen at 1.75 mg/m2. Although the response rate was significantly greater with the standard regimen (23% vs. 3%), the disproportionally low incidence of grade 3/4 neutropenia in the weekly regimen arm suggests that those patients received suboptimal dosing. Therefore, it was thought that weekly administration of higher doses of topotecan might be associated with improved antitumor activity. The feasibility of a weekly bolus topotecan regimen was investigated in a phase I/II dose-escalation study in 32 previously treated patients with ovarian cancer [33]. In that study, the maximum tolerated dose of weekly topotecan without G-CSF support was 6 mg/ m2, and the maximum recommended dose for further study was 4 mg/m2, because of fatigue, grade 2 anemia, and
246
D.M. O’Malley et al. / Gynecologic Oncology 98 (2005) 242 – 248
gastrointestinal toxicity. Weekly topotecan doses >2.0 mg/ m2 were associated with activity. Levy et al. [34] recently reported the results of a phase II trial of weekly topotecan 4 mg/m2/week for 3 weeks of a 4-week cycle in women with recurrent or persistent ovarian or peritoneal cancer. In 23 patients, this regimen produced 4 CRs and 7 PRs, for an overall response rate of 48%. Therapy was generally well tolerated, with thrombocytopenia as the dose-limiting hematologic toxicity and fatigue being the most common nonhematologic toxicity. Consistent with these observations, weekly topotecan 4.0 mg/m2/week has demonstrated antitumor activity in an ongoing phase II study in patients with platinum-sensitive ovarian cancer, with 7 of the 26 (32%) patients achieving a PR and 10 (45%) additional patients experiencing SD [16]. Weekly topotecan at 4.0 mg/ m2 was not associated with severe myelosuppression and fatigue, and gastrointestinal toxicity and was reported in <1% of the weekly treatments. Recently, in a retrospective review of weekly topotecan therapy, Bhoola et al. [35] reported similar results with weekly bolus topotecan in patients who had received 2 prior chemotherapy regimens. Although previous reports have demonstrated that weekly bolus topotecan at a dose of 4.0 mg/m2 is well tolerated, a concern remains that this dose may be associated with unacceptable toxicity in some patients. For example, the topotecan dose-escalation study by Homesley et al. [33] excluded patients who had received prior radiation therapy or more than 2 prior chemotherapies and patients whose performance status was >2. In practice, a starting dose of <4.0 mg/m2 is more frequently used because of the concern of myelosuppression in heavily pretreated patients. Indeed, using reduced starting doses of topotecan for patients who have received multiple prior therapies or radiation therapy, have reduced renal function, or are elderly is consistent with the current dosing guidelines for the standard regimen of topotecan in this setting [36]. In an attempt to identify a more accurate – and perhaps realistic – depiction of safety and efficacy in the clinical setting, we initiated the current retrospective review of our clinical experience using weekly topotecan. Review of 35 patient records showed the median starting dose of weekly topotecan to be 2.5 mg/m2. Nine patients were treated with a starting dose of 3.0 mg/m2 and 2 patients were treated with a starting dose of 4.0 mg/m2. Grade 3 leukopenia, neutropenia, and thrombocytopenia were reported in only 3 patients, all of whom had received a starting dose at 3.0 mg/m2 (2 patients) or 5.0 mg/m2 (1 patient). Although all 3 of these patients received erythropoietin, none of these patients received G-CSF or blood product transfusion. Importantly, none of the patients in the analysis received G-CSF support. Because weekly topotecan was associated with a favorable profile with a median dose of 2.5 mg/m2 without G-CSF, it is likely that higher starting doses would have been feasible with growth factor support. Although the median starting dose was lower than that used in the controlled clinical trials in our analysis, weekly
topotecan in our analysis was associated with clinical benefit as measured by CA-125 levels with an overall response rate of 18% and an SD rate of 38%. These response rates are comparable with those previously reported in studies investigating weekly topotecan [16,18,33,35]. In addition, the response rates with weekly topotecan in the present report are comparable with those reported for a phase III crossover study of the standard 5day topotecan regimen in the second-line or third-line EOC settings (overall response rate: second-line, 20.5%; thirdline, 13.1%) [37,38]. Because the safety profile of weekly topotecan in our experience was favorable, an increase in starting dose with or without G-CSF support is likely feasible and may result in higher response rates. Indeed, although the number of cases reviewed was small, there appeared to be an incremental increase in the proportion of patients who achieved clinical benefit at the higher topotecan dose levels. The tolerability and activity of weekly topotecan in treating patients with relapsed ovarian cancer suggest that topotecan may be an appropriate agent to combine with other cytotoxic agents that are also administered on a weekly schedule. The feasibility of weekly combination cisplatin, topotecan, and paclitaxel with G-CSF support was established in a dose-finding study in patients with ovarian cancer or small cell lung cancer (SCLC) with a recommended topotecan dose of 2.25 mg/m2 for phase II studies [39]. The safety and efficacy of this weekly combination regimen were further investigated in a phase II study of chemotherapy-naive patients with extensive SCLC [40]. In that study, weekly cisplatin –topotecan –paclitaxel therapy was associated with response rates at least similar to those observed with the standard front-line treatment for SCLC. Similarly, in a dose-escalation study of weekly topotecan, cisplatin, and gemcitabine, Guarino et al. [41] reported that the combination regimen was well tolerated in patients with advanced non-small cell lung cancer, with favorable response rates, and recommended additional phase II trials. In a phase I study, Homesley et al. [42] reported on the feasibility of weekly topotecan combined with weekly paclitaxel in previously treated patients with ovarian cancer. The authors concluded that results from the phase I study supported future studies of this weekly combination regimen with a starting dose for topotecan of 3.0 mg/m2 when combined with paclitaxel 80 mg/m2. More recently, phase I studies have investigated weekly topotecan in combination with docetaxel and 5-fluorouracil/leucovorin in patients with solid tumors [43,44]. Future phase II studies are needed to ascertain the most active weekly topotecan combination therapy in patients with ovarian cancer. In summary, weekly topotecan was well tolerated and associated with reduced toxicity and similar antitumor activity compared with the standard topotecan dosing regimen. Data suggest that dose escalation with or without an increase in G-CSF support may potentially improve activity. Future randomized, controlled clinical trials on the
D.M. O’Malley et al. / Gynecologic Oncology 98 (2005) 242 – 248
use of weekly topotecan are warranted and will determine the role of weekly administration of single-agent and topotecan-based regimens in the treatment of patients with relapsed ovarian cancer.
