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Update on the Role of Topotecan in the Treatment of Recurrent Ovarian Cancer

Washington University School of Medicine, St. Louis, Missouri, USA

Correspondence: Thomas J. Herzog, M.D., Washington University School of Medicine, Washington University Medical Center, 4911 Barnes-Jewish Hospital Plaza, 3rd Floor, Maternity Building, St. Louis, Missouri 63110-1094, USA. Telephone: 314-362-3181; Fax: 314-362-2893; e-mail: herzogt{at}msnotes.wustl.edu

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Topotecan Efficacy Topotecan Safety Alternative Dosing Strategies Summary References Selected Reading

 
After completing this course, the reader will be able to:

1. Describe the latest literature on the use of topotecan in recurrent ovarian cancer.
   
2. Compare and contrast the efficacy and safety of topotecan with other agents used for the treatment of recurrent ovarian cancer.
   
3. Identify the toxicity profile of topotecan in recurrent ovarian cancer patients.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Topotecan Efficacy Topotecan Safety Alternative Dosing Strategies Summary References Selected Reading

 
Ovarian cancer is the fifth leading cause of cancer death in women. Most patients with ovarian cancer respond to first-line chemotherapy, but many relapse within 18 to 22 months. The development of efficacious salvage therapies that increase overall survival while maintaining quality of life is a great challenge in the treatment of this disease. Topotecan, a novel topoisomerase I inhibitor, is currently indicated for the treatment of recurrent metastatic carcinoma of the ovary. In patients with relapsed ovarian cancer, the overall response rates on treatment with topotecan range from 19%-33% in platinum-sensitive patients, 14%-18% in platinum-resistant patients, and 5%-11% in platinum-refractory patients. The proportion of patients achieving stable disease ranges between 17% in refractory and 48% in sensitive patients. In phase III studies, topotecan was shown to be equivalent in efficacy to both paclitaxel and liposomal doxorubicin as second-line therapy in patients with relapsed ovarian cancer. Further, non-cross-resistance between topotecan and paclitaxel was demonstrated in a third-line, phase III crossover study, suggesting that topotecan may be effective in the first-line setting with paclitaxel and/or platinum. Hematologic toxicities include neutropenia, thrombocytopenia, and anemia; however, these toxicities are usually short lived, noncumulative, and manageable with dose modifications, including low-dose topotecan regimens. Nonhematologic toxicities are usually mild to moderate in severity. These data support the use of topotecan for second-line therapy and suggest that topotecan may also be effective in first-line therapy. Further studies with topotecan alone and in combination with other agents are needed to fully characterize the role and sequencing of topotecan in the salvage and first-line settings.

Key Words. Topotecan • Efficacy • Recurrence • Ovarian neoplasms • Paclitaxel

	INTRODUCTION

Top Learning Objectives Abstract Introduction Topotecan Efficacy Topotecan Safety Alternative Dosing Strategies Summary References Selected Reading

 
Ovarian cancer ranks as the fifth leading cause of cancer death in women in the U.S. and represents approximately 4% of all new cancer cases projected for the year 2002 [1]. It is estimated that 23,300 cases of ovarian cancer will be diagnosed in 2002 [1], and that approximately 70%-80% of ovarian cancer patients will ultimately die of their disease [2]. Most women with ovarian cancer are between 50 and 65 years of age. Women with a family history of cancer of the ovary, who have had a late onset of menopause, or who have experienced prolonged intervals of ovulation uninterrupted by pregnancy are at a greater risk of developing ovarian cancer. Unfortunately, ovarian cancer is usually asymptomatic until the tumor has progressed to an advanced stage. Approximately 70% of women with ovarian cancer initially present with stage III or IV disease. At presentation, patients may complain of pelvic or abdominal fullness or pain. Sometimes this is accompanied by postmenopausal bleeding or gastrointestinal symptoms, but often the symptoms are subtle. Once diagnosed, ovarian cancer is surgically staged and/or debulked by exploratory laparotomy and treated with systemic chemotherapy. Most patients with advanced-stage cancer relapse after initial chemotherapy, and it is not uncommon for patients to receive 4 or 5 salvage chemotherapy regimens before succumbing to their disease.

