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Extending the Platinum-Free Interval in Recurrent Ovarian Cancer: The Role of Topotecan in Second-Line Chemotherapy

Medical Gynecologic Oncology, Medical Information Management, Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

Correspondence: Michael A. Bookman, M.D., Medical Gynecologic Oncology, Medical Information Management, Department of Medical Oncology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, Pennsylvania, 19111 USA. Telephone: 215-728-2987; Fax: 215-728-3639; e-mail: ma_bookman{at}fccc.edu

	Abstract

Top Abstract Introduction Definitions of Platinum... Importance of the Platinum-Free... Topotecan Safety and Efficacy... Extending the Platinum-Free... Conclusions References

 
Although the combination of platinum and paclitaxel offers effective chemotherapy for advanced ovarian cancer, the majority of women will eventually relapse with development of drug-resistant disease. Topotecan is the most extensively studied agent currently available for management of recurrent ovarian cancer and has been approved by the FDA for that particular indication. Early use of topotecan offers an effective and tolerable strategy that can prolong the platinum-free interval and optimize subsequent retreatment with platinum.

Key Words. Platinum-free interval (PFI) • Ovarian cancer • Topotecan • Relapsed or recurrent disease • Second-line chemotherapy

	Introduction

Top Abstract Introduction Definitions of Platinum... Importance of the Platinum-Free... Topotecan Safety and Efficacy... Extending the Platinum-Free... Conclusions References

 
The optimal therapeutic approach for relapsed ovarian cancer is based on an understanding of the biology of the disease and the limitations of initial therapy [1]. Currently, the standard of care for newly diagnosed advanced-stage ovarian cancer includes cytoreductive surgery followed by combination chemotherapy with platinum (either cisplatin or carboplatin) and paclitaxel. Despite high overall clinical response rates achieved with platinum-based therapy (up to 80%), including a high proportion of complete responses, most patients subsequently relapse and require additional treatment [2]. The goals of second-line therapy include control of disease to maintain quality of life and extend survival. Therapeutic options include retreatment with platinum and/or paclitaxel, although patients retreated with carboplatin and paclitaxel are at increased risk from cumulative hematologic toxicity. Other treatment options in the relapsed setting include initiation of a non-cross-resistant chemotherapy agent or the use of investigational agents in the context of a clinical trial.

The outcome of second-line chemotherapy in relapsed ovarian cancer can be partially predicted by whether the disease is drug-sensitive (response duration more than six months) or drug-resistant (response duration less than six months) [2, 3]. Patients with tumors classified as drug sensitive have demonstrated relatively high response rates (40% to 50%) to second-line platinum-based therapy [4]. In general, the longer the platinum-free interval—the time elapsed since completing platinum-based therapy—the higher the response to retreatment. In contrast, patients who relapse within six months of completing initial therapy have had response rates to second-line platinum-based therapy as low as 10% (Table 1, Table 2) [5]. This difference between drug-sensitive and drug-resistant tumors was initially described in relationship to platinum-based therapy but is also applicable to other chemotherapy regimens (Table 3).

This review will discuss the rationale for extending the platinum-free interval in the treatment of relapsed or recurrent ovarian cancer by using topotecan as second-line chemotherapy. Topics include: defining platinum sensitivity; an overview of key studies in relapsed ovarian cancer and the impact of extending the platinum-free interval, and a review of topotecan studies in relapsed ovarian cancer focusing on the responses in relation to platinum sensitivity.

	Definitions of Platinum Sensitivity

Top Abstract Introduction Definitions of Platinum... Importance of the Platinum-Free... Topotecan Safety and Efficacy... Extending the Platinum-Free... Conclusions References

 
There are a number of prognostic indicators in relapsed ovarian cancer, including performance status, tumor volume, tumor histology, and CA-125 levels (Table 4) [3, 11-13]. In particular, platinum sensitivity, as defined by the disease-free or treatment-free interval, has emerged as an important and significant predictor of response to second-line chemotherapy in a number of clinical studies conducted over the past two decades [4, 5, 14, 15]. Patients who responded to first-line therapy and demonstrated a significant treatment-free interval had a high probability of responding again to platinum-based treatment [3].

	Importance of the Platinum-Free Interval

Top Abstract Introduction Definitions of Platinum... Importance of the Platinum-Free... Topotecan Safety and Efficacy... Extending the Platinum-Free... Conclusions References

 
In the second-line and salvage treatment settings, the likelihood of response to retreatment with platinum-based compounds and other agents increases as the platinum-free and treatment-free intervals increase. This is well documented in the medical literature. Some of the key studies in relapsed ovarian cancer and the impact of the platinum-free interval are presented below.

Blackledge and Colleagues (1989) [5]
In a univariate and multivariate analysis of five phase II studies, the platinum-free interval was the most significant variable in predicting the response to second-line chemotherapy. Among 92 patients with relapsed ovarian cancer, 26/42 (62%) patients with a treatment-free interval of seven months responded to second-line chemotherapy, compared with 5/50 (10%) patients with a treatment-free interval of six months (Table 1). Patients with a treatment-free interval of >21 months had the highest response rates (94%) to second-line therapy.