Acknowledgments The authors wish to kindly thank the Yale chemotherapy nurses, Lisa Baker, Karen Coombe, and Karen Lynch, for their continued support and care of our patients and for their assistance with this project. This research was supported by an educational grant from GlaxoSmithKline.
References [1] Jemal A, Murray T, Ward E, et al. Cancer Statistics, 2005. CA Cancer J Clin 2005;55:10 – 30. [2] Ozols RF, Schwartz PE, Eifel PJ. Ovarian cancer, fallopian tube carcinoma, and peritoneal carcinoma. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Philadelphia’ Lippincott Williams and Wilkins; 2001. p. 1597 – 632. [3] Engel J, Eckel R, Schubert-Fritschle G, et al. Moderate progress for ovarian cancer in the last 20 years: prolongation of survival, but no improvement in the cure rate. Eur J Cancer 2002;38: 2435 – 45. [4] Gronlund B, Hogdall C, Christensen IJ, Engelholm SA, Hansen HH. Is stabilization of disease a useful indicator for survival in second-line treatment of ovarian carcinoma pre-treated with paclitaxel-platinum? Gynecol Oncol 2004;94:409 – 15. [5] Armstrong DK. Relapsed ovarian cancer: challenges and management strategies for a chronic disease. Oncologist 2002;7:20 – 8. [6] Herzog TJ. Update on the role of topotecan in the treatment of recurrent ovarian cancer. Oncologist 2002;7(Suppl 5):3 – 10. [7] Dunton CJ. Management of treatment-related toxicity in advanced ovarian cancer. Oncologist 2002;7(Suppl 5):11 – 9. [8] Bookman MA, Malmstrom H, Bolis G, 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. [9] McGuire WP, Blessing JA, Bookman MA, et al. Topotecan has substantial antitumor activity as first-line salvage therapy in platinumsensitive epithelial ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2000;18:1062 – 7. [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 1996;14:3056 – 61. [11] Swisher EM, Mutch DG, Rader JS, et al. Topotecan in platinumand paclitaxel-resistant ovarian cancer. Gynecol Oncol 1997;66: 480 – 6. [12] Eckardt J, Depierre A, Ardizzoni A, Von Pawel J, Fields S. Pooled analysis of topotecan (T) in the second-line treatment of patients (pts) with sensitive small cell lung cancer (SCLC). [abstract]. Proc Am Soc Clin Oncol 1997;16:452a [Abstract 1624]. [13] O’Reilly S, Rowinsky EK, Slichenmyer W, et al. Phase I and pharmacologic study of topotecan in patients with impaired renal function. J Clin Oncol 1996;14:3062 – 73. [14] Armstrong D, O’Reilly S. Clinical guidelines for managing topotecanrelated hematologic toxicity. Oncologist 1998;3:4 – 10.
247
[15] Morris R, Munkarah A. Alternate dosing schedules for topotecan in the treatment of recurrent ovarian cancer. Oncologist 2002;7(Suppl 5): 29 – 35. [16] Morris R, Alvarez RD, Andrews S, Malone J, Bryant C, Munkarah A. Topotecan weekly bolus chemotherapy for potentially chemosensitive relapsed ovarian and peritoneal cancer—An update [abstract]. Proc Am Soc Clin Oncol 2003;22:459 [Abstract 1846]. [17] Rowinsky EK. Weekly topotecan: an alternative to topotecan’s standard daily 5 schedule? Oncologist 2002;7:324 – 30. [18] Bhoola S, Estes J, Morris R, Bryant CS, Coleman R, Alvarez RD. Retrospective analysis of weekly topotecan as salvage therapy in relapsed ovarian cancer (OC). [abstract]. Proc Am Soc Clin Oncol 2003;22:474 [Abstract 1905]. [19] Rustin GJ. Use of CA-125 to assess response to new agents in ovarian cancer trials. J Clin Oncol 2003;21(Suppl 10):187 – 93. [20] Markman M, Kennedy A, Webster K, Kulp B, Peterson G, Belinson J. Phase 2 evaluation of topotecan administered on a 3-day schedule in the treatment of platinum- and paclitaxel-refractory ovarian cancer. Gynecol Oncol 2000;79:116 – 69. [21] Miller DS, Blessing JA, Lentz SS, McMeekin DS. Phase II evaluation of three-day topotecan in recurrent platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. Cancer 2003;98:1664 – 9. [22] Markman M, Blessing JA, DeGeest K, et al. Lack of efficacy of 24-h infusional topotecan in platinum-refractory ovarian cancer: a Gynecologic Oncology Group trial. Gynecol Oncol 1999;75:444 – 6. [23] Brown III JV, Peters III WA, Rettenmaier MA, et al. Threeconsecutive-day topotecan is an active regimen for recurrent epithelial ovarian cancer. Gynecol Oncol 2003;88:136 – 40. [24] Markman M, Blessing JA, Alvarez RD, Hanjani P, Waggoner S, Hall K. Phase II evaluation of 24-h continuous infusion topotecan in recurrent, potentially platinum-sensitive ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2000;77:112 – 5. [25] Kaern J, Baekelandt M, Trope CG. A phase II study of weekly paclitaxel in platinum and paclitaxel-resistant ovarian cancer patients. Eur J Gynaecol Oncol 2002;23:383 – 9. [26] Rosenberg P, Andersson H, Boman K, et al. Randomized trial of single agent paclitaxel given weekly versus every three weeks and with peroral versus intravenous steroid premedication to patients with ovarian cancer previously treated with platinum. Acta Oncol 2002; 41:418 – 24. [27] D’Agostino G, Amant F, Berteloot P, Scambia G, Vergote I. Phase II study of gemcitabine in recurrent platinum- and paclitaxel-resistant ovarian cancer. Gynecol Oncol 2003;88:266 – 9. [28] Fowler Jr WC, Van Le L. Gemcitabine as a single-agent treatment for ovarian cancer. Gynecol Oncol 2003;90:S21 – 3. [29] Bence AK, Mattingly CA, Desimone PA, Doukas MA, Adams VR. Evaluation of topotecan cytotoxicity and topoisomerase I levels in non-small cell lung cancer cells. [abstract]. Proc Am Assoc Cancer Res 2002;43:247 [Abstract 1227]. [30] McCabe FL, Johnson RK. Comparative activity of oral and parenteral topotecan in murine tumor models: efficacy of oral topotecan. Cancer Invest 1994;12:308 – 13. [31] Haas NB, LaCreta FP, Walczak J, et al. Phase I/pharmacokinetic study of topotecan by 24-hour continuous infusion weekly. Cancer Res 1994;54:1220 – 6. [32] Hoskins P, Eisenhauer E, Beare S, 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. [33] Homesley HD, Hall DJ, Martin DA, et al. A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients. Gynecol Oncol 2001;83:394 – 9. [34] Levy T, Inbar M, Menczer J, et al. Phase II study of weekly topotecan in patients with recurrent or persistent epithelial ovarian cancer. Gynecol Oncol 2004;95:686 – 90.