The current standard of care for first-line chemotherapy is a combination of a platinum compound with a taxane. The majority of newly diagnosed patients will respond to first-line platinum-based and paclitaxel chemotherapy. However, 50%-80% of the patients who respond to this combination regimen will eventually relapse [3]. Patients who relapse within 6 months are less likely to respond to a second round of platinum-based therapy [4]. Therefore, advanced ovarian cancer tumors that have recurred are classified as being platinum-sensitive if relapse occurs >6 months after initial platinum-based therapy, platinum-resistant if relapse occurs 6 months after platinum-based therapy, and refractory if no response or disease regression occurs during platinum-based therapy. Defining recurrent disease by platinum sensitivity aids in developing strategies for continued treatment.

For patients who experience a relapse with a platinum-sensitive tumor, second-line therapy often consists of retreatment using carboplatin/cisplatin with or without paclitaxel. For patients who relapse with a platinum- and paclitaxel-resistant tumor, retreatment with these agents is generally of little benefit. Further, because currently available treatment options are generally no longer curative once patients have relapsed, the long-term prognosis for these patients is poor, and treatment objectives are shifted away from tumor elimination and toward the objectives of controlling tumor growth, prolonging survival, and maintaining quality of life [4]. Therefore, tremendous effort has been invested in developing agents with novel mechanisms of action that do not have cross-reactivity with platinum-based agents or paclitaxel. Effective second-line therapies extend progression-free survival and improve patient quality of life through symptom palliation, ideally with minimal noncumulative toxicity. Further, effective second-line therapies should have minimal overlapping toxicities with first-line agents and should not limit the use of future therapies. Available agents in the second-line or relapsed settings include topotecan, liposomal doxorubicin, gemcitabine, oral etoposide, hexamethylmelamine, vinorelbine, and docetaxel [5-10]. Among this group, topotecan is one of the best-characterized and most-studied agents.

	TOPOTECAN EFFICACY

Top Learning Objectives Abstract Introduction Topotecan Efficacy Topotecan Safety Alternative Dosing Strategies Summary References Selected Reading

 
Topotecan (Hycamtin^®; GlaxoSmithKline; Philadelphia, PA) is a topoisomerase I inhibitor that is currently indicated for the treatment of relapsed metastatic ovarian cancer after failure of initial or subsequent chemotherapy. Several phase II and III studies have demonstrated the efficacy of topotecan in this patient population. The following is an overview of these studies.

Phase II Studies
Several phase II trials have investigated the activity of topotecan as second-line therapy in relapsed ovarian cancer patients who had already received one to two courses of platinum-based chemotherapy (Table 1) [11-16]. Overall response (OR) rates in these clinical trials ranged from 14%-33% and, notably, an additional 18%-48% of patients in these trials achieved stable disease (SD). The efficacy of topotecan was dependent on the platinum sensitivity of the tumors; the OR to topotecan was higher in patients with platinum-sensitive disease (19%-33%) than in patients with platinum-resistant disease (14%-18%). Patients in these trials who achieved a response experienced a response duration of 4.5 to 11.2 months, with a median survival of 6 to 21 months (Table 2) [11-15].

Many of the topotecan phase II studies included or focused on patients with platinum-refractory or platinum-resistant relapsed ovarian cancer. The antitumor activity of topotecan as second-line therapy in ovarian cancer patients with platinum-sensitive tumors was evaluated in a Gynecologic Oncology Group (GOG) phase II study [15]. In GOG-0146C, 48 patients with platinum-sensitive tumors were treated with topotecan, 1.5 mg/m²/day on days 1 through 5 of a 21-day course. Patients had a median platinum-free interval of 10 months and received a median of six courses of topotecan. For the 46 evaluable patients, the OR rate was 33% (95% confidence interval, 19.5%-48%), with 4% CR and 28% PR (Table 1) [11-15]. The median response duration was 11.2 months, and median survival had not been reached at the time of the report, but was >21.5 months (Table 2) [11-15]. Additionally, topotecan therapy resulted in SD in 46 of 117 (39%) patients with platinum-resistant and 34 of 102 (33%) patients with platinum-sensitive disease. This study demonstrated that topotecan was particularly efficacious in platinum-sensitive tumors.