248
D.M. O’Malley et al. / Gynecologic Oncology 98 (2005) 242 – 248
[35] Bhoola SM, Coleman RL, Herzog T, et al. Retrospective analysis of weekly topotecan as salvage therapy in relapsed ovarian cancer. Gynecol Oncol 2004;95:564 – 9. [36] Armstrong DK. Topotecan dosing guidelines in ovarian cancer: reduction and management of hematologic toxicity. Oncologist 2004;9:33 – 42. [37] ten Bokkel Huinink W, Gore M, Carmichael J, et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 1997;15:2183 – 93. [38] Gore M, ten Bokkel Huinink W, Carmichael J, et al. Clinical evidence for topotecan – paclitaxel non-cross-resistance in ovarian cancer. J Clin Oncol 2001;19:1893 – 900. [39] Frasci G, Panza N, Comella P, et al. Cisplatin – topotecan – paclitaxel weekly administration with G-CSF support for ovarian and small-cell lung cancer patients: a dose-finding study. Ann Oncol 1999;10:355 – 8. [40] Frasci G, Nicolella G, Comella P, et al. A weekly regimen of cisplatin, paclitaxel and topotecan with granulocyte-colony stimulating factor
[41]
[42]
[43]
[44]
support for patients with extensive disease small cell lung cancer: a phase II study. Br J Cancer 2001;84:1166 – 71. Guarino MJ, Schneider CJ, Grubbs SS, et al. A dose-escalation study of weekly topotecan, cisplatin, and gemcitabine front-line therapy in patients with inoperable non-small cell lung cancer. Oncologist 2002;7:509 – 15. Homesley H, Benigno B, Williams J, Vaccarello L. A phase I study of weekly topotecan and paclitaxel in previously treated epithelial ovarian carcinoma patients. Gynecol Oncol 2002;87:171 – 7. Kuzur ME, Jones S, Willcutt N, et al. A phase I trial of weekly topotecan and docetaxel. [abstract]. Proc Am Soc Clin Oncol 2003;22:706 [Abstract 2840]. Axelrod RS, Rose L, Biermann W, Nathan FE, Hauck W, Hogaboom K. Phase I study of weekly topotecan plus weekly 5fluorouracil (5-FU)/leucovorin (LV) in patients with advanced malignancies: an update. [abstract]. Proc Am Soc Clin Oncol 2003;22:349 [Abstract 1403].
Weekly topotecan in heavily pretreated patients with recurrent epithelial ovarian carcinoma David M. O’Malley*, Masoud Azodi, Anita Makkenchery, Jacob Tangir, Jessica McAlpine, Michael Kelly, Peter Schwartz, Thomas Rutherford Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, PO Box 208063, New Haven, CT 06520, USA Received 20 December 2004
Abstract Objective. To investigate weekly topotecan in heavily pretreated patients with recurrent ovarian cancer. Methods. The records of patients with recurrent epithelial ovarian cancer who were treated with weekly topotecan after failure of 1 prior regimen were reviewed. Patients received topotecan (median starting dose ¨2.5 mg/m2) on days 1, 8, and 15 of a 28-day cycle. Antitumor response was assessed after 2 cycles by serial CA-125 levels. Results. Thirty-five heavily pretreated patients received a mean of 5 cycles of topotecan (range, 1 – 13 cycles). Thirty-two patients had definable platinum sensitivity (16 sensitive, 8 resistant, 8 refractory). Median age was 56 years. A total of 177 cycles (534 weeks) of topotecan was administered. Hematologic toxicity was generally mild, and no grade 4 toxicities were observed. Grade 3 hematologic toxicity, including leukopenia, neutropenia, thrombocytopenia, and anemia, was observed in 2, 2, 1, and 0 patients, respectively. No patients experienced grade 3 or 4 nonhematologic toxicity. Based on serial CA-125 measurements, there were 1 (3%) complete and 5 (15%) partial responses, with 1 of the partial responses in a patient with platinum-refractory disease. Stable disease was reported in 13 (38%) patients, including 5 patients with platinum-resistant/refractory disease. Conclusion. Weekly topotecan demonstrates activity and is well tolerated compared with historical data with the standard 5-day schedule. Higher doses may be warranted because of the high tolerability shown for weekly topotecan. Weekly topotecan may be an appropriate treatment option for patients with recurrent ovarian cancer, especially heavily pretreated patients who might require dosing schedules with improved tolerability. D 2005 Elsevier Inc. All rights reserved. Keywords: Alternate treatment regimens; Ovarian cancer; Retrospective analysis; Topotecan
Introduction Ovarian cancer is the fourth leading cause of cancerrelated deaths in women, with 22,220 new cases and 16,210 associated deaths predicted to occur in 2005 [1]. Although ovarian cancer typically responds to first-line platinumbased therapy, most patients experience disease relapse and eventually succumb to their disease [2,3]. In this setting, quality of survival is an important issue, disease stabiliza-
* Corresponding author. Fax: +1 203 785 6782. E-mail address: [email protected] (D.M. O’Malley). 0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.04.032
tion is considered a treatment benefit [4], and therapies with noncumulative toxicities are favored even if their overall response rates are relatively low [5]. With advances in chemotherapy and patient care, ovarian cancer is increasingly viewed as a chronic disease, with many patients progressing through a variety of chemotherapy regimens [5,6]. Unfortunately, many of the aggressive chemotherapy agents used in early treatment are associated with cumulative toxicities [5,6]. Accordingly, patients may become predisposed to adverse events and poorer quality of life with each additional regimen [5,7]. In addition, the rate and duration of response progressively decrease with each successive line of therapy.
D.M. O’Malley et al. / Gynecologic Oncology 98 (2005) 242 – 248
Topotecan (HYCAMTIN\; GlaxoSmithKline, Philadelphia, PA) is a topoisomerase I inhibitor that has demonstrated antitumor activity in relapsed epithelial ovarian cancer (EOC). The US Food and Drug Administrationapproved dose and schedule for topotecan are 1.5 mg/m2/ day via 30-min intravenous (IV) infusion on days 1 through 5 of a 21-day cycle. Overall response rates for this regimen in the second-line EOC setting range from 19% to 33% for platinum-sensitive disease [8,9] and 12 –18% for platinumresistant disease [8,10]. Additionally, stable disease (SD) is reported in up to 46% of patients receiving topotecan therapy [10,11]. After relapse, ovarian cancer is considered a chronic disease condition, and patients typically receive multiple rounds of treatment to manage their disease, with the response rate and duration of response typically decreasing with each successive round of chemotherapy [5]. Topotecan is associated with few nonhematologic toxicities and a manageable, noncumulative, reversible hematologic toxicity profile. Nonetheless, hematologic toxicity limits the use of topotecan, particularly in patients with advanced age, poorer performance status, or comorbidities. Tolerability to topotecan therapy may also be reduced in heavily pretreated patients who have experienced cumulative toxicities from prior chemotherapy regimens. Treatment delays, dose reductions, and the administration of growth factors are often employed to manage myelosuppression in these patients [12 – 14]. Indeed, there appears to be a positive correlation between the number of prior myelosuppressive chemotherapy agents and the requirement for growth factor support [14]. The chronic course and the palliative goals in the treatment of recurrent ovarian cancer require alternative dosing and scheduling strategies for heavily pretreated patients who are susceptible to myelosuppression. Lowdose topotecan, continuous IV infusions (CIV), and weekly administration have all been investigated as alternative regimens in patients with relapsed ovarian cancer [15]. Although only preliminary results have been reported, weekly topotecan appears to be a promising alternative regimen. Weekly topotecan is associated with reduced myelosuppression compared with the standard regimen and is associated with antitumor efficacy [15 – 18]. In this retrospective analysis, we report on the use of weekly topotecan in our clinical experience in heavily pretreated patients with relapsed ovarian cancer.
Materials and methods Patient population and treatment We retrospectively examined medical records of patients with recurrent ovarian cancer who were treated with weekly topotecan at the Yale University School of Medicine/YaleNew Haven Hospital (New Haven, CT) between January 2001 and December 2003. Eligible patients had received 1
243
prior regimen, 1 of which must have contained a platinum agent. Patients who had received 4 weeks of topotecan infusions were eligible for the analysis. These criteria were chosen because patients who had just initiated therapy would not have provided an accurate reflection of the efficacy of therapy and would not have provided insight into whether the associated toxicity was cumulative or noncumulative in nature. Patients with either platinum-sensitive (relapse >6 months after primary therapy), platinumresistant (relapse during or 6 months after primary therapy), or platinum-refractory disease (progressive disease while on platinum therapy) were eligible. Patients received topotecan on days 1, 8, and 15 of a 28-day cycle (or a small variation of this schedule). Hematologic toxicity was managed by dose delays, reductions and adjustments, and growth factor and/or blood product support. Dose escalation was also permitted. Patients were treated until progression or until complete clinical response. Institutional Review Board/Human Investigative Committee approval was obtained. Patient assessment All patients who received 1 cycle of weekly topotecan were considered evaluable for safety. Hematologic and nonhematologic toxicities were assessed by clinical reports and laboratory assessments, including hemoglobin, leukocyte, neutrophil, and platelet nadir measurements. Toxicity was evaluated according to National Cancer Institute Common Toxicity Criteria. Dose escalation, reduction, and treatment delays were noted, as well as growth factor support, including granulocyte colony-stimulating factor (G-CSF), erythropoietin, and blood product support. Antitumor response was assessed after two 28-day cycles by serial cancer antigen 125 (CA-125) levels. Response rates are reported based on best response. Response rates were based on a modification of the Rustin CA-125 criteria [19] or Response Evaluation Criteria in Solid Tumors (RECIST) in the cases for which CA-125 levels were not a tumor marker. In the clinical practice setting, patients who are being treated for ovarian cancer that has relapsed multiple times are often managed according to their symptoms, with the intention of maximizing quality of life. Therefore, response evaluations are often performed less frequently than in the clinical trial setting. Moreover, CA125 evaluations during chemotherapy are often performed only when a response or disease progression is suspected, and the scans necessary for evaluating measurable disease are often forgone because of cost and scheduling issues for the patient. Response definitions must therefore factor in the limited disease evaluation data that are available in this setting. For patients who had no follow-up scans for measurable disease, CA-125 levels were used as surrogate criteria for disease response. If follow-up CA-125 assessments were available, these were used to confirm responses. Complete response (CR) was defined as normalization of
244
D.M. O’Malley et al. / Gynecologic Oncology 98 (2005) 242 – 248
CA-125 levels (to <35 U/ml) with no clinical or radiologic evidence of disease. Partial response (PR) was defined as a 50% reduction in CA-125 levels. Progressive disease was defined as at least a doubling in CA-125 levels or clinical or radiologic evidence of progressive disease. Patients who did not fit these criteria were considered to have SD.