Phase III Studies
Based on the demonstrated efficacy of topotecan in phase II trials, a randomized, phase III trial was conducted to compare topotecan with paclitaxel in ovarian cancer patients who had developed progressive disease after receiving one platinum-based regimen [18]. Patients received either topotecan, 1.5 mg/m²/day administered as a 30-minute i.v. infusion on days 1 through 5 of a 21-day course, or paclitaxel, 175 mg/m² administered as a 3-hour i.v. infusion every 21 days. Intent-to-treat and independent radiographic review parameters were used in the analysis. Patients who had platinum-resistant disease had similar OR rates of 13% and 7% to topotecan and paclitaxel, respectively (Fig. 1) [18, 19]. Patients with platinum-sensitive disease who were treated with topotecan or paclitaxel also had similar response rates of 29% and 20%, respectively. On final analysis, the OR was 21% and 14% for patients treated with topotecan and paclitaxel, respectively (p = 0.196) [20]. The median duration of response was 26 weeks and 22 weeks for topotecan and paclitaxel, respectively, and the median time to progression was 19 weeks and 15 weeks for topotecan and paclitaxel, respectively. The median survival for patients treated with topotecan was 63 weeks and the median survival for patients treated with paclitaxel was 53 weeks. None of the time-to-event analyses were statistically significant. The results of this phase III trial demonstrated that topotecan was at least equivalent to paclitaxel in the second-line setting.

View larger version (17K): [in this window] [in a new window]   Figure 1. Efficacy of topotecan compared with paclitaxel in relapsed ovarian cancer according to platinum sensitivity. Shown are the overall response rates of patients receiving topotecan (gray bars) or paclitaxel (open bars). Patients with platinum-sensitive tumors relapsed >6 months following initial platinum therapy, patients with platinum-resistant tumors had recurrence within 6 months of initial platinum therapy, and patients who did not respond or experienced disease progression during platinum therapy had platinum-refractory disease [18, 19]. Numbers of patients are in parentheses.

The antitumor activities of topotecan and liposomal doxorubicin were recently compared in a large phase III trial [10]. A total of 474 relapsed ovarian cancer patients were randomized to receive either topotecan, 1.5 mg/m²/day on days 1 through 5 every 3 weeks, or liposomal doxorubicin, 50 mg/m² as a 1-hour infusion every 4 weeks. Overall response rates were 17% and 20% for topotecan and liposomal doxorubicin, respectively (p = 0.39). Further, there was no statistically significant difference in median progression-free survival (p = 0.095) or median survival (p = 0.341) between patients treated with topotecan and those treated with doxorubicin. Doxorubicin demonstrated a statistically significant greater median survival in platinum-sensitive patients compared with topotecan (108 versus 71 weeks, p = 0.008), whereas topotecan demonstrated a nonstatistically significant trend toward greater median survival in patients with platinum-refractory disease (41.3 versus 35.6 weeks, p = 0.455). Survival data did not account for crossover, and survival was a secondary end point of this trial. Toxicity assessment revealed greater myelosuppression for the topotecan arm and greater mucositis and plantar-palmar erythrodysesthesia (PPE) for patients treated with liposomal doxorubicin.

	TOPOTECAN SAFETY

Top Learning Objectives Abstract Introduction Topotecan Efficacy Topotecan Safety Alternative Dosing Strategies Summary References Selected Reading

 
In addition to establishing the efficacy of topotecan in relapsed ovarian cancer patients, the phase II and III studies also established the safety profile of topotecan in this patient population. Hematologic toxicities were usually predictable, manageable, noncumulative, and was generally of short duration. Nonhematologic toxicities were generally mild, with grade 3/4 nausea/vomiting and fatigue reported in up to 10% of patients.

Hematologic Toxicity
The dose-limiting toxicity associated with topotecan treatment was myelosuppression. Grade 3 or 4 neutropenia was experienced by 15% and 79% of patients treated with topotecan, respectively [18, 20]. Neutropenia was noncumulative, and the incidence of grade 4 neutropenia decreased after the use of G-CSF, indicating that grade 4 neutropenia associated with topotecan treatment is manageable. Grade 4 thrombocytopenia and anemia were experienced by 25% and 4%, respectively, of patients treated with topotecan. The median onset of grade 4 neutropenia in patients treated with topotecan in the ten Bokkel Huinink et al. [18] study occurred on day 9, with a median duration of 6 days.

In a combined population of relapsed ovarian and small cell lung cancer patients, the median onset of grade 4 neutropenia was similar. The median neutrophil and platelet nadirs for this combined population by treatment cycle are shown in Figure 2 [19]. After the first cycle, patients may have received G-CSF support or reduced doses of topotecan, and some may have discontinued topotecan due to myelosuppression. In general, grade 4 neutropenia had an onset of 10 days with a nadir at 12 days and a duration of 7 days [19]. Grade 4 thrombocytopenia had an onset and nadir at 15 days and a duration of 5 days. Grade 3/4 anemia had an onset of 13 days with nadir at 15 days and duration of 6 days. The profile of this myelosuppression reflects the noncumulative nature of the grade 3/4 neutropenia and thrombocytopenia experienced by patients treated with topotecan, as the platelet and neutrophil nadirs were less severe in subsequent cycles once an appropriate dose level was found.