Table 2 Incidence of hematologic toxicity Patients, n (%) (N = 35)
Anemia Leukopenia Neutropenia Thrombocytopenia
Grade 1
Grade 2
Grade 3
Grade 4
10 (29) 2 (6) 0 1 (3)
11 (31) 2 (6) 4 (11) 0
0 2 (6) 2 (6) 1 (3)
0 0 0 0
Results Safety and tolerability Patients Thirty-five pretreated patients who had received weekly topotecan therapy for recurrent epithelial ovarian cancer were evaluated. A summary of patient and baseline disease characteristics is provided in Table 1. Median age of this patient population was 56 years (range, 37 – 82 years). Thirty-three (94%) patients had been diagnosed with stage III disease, with ¨60% diagnosed with stage IIIC/IV disease. Nearly 50% of the patients had received 3 prior chemotherapy regimens and approximately two thirds of the patients had received 2 prior chemotherapy regimens. All patients had received prior platinum therapy and approximately half of the patients had platinum-sensitive disease. Mean (Tstandard deviation) baseline CA-125 at level at study entry was 263 T 433 U/ml. Table 1 Patient demographics and baseline disease characteristics Characteristic
Patients (N = 35)
Median age, years (range) Stage, n (%) IC IIC III IIIA IIIB IIIC IV Unknown Prior treatment regimens, n (%) 1 2 3 4 Platinum status, n (%) Sensitive Resistant/refractory Unknowna Baseline CA-125 level, U/ml Mean T standard deviation Median Range Measurable disease, n (%) Yes No
56 (37 – 82) 1 (3) 1 (3) 11 (31) 1 (3) 1 (3) 14 (40) 5 (14) 1 (3) 13 (37) 5 (14) 7 (20) 10 (29) 16 (46) 16 (46) 3 (9) 263 T 433 99 11 – 2231 6 (17) 29 (83)
CA-125 = Cancer antigen 125. a Patients had an allergic reaction to carboplatin; therefore, chemosensitivity could not be determined.
All 35 patients were evaluable for safety and tolerability. A total of 534 weekly infusions was administered (median, 12 weekly infusions) for a median of 4 cycles of therapy (total of 177 cycles). The median starting dose of topotecan was 2.5 mg/m2, with 21 patients starting at this dose. Eleven patients started at doses >2.5 mg/m2 (range, 3– 5 mg/m2) and 3 patients started at doses <2.5 mg/m2 (range, 1.5– 2 mg/m2). Two patients had dose escalations and 3 patients had dose reductions after the first cycle; 1 of these patients underwent a second dose reduction after the third treatment cycle. Although all 35 patients had received prior treatment, no patients experienced any grade 4 hematologic toxicities (Table 2). Grade 3 neutropenia and grade 3 leukopenia were each reported in 2 (6%) patients. Seven patients experienced treatment delays because of grade 2 or 3 neutropenia or leukopenia, with a median delay of 1 week (range, 1– 3 weeks). Grades 1 and 2 anemia were the most common hematologic toxicity, with 21 (60%) patients experiencing mild to moderate anemia. Fifteen of these patients received erythropoietin, with 5 patients requiring transfusions. Grade 1/2 thrombocytopenia was less common, occurring in <10% of patients. In this patient population, weekly topotecan was also associated with a favorable nonhematologic toxicity profile. No grade 3 or 4 nonhematologic toxicities were reported and only 7 patients reported grade 1 or 2 nonhematologic toxicities. Nonhematologic toxicities included fatigue (n = 3), neuropathy (n = 3), small bowel obstruction (n = 1), nausea (n = 2), abdominal pain (n = 1), and renal toxicity (n = 1). Antitumor activity Patients were followed with clinical examination and serial CA-125 levels, which is the standard protocol at our institution. Computed tomography (CT) scans were only obtained if indicated by clinical history or when disease status was not evaluable by serial CA-125 measurement or clinical exam. Thirty-four of the 35 patients were evaluable for response. Twenty-eight of the 34 (82%) patients were evaluable for response by serial CA-125 assessment. Six patients (18%) did not have elevated CA-125, yet had clinically or radiologically measurable disease. The overall response rate for 34 evaluable patients was 21%, with 1
D.M. O’Malley et al. / Gynecologic Oncology 98 (2005) 242 – 248 Table 3 Best responses to weekly topotecan therapy Parameter
Patients, n (%) (N = 34) Sensitive Resistant/refractory Unknowna Total
Complete response 1 Partial response 3 Stable disease 6 Progressive disease 6 Total 16
(3) (9) (18) (18) (47)
0 1 5 9 15
(3) (15) (26) (44)
0 1 (3) 2 (6) 0 3 (9)
1 5 13 15 34
(3) (15) (38) (44) (100)
a These patients had a reaction to carboplatin that prevented platinum sensitivity assessment.
(3%) patient achieving a CR, 5 (15%) patients achieving a PR (Table 3), and 13 (38%) patients achieving SD. One (6%) of the 16 patients with platinum-sensitive disease achieved a CR and 3 (19%) achieved a PR. An additional 6 (38%) patients experienced SD. Five of the 15 patients with platinum-resistant or -refractory disease experienced SD, and 1 achieved a PR. One of the 3 patients whose disease chemosensitivity was unknown achieved a PR, and the other 2 patients experienced SD. Among the 23 patients who were treated with weekly topotecan at doses 2.5 mg/m2, 12 (52%) experienced clinical benefit (CR, PR, or SD). Among the 11 patients who were treated with weekly topotecan >2.5 mg/m2, 7 (64%) experienced clinical benefit. One patient received 6 cycles of topotecan therapy after neoadjuvant chemotherapy (carboplatin/paclitaxel) followed by an optimal tumor debulking. She had a normal CA-125 level and no measurable disease at the initiation of therapy; therefore, she was not evaluable for tumor response. At the completion of her 6 cycles of topotecan therapy, she had normal CA125 and no clinical evidence of disease by CT scan for 20 weeks when she presented with new onset of ascites. The patient who achieved a CR received 12 cycles of therapy. Following therapy she had no evidence of disease on CT scan and a normal CA-125. Twelve months after completing therapy, she is alive without evidence of disease. The median response duration was 28 weeks (range, 16 –44 weeks) for patients who achieved a PR. Median duration of SD was 20 weeks (range, 12– 52 weeks). At the time of this analysis, median follow-up was 19.2 months, and 2 patients had died (survival of 4 months and 10.5 months after the initiation of weekly topotecan). Median overall survival had not been reached.