View larger version (11K): [in this window] [in a new window]   Figure 2. Median neutrophil (A) and platelet (B) nadirs by cycle on treatment with topotecan. Data are from 453 patients with relapsed metastatic ovarian cancer and 426 patients with small cell lung cancer treated with topotecan. After the first cycle, patients may have received G-CSF or reduced doses of topotecan. Some patients may have discontinued topotecan due to myelosuppression. Numbers in parenthesis are the numbers of patients with data available at each cycle [19].

Nonhematologic Toxicity
Nonhematologic toxicity of topotecan is generally mild, with grade 3/4 nonhematologic toxicities occurring in >10% of patients. The most common grade 3/4 nonhematologic toxicities experienced by patients in the phase III topotecan versus paclitaxel trial were nausea (10%), vomiting (10%), and fatigue (8%) [18]. Anemia-induced fatigue may require dose reductions for some patients. In the two phase III trials with topotecan, patients treated with paclitaxel experienced less gastrointestinal toxicity but more alopecia, peripheral neuropathy, arthralgia, myalgia, and abdominal pain than those treated with topotecan [18]. Topotecan demonstrated significantly more myelotoxicity than liposomal doxorubicin. However, topotecan had a significantly improved nonhematologic toxicity profile than liposomal doxorubicin in the phase III randomized trial [10]. Of patients treated with liposomal doxorubicin, 23% and 8% experienced grade 3/4 PPE and stomatitis, respectively. In contrast, no patients treated with topotecan experienced PPE and <1% of topotecan-treated patients experienced grade 3/4 stomatitis. Further, a statistically significant difference in pain scores was reported. Maintenance of, or improvement in pain scores was experienced in 81% of topotecan-treated patients, compared with 64% of liposomal doxorubicin-treated patients [24]. This difference may be explained by the presence of PPE in patients treated with liposomal doxorubicin. Further quality-of-life data are needed from these trials. (For more details on the nonhematologic profile of liposomal doxorubicin and other agents, see Dunton review [23].) The favorable nonhematologic toxicity profile and manageable hematologic toxicity profile make topotecan an attractive agent for use in ovarian cancer patients.

	ALTERNATIVE DOSING STRATEGIES

Top Learning Objectives Abstract Introduction Topotecan Efficacy Topotecan Safety Alternative Dosing Strategies Summary References Selected Reading

 
Topotecan is an S-phase-specific cytotoxic agent, and thus, may be schedule dependent [25]. To optimize efficacy and patient convenience while striving to decrease toxicity, alternative dosing strategies are being examined, including 21-day continuous infusion, daily x 3, and weekly schedules ([26] and see Morris review pp 29-35 [27]). These alternate dosing regimens may allow for better toxicity profiles, sparing hematopoietic and mucosal progenitor cells while maintaining the therapeutic efficacy of topotecan treatment [28].

Lower-Dose Topotecan
In addressing the significant hematologic toxicity observed with the dosing schedule of 1.5 mg/m²/day on days 1 through 5 of a 21-day cycle, dose reduction has been performed with the goal of preserving the efficacy observed with standard dose levels. Despite the noncumulative and reversible nature of the hematologic toxicity associated with topotecan therapy, high-risk patients are more likely to incur higher-grade acute toxicities during the standard regimen of 1.5 mg/m²/day topotecan on days 1 through 5 of a 21-day cycle. High-risk patients include those who are of advanced age, have renal impairment, have received radiation therapy, or have received extensive pretreatment. Patients at risk also include those who have received prior platinum regimens, which are associated with cumulative hematologic toxicity. Because the standard first-line chemotherapy for ovarian cancer patients is a platinum-containing regimen, all current relapsed ovarian cancer patients are, therefore, at risk for developing severe hematologic toxicity. Guidelines for managing topotecan-related hematologic toxicity have been established and include dose reductions and the use of hematopoietic growth factors [22, 23]. The toxicity and efficacy profiles of lower doses of topotecan, delivered on the same daily x 5 schedule as conventional therapy, have been studied in high-risk patients during recent clinical trials.