Discussion Topotecan is currently approved for the treatment of patients with relapsed ovarian cancer. However, the standard regimen for topotecan (1.5 mg/m2 on days 1– 5 of a 21-day cycle) often is not well tolerated by patients with advanced age, comorbidities, poor performance status, or a susceptibility to myelosuppression because of prior treatment. Therefore, alternative regimens for this active agent have
245
been explored. Alternative dosing schedules have included a 21-day, 24-h CIV infusion; 3-day bolus IV infusion; and several weekly regimens [15]. Alternate regimens that decrease the number of treatment days and reduce the need for blood factor or hematopoietic growth factor support could also increase the convenience of therapy. However, although reducing the number of treatment days from the standard 5-day regimen to 3 days or one 24-h infusion per 21-day cycle has resulted in more favorable hematologic toxicity profiles, such regimens have demonstrated limited activity, especially in patients with platinum-resistant or platinum-refractory disease [20 – 24]. In contrast, there is increasing evidence that weekly bolus infusions of topotecan are active in this setting. Topotecan targets topoisomerase I activity during the Sphase of the cell cycle. In early studies, it was thought that the cytotoxicity of topotecan was solely dependent on the duration of exposure [17]. As a result, it was thought that an intermittent regimen would not be effective. However, intermittent schedules with several other schedule-dependent cytotoxic agents (e.g., paclitaxel and gemcitabine) have demonstrated activity in relapsed ovarian cancer with a weekly regimen [25 – 28]. In addition, preclinical studies in a non-small cell lung cancer cell model indicate that prolonged exposure to topotecan may not provide superior cytotoxic activity because of topoisomerase I modulation [29]. On prolonged exposure, topoisomerase I levels decreased but also appeared to return to baseline levels after 1 week, suggesting that a weekly regimen may target cells when they are most vulnerable to topotecan therapy. More importantly, preclinical studies with topotecan in human colon carcinoma xenografts, B16 melanoma, and Lewis lung carcinoma murine models have shown that topotecan administered in schedules equivalent to a weekly schedule in humans is associated with antitumor activity, delays in tumor growth, and improved survival [15,17,30]. Results from the preclinical studies and other observations prompted investigators to study weekly administration of topotecan in patients. An early phase I study determined that a weekly 24-h CIV regimen was feasible in patients with solid tumors [31]. Subsequently, Hoskins et al. [32] compared the standard topotecan dosing regimen with a weekly 24-h CIV regimen at 1.75 mg/m2. Although the response rate was significantly greater with the standard regimen (23% vs. 3%), the disproportionally low incidence of grade 3/4 neutropenia in the weekly regimen arm suggests that those patients received suboptimal dosing. Therefore, it was thought that weekly administration of higher doses of topotecan might be associated with improved antitumor activity. The feasibility of a weekly bolus topotecan regimen was investigated in a phase I/II dose-escalation study in 32 previously treated patients with ovarian cancer [33]. In that study, the maximum tolerated dose of weekly topotecan without G-CSF support was 6 mg/ m2, and the maximum recommended dose for further study was 4 mg/m2, because of fatigue, grade 2 anemia, and
246
D.M. O’Malley et al. / Gynecologic Oncology 98 (2005) 242 – 248
gastrointestinal toxicity. Weekly topotecan doses >2.0 mg/ m2 were associated with activity. Levy et al. [34] recently reported the results of a phase II trial of weekly topotecan 4 mg/m2/week for 3 weeks of a 4-week cycle in women with recurrent or persistent ovarian or peritoneal cancer. In 23 patients, this regimen produced 4 CRs and 7 PRs, for an overall response rate of 48%. Therapy was generally well tolerated, with thrombocytopenia as the dose-limiting hematologic toxicity and fatigue being the most common nonhematologic toxicity. Consistent with these observations, weekly topotecan 4.0 mg/m2/week has demonstrated antitumor activity in an ongoing phase II study in patients with platinum-sensitive ovarian cancer, with 7 of the 26 (32%) patients achieving a PR and 10 (45%) additional patients experiencing SD [16]. Weekly topotecan at 4.0 mg/ m2 was not associated with severe myelosuppression and fatigue, and gastrointestinal toxicity and was reported in <1% of the weekly treatments. Recently, in a retrospective review of weekly topotecan therapy, Bhoola et al. [35] reported similar results with weekly bolus topotecan in patients who had received 2 prior chemotherapy regimens. Although previous reports have demonstrated that weekly bolus topotecan at a dose of 4.0 mg/m2 is well tolerated, a concern remains that this dose may be associated with unacceptable toxicity in some patients. For example, the topotecan dose-escalation study by Homesley et al. [33] excluded patients who had received prior radiation therapy or more than 2 prior chemotherapies and patients whose performance status was >2. In practice, a starting dose of <4.0 mg/m2 is more frequently used because of the concern of myelosuppression in heavily pretreated patients. Indeed, using reduced starting doses of topotecan for patients who have received multiple prior therapies or radiation therapy, have reduced renal function, or are elderly is consistent with the current dosing guidelines for the standard regimen of topotecan in this setting [36]. In an attempt to identify a more accurate – and perhaps realistic – depiction of safety and efficacy in the clinical setting, we initiated the current retrospective review of our clinical experience using weekly topotecan. Review of 35 patient records showed the median starting dose of weekly topotecan to be 2.5 mg/m2. Nine patients were treated with a starting dose of 3.0 mg/m2 and 2 patients were treated with a starting dose of 4.0 mg/m2. Grade 3 leukopenia, neutropenia, and thrombocytopenia were reported in only 3 patients, all of whom had received a starting dose at 3.0 mg/m2 (2 patients) or 5.0 mg/m2 (1 patient). Although all 3 of these patients received erythropoietin, none of these patients received G-CSF or blood product transfusion. Importantly, none of the patients in the analysis received G-CSF support. Because weekly topotecan was associated with a favorable profile with a median dose of 2.5 mg/m2 without G-CSF, it is likely that higher starting doses would have been feasible with growth factor support. Although the median starting dose was lower than that used in the controlled clinical trials in our analysis, weekly
topotecan in our analysis was associated with clinical benefit as measured by CA-125 levels with an overall response rate of 18% and an SD rate of 38%. These response rates are comparable with those previously reported in studies investigating weekly topotecan [16,18,33,35]. In addition, the response rates with weekly topotecan in the present report are comparable with those reported for a phase III crossover study of the standard 5day topotecan regimen in the second-line or third-line EOC settings (overall response rate: second-line, 20.5%; thirdline, 13.1%) [37,38]. Because the safety profile of weekly topotecan in our experience was favorable, an increase in starting dose with or without G-CSF support is likely feasible and may result in higher response rates. Indeed, although the number of cases reviewed was small, there appeared to be an incremental increase in the proportion of patients who achieved clinical benefit at the higher topotecan dose levels. The tolerability and activity of weekly topotecan in treating patients with relapsed ovarian cancer suggest that topotecan may be an appropriate agent to combine with other cytotoxic agents that are also administered on a weekly schedule. The feasibility of weekly combination cisplatin, topotecan, and paclitaxel with G-CSF support was established in a dose-finding study in patients with ovarian cancer or small cell lung cancer (SCLC) with a recommended topotecan dose of 2.25 mg/m2 for phase II studies [39]. The safety and efficacy of this weekly combination regimen were further investigated in a phase II study of chemotherapy-naive patients with extensive SCLC [40]. In that study, weekly cisplatin –topotecan –paclitaxel therapy was associated with response rates at least similar to those observed with the standard front-line treatment for SCLC. Similarly, in a dose-escalation study of weekly topotecan, cisplatin, and gemcitabine, Guarino et al. [41] reported that the combination regimen was well tolerated in patients with advanced non-small cell lung cancer, with favorable response rates, and recommended additional phase II trials. In a phase I study, Homesley et al. [42] reported on the feasibility of weekly topotecan combined with weekly paclitaxel in previously treated patients with ovarian cancer. The authors concluded that results from the phase I study supported future studies of this weekly combination regimen with a starting dose for topotecan of 3.0 mg/m2 when combined with paclitaxel 80 mg/m2. More recently, phase I studies have investigated weekly topotecan in combination with docetaxel and 5-fluorouracil/leucovorin in patients with solid tumors [43,44]. Future phase II studies are needed to ascertain the most active weekly topotecan combination therapy in patients with ovarian cancer. In summary, weekly topotecan was well tolerated and associated with reduced toxicity and similar antitumor activity compared with the standard topotecan dosing regimen. Data suggest that dose escalation with or without an increase in G-CSF support may potentially improve activity. Future randomized, controlled clinical trials on the
D.M. O’Malley et al. / Gynecologic Oncology 98 (2005) 242 – 248
use of weekly topotecan are warranted and will determine the role of weekly administration of single-agent and topotecan-based regimens in the treatment of patients with relapsed ovarian cancer.
Acknowledgments The authors wish to kindly thank the Yale chemotherapy nurses, Lisa Baker, Karen Coombe, and Karen Lynch, for their continued support and care of our patients and for their assistance with this project. This research was supported by an educational grant from GlaxoSmithKline.
References [1] Jemal A, Murray T, Ward E, et al. Cancer Statistics, 2005. CA Cancer J Clin 2005;55:10 – 30. [2] Ozols RF, Schwartz PE, Eifel PJ. Ovarian cancer, fallopian tube carcinoma, and peritoneal carcinoma. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Philadelphia’ Lippincott Williams and Wilkins; 2001. p. 1597 – 632. [3] Engel J, Eckel R, Schubert-Fritschle G, et al. Moderate progress for ovarian cancer in the last 20 years: prolongation of survival, but no improvement in the cure rate. Eur J Cancer 2002;38: 2435 – 45. [4] Gronlund B, Hogdall C, Christensen IJ, Engelholm SA, Hansen HH. Is stabilization of disease a useful indicator for survival in second-line treatment of ovarian carcinoma pre-treated with paclitaxel-platinum? Gynecol Oncol 2004;94:409 – 15. [5] Armstrong DK. Relapsed ovarian cancer: challenges and management strategies for a chronic disease. Oncologist 2002;7:20 – 8. [6] Herzog TJ. Update on the role of topotecan in the treatment of recurrent ovarian cancer. Oncologist 2002;7(Suppl 5):3 – 10. [7] Dunton CJ. Management of treatment-related toxicity in advanced ovarian cancer. Oncologist 2002;7(Suppl 5):11 – 9. [8] Bookman MA, Malmstrom H, Bolis G, 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. [9] McGuire WP, Blessing JA, Bookman MA, et al. Topotecan has substantial antitumor activity as first-line salvage therapy in platinumsensitive epithelial ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2000;18:1062 – 7. [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 1996;14:3056 – 61. [11] Swisher EM, Mutch DG, Rader JS, et al. Topotecan in platinumand paclitaxel-resistant ovarian cancer. Gynecol Oncol 1997;66: 480 – 6. [12] Eckardt J, Depierre A, Ardizzoni A, Von Pawel J, Fields S. Pooled analysis of topotecan (T) in the second-line treatment of patients (pts) with sensitive small cell lung cancer (SCLC). [abstract]. Proc Am Soc Clin Oncol 1997;16:452a [Abstract 1624]. [13] O’Reilly S, Rowinsky EK, Slichenmyer W, et al. Phase I and pharmacologic study of topotecan in patients with impaired renal function. J Clin Oncol 1996;14:3062 – 73. [14] Armstrong D, O’Reilly S. Clinical guidelines for managing topotecanrelated hematologic toxicity. Oncologist 1998;3:4 – 10.