A number of studies have been published on the efficacy and safety of lower-dose topotecan in patients with ovarian cancer (Table 3) [13, 29-31]. In an early report, Swisher et al. [13] investigated a low-dose topotecan regimen in platinum- or paclitaxel-resistant patients with ovarian cancer. In this study, 26 of the 28 evaluable patients were resistant to both platinum and paclitaxel. The median number of prior chemotherapy regimens was three (range one to seven). Patients were treated with topotecan 1.25 mg/m²/day given days 1 through 5 of a 21-day course. Of the 28 patients, four (14%) achieved PRs, which is comparable with the results observed in other trials in heavily pretreated patients (Table 3) [13, 29-31]. Grade 3/4 neutropenia and thrombocytopenia were experienced by 92% and 67% of patients, respectively. This toxicity was somewhat lower than the grade 4 neutropenia that would be expected in such a heavily pretreated population.

Recently, in a retrospective study, Rodriguez et al. [31] investigated whether lower doses of topotecan administered according to the standard 5-day schedule would provide comparable efficacy with a higher tolerability in patients with recurrent ovarian cancer compared with the standard dose level of 1.5 mg/m²/day. Treatment records were reviewed for 37 women with heavily pretreated (median of three previous treatment regimens) recurrent ovarian cancer who were treated with topotecan, 1.0 mg/m² given over a 30-minute i.v. infusion for 5 days every 21 days. These patients were treated with a median of three courses of 1.0 mg/m²/day on days 1 through 5 of a 21-day cycle. Of the 36 patients evaluable for response, eight (22%) achieved a PR. An additional eight (22%) patients achieved SD. Major toxicities included grade 4 neutropenia (49%), thrombocytopenia (5%), and anemia (5%). G-CSF support was required in 37% of patients. A lower dose of topotecan administered according to the standard dosing schedule decreased the hematologic toxicity associated with the standard regimen without loss of efficacy. As with each of the alternative dosing strategies, a direct comparative study to confirm these results is warranted.

	SUMMARY

Top Learning Objectives Abstract Introduction Topotecan Efficacy Topotecan Safety Alternative Dosing Strategies Summary References Selected Reading

 
The majority of ovarian cancer patients are diagnosed with advanced disease. Although most of these patients achieve a CR with initial chemotherapy, many will endure several relapses before ultimately succumbing to this chronic disease. Therefore, there is a critical need for the development and refinement of second-line therapies and strategies.

Currently, topotecan is approved for use for recurrent ovarian cancer. Topotecan has demonstrated antitumor activity in platinum-sensitive, platinum-resistant, and paclitaxel-resistant tumors [11-16]. Importantly, the reversible, noncumulative hematologic toxicity profile of topotecan is predictable and manageable, especially with dose modifications such as the lower-dose topotecan regimens [15, 23, 32]. Further, patients treated with topotecan rarely experience nonhematologic toxicities that are dose limiting. Other agents may be associated with resistance and with cumulative toxicities, such as peripheral neuropathy [33, 34]. Therefore, topotecan should continue to play a prominent role in the armamentarium for relapsed ovarian cancer due to its favorable therapeutic index [31].

In the future, the goal is to develop second-line therapies that can significantly increase time to progression and ultimately lead to greater overall survival. Currently, several GOG studies are planned or are under way that will characterize novel formulations, doses, and schedules of topotecan alone or in combination with other agents in the second-line therapy setting.

	ACKNOWLEDGMENT

Top Learning Objectives Abstract Introduction Topotecan Efficacy Topotecan Safety Alternative Dosing Strategies Summary References Selected Reading

 
This research was supported by an unrestricted educational grant from GlaxoSmithKline, Philadelphia, Pennsylvania. At the time of publication, this paper discusses the unlabeled usage of topotecan.

	SELECTED READING

Top Learning Objectives Abstract Introduction Topotecan Efficacy Topotecan Safety Alternative Dosing Strategies Summary References Selected Reading

 

ten Bokkel Huinink WW. Chemotherapy and complications in gynecologic cancer. Curr Opin Oncol 1991;3:930–932.[Medline]

Bookman MA. Developmental chemotherapy in advanced ovarian cancer: incorporation of newer cytotoxic agents in a phase III randomized trial of the Gynecologic Oncology Group (GOG-0182). Semin Oncol 2002;29(suppl 1):20–31.

Möbus V, Pfaff PN, Volm T et al. Long time therapy with topotecan in patients with recurrence of ovarian carcinoma. Anticancer Res 2002;21:3551–3556.

	REFERENCES

Top Learning Objectives Abstract Introduction Topotecan Efficacy Topotecan Safety Alternative Dosing Strategies Summary References Selected Reading

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This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Herzog, T. J. Search for Related Content PubMed PubMed Citation Articles by Herzog, T. J.