247
[15] Morris R, Munkarah A. Alternate dosing schedules for topotecan in the treatment of recurrent ovarian cancer. Oncologist 2002;7(Suppl 5): 29 – 35. [16] Morris R, Alvarez RD, Andrews S, Malone J, Bryant C, Munkarah A. Topotecan weekly bolus chemotherapy for potentially chemosensitive relapsed ovarian and peritoneal cancer—An update [abstract]. Proc Am Soc Clin Oncol 2003;22:459 [Abstract 1846]. [17] Rowinsky EK. Weekly topotecan: an alternative to topotecan’s standard daily 5 schedule? Oncologist 2002;7:324 – 30. [18] Bhoola S, Estes J, Morris R, Bryant CS, Coleman R, Alvarez RD. Retrospective analysis of weekly topotecan as salvage therapy in relapsed ovarian cancer (OC). [abstract]. Proc Am Soc Clin Oncol 2003;22:474 [Abstract 1905]. [19] Rustin GJ. Use of CA-125 to assess response to new agents in ovarian cancer trials. J Clin Oncol 2003;21(Suppl 10):187 – 93. [20] Markman M, Kennedy A, Webster K, Kulp B, Peterson G, Belinson J. Phase 2 evaluation of topotecan administered on a 3-day schedule in the treatment of platinum- and paclitaxel-refractory ovarian cancer. Gynecol Oncol 2000;79:116 – 69. [21] Miller DS, Blessing JA, Lentz SS, McMeekin DS. Phase II evaluation of three-day topotecan in recurrent platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. Cancer 2003;98:1664 – 9. [22] Markman M, Blessing JA, DeGeest K, et al. Lack of efficacy of 24-h infusional topotecan in platinum-refractory ovarian cancer: a Gynecologic Oncology Group trial. Gynecol Oncol 1999;75:444 – 6. [23] Brown III JV, Peters III WA, Rettenmaier MA, et al. Threeconsecutive-day topotecan is an active regimen for recurrent epithelial ovarian cancer. Gynecol Oncol 2003;88:136 – 40. [24] Markman M, Blessing JA, Alvarez RD, Hanjani P, Waggoner S, Hall K. Phase II evaluation of 24-h continuous infusion topotecan in recurrent, potentially platinum-sensitive ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2000;77:112 – 5. [25] Kaern J, Baekelandt M, Trope CG. A phase II study of weekly paclitaxel in platinum and paclitaxel-resistant ovarian cancer patients. Eur J Gynaecol Oncol 2002;23:383 – 9. [26] Rosenberg P, Andersson H, Boman K, et al. Randomized trial of single agent paclitaxel given weekly versus every three weeks and with peroral versus intravenous steroid premedication to patients with ovarian cancer previously treated with platinum. Acta Oncol 2002; 41:418 – 24. [27] D’Agostino G, Amant F, Berteloot P, Scambia G, Vergote I. Phase II study of gemcitabine in recurrent platinum- and paclitaxel-resistant ovarian cancer. Gynecol Oncol 2003;88:266 – 9. [28] Fowler Jr WC, Van Le L. Gemcitabine as a single-agent treatment for ovarian cancer. Gynecol Oncol 2003;90:S21 – 3. [29] Bence AK, Mattingly CA, Desimone PA, Doukas MA, Adams VR. Evaluation of topotecan cytotoxicity and topoisomerase I levels in non-small cell lung cancer cells. [abstract]. Proc Am Assoc Cancer Res 2002;43:247 [Abstract 1227]. [30] McCabe FL, Johnson RK. Comparative activity of oral and parenteral topotecan in murine tumor models: efficacy of oral topotecan. Cancer Invest 1994;12:308 – 13. [31] Haas NB, LaCreta FP, Walczak J, et al. Phase I/pharmacokinetic study of topotecan by 24-hour continuous infusion weekly. Cancer Res 1994;54:1220 – 6. [32] Hoskins P, Eisenhauer E, Beare S, 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. [33] Homesley HD, Hall DJ, Martin DA, et al. A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients. Gynecol Oncol 2001;83:394 – 9. [34] Levy T, Inbar M, Menczer J, et al. Phase II study of weekly topotecan in patients with recurrent or persistent epithelial ovarian cancer. Gynecol Oncol 2004;95:686 – 90.
248
D.M. O’Malley et al. / Gynecologic Oncology 98 (2005) 242 – 248
[35] Bhoola SM, Coleman RL, Herzog T, et al. Retrospective analysis of weekly topotecan as salvage therapy in relapsed ovarian cancer. Gynecol Oncol 2004;95:564 – 9. [36] Armstrong DK. Topotecan dosing guidelines in ovarian cancer: reduction and management of hematologic toxicity. Oncologist 2004;9:33 – 42. [37] ten Bokkel Huinink W, Gore M, Carmichael J, et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 1997;15:2183 – 93. [38] Gore M, ten Bokkel Huinink W, Carmichael J, et al. Clinical evidence for topotecan – paclitaxel non-cross-resistance in ovarian cancer. J Clin Oncol 2001;19:1893 – 900. [39] Frasci G, Panza N, Comella P, et al. Cisplatin – topotecan – paclitaxel weekly administration with G-CSF support for ovarian and small-cell lung cancer patients: a dose-finding study. Ann Oncol 1999;10:355 – 8. [40] Frasci G, Nicolella G, Comella P, et al. A weekly regimen of cisplatin, paclitaxel and topotecan with granulocyte-colony stimulating factor
[41]
[42]
[43]
[44]
support for patients with extensive disease small cell lung cancer: a phase II study. Br J Cancer 2001;84:1166 – 71. Guarino MJ, Schneider CJ, Grubbs SS, et al. A dose-escalation study of weekly topotecan, cisplatin, and gemcitabine front-line therapy in patients with inoperable non-small cell lung cancer. Oncologist 2002;7:509 – 15. Homesley H, Benigno B, Williams J, Vaccarello L. A phase I study of weekly topotecan and paclitaxel in previously treated epithelial ovarian carcinoma patients. Gynecol Oncol 2002;87:171 – 7. Kuzur ME, Jones S, Willcutt N, et al. A phase I trial of weekly topotecan and docetaxel. [abstract]. Proc Am Soc Clin Oncol 2003;22:706 [Abstract 2840]. Axelrod RS, Rose L, Biermann W, Nathan FE, Hauck W, Hogaboom K. Phase I study of weekly topotecan plus weekly 5fluorouracil (5-FU)/leucovorin (LV) in patients with advanced malignancies: an update. [abstract]. Proc Am Soc Clin Oncol 2003;22:349 [Abstract 1403].