Gore and Colleagues (1990) [14]
Similar results were observed in a study of ovarian cancer patients who subsequently relapsed following initial treatment with cisplatin or carboplatin and were either crossed over to the other platinum compound (n = 43) or retreated with the same drug (n = 11). Again, the progression-free interval was a highly significant prognostic variable for response to treatment (Table 5). Among patients who relapsed 18 months after the end of initial platinum-based therapy, 10/19 (53%) responded to crossover treatment or retreatment. In contrast, among those patients who relapsed within 18 months, 6/35 (17%) responded (p = 0.006).

The overall response rate for the 72 assessable patients was 43%, which included 10 complete and 21 partial responses. When results were analyzed according to the platinum-free interval, response rates increased with greater distance from the initial therapy (Table 2). The difference in response rates between a platinum-free interval of >24 months versus <24 months was statistically significant (p < 0.025). Response rates were also examined according to the treatment-free interval, defined as the time elapsed since the last antineoplastic treatment (regardless of the drugs used) and initiation of second-line platinum therapy. Again, response rate was greatest in patients with the longest treatment-free interval.

Kavanagh and Colleagues (1995) [15]
An important study conducted by Kavanagh and colleagues demonstrated that extending the platinum-free interval in relapsed ovarian cancer by using a non-platinum agent is associated with higher responses to platinum retreatment. In this study, patients had originally received the two-drug combination of cyclophosphamide and cisplatin or carboplatin. A total of 33 patients with platinum-refractory disease subsequently relapsed or progressed on a taxane (paclitaxel or docetaxel) and were then retreated with single-agent carboplatin. The median time from previous platinum-based therapy to platinum reinduction after taxane failure was 15 months (range, 8 to 33); there were 26 patients with a platinum-free interval of 12 months.

The overall response rate to platinum reinduction was 21%, with 7/33 patients achieving a partial response (Table 6). Another six patients (18%) had stable disease. The median duration of response was 7+ months. Responses were noted only in patients with a platinum-free interval of 12 months and initial taxane sensitivity; no responses were noted in any patient who was taxane-resistant. The response rate for the subgroup of 26 patients with a platinum-free interval of 12 months was 27% (7/26).

The findings of Kavanagh and colleagues are pivotal because they effectively demonstrate that prolonging the platinum-free interval with a non-platinum agent in relapsed or refractory ovarian cancer can increase the likelihood of response to platinum reinduction at the next relapse. Moreover, the study showed an apparent reversal of platinum-refractory disease in some patients.

With the results of randomized phase III trials, such as GOG-111 [19], the combination of platinum and paclitaxel has become the standard of care for the management of newly diagnosed advanced disease. However, even with paclitaxel-based regimens, the majority of patients will eventually relapse and develop drug-resistant disease. When relapse occurs, it has been common practice to retreat platinum-sensitive patients using a combination of platinum and paclitaxel, and high response rates have been reported [20]. However, both cisplatin and carboplatin are associated with potential long-term hematologic and nonhematologic toxicities that may limit the amount and/or duration of therapy. Recurrent ovarian cancer is generally incurable, and therapeutic strategies need to be integrated with maintenance of quality of life and associated endpoints. In this regard, the use of non-platinum-based therapies to extend the platinum-free interval may maintain a higher quality of life and improve the likelihood of responding to subsequent retreatment with platinum with better tolerability.

Recent clinical trials have yielded an impressive array of agents with diverse mechanisms of action that achieve responses in a proportion of patients with recurrent platinum-resistant and platinum-sensitive disease. These agents include tamoxifen [21], weekly paclitaxel [22], topotecan, gemcitabine, prolonged oral etoposide [23], docetaxel [24], liposomal doxorubicin [25], and 5-fluorouracil with leucovorin. In many cases, the mechanism of drug resistance appears distinct from platinum, which is an added advantage. To date, randomized studies have not documented the superiority of one approach over the other, and individual treatment decisions require thoughtful discussion between patient and physician. Among newer agents with established activity in the management of recurrent disease, there is a large volume of data related to topotecan, which serves as the best prototype for discussion.

	Topotecan Safety and Efficacy in Recurrent Ovarian Cancer

Top Abstract Introduction Definitions of Platinum... Importance of the Platinum-Free... Topotecan Safety and Efficacy... Extending the Platinum-Free... Conclusions References

 
Topotecan has been available since 1996 for the treatment of metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy. FDA approval of topotecan was based on the results of one comparative and three noncomparative clinical trials in relapsed ovarian cancer. The majority of patients enrolled in these trials (>70%) were defined as either platinum-refractory or platinum-resistant, while less than a third were defined as platinum-sensitive [6-8]. The initial topotecan dose was 1.5 mg/m² given by intravenous infusion over 30 min for five consecutive days, starting on day 1 of a 21-day course.

ten Bokkel Huinink and colleagues compared topotecan with paclitaxel in a large multicenter, prospective, randomized phase III trial involving patients treated with topotecan (n = 112) or paclitaxel (n = 114) [6]. All patients had recurrent ovarian cancer after a platinum-containing regimen or had not responded to at least one prior platinum-containing regimen. None of the patients had received prior therapy with paclitaxel. Objective responses were observed in 23/112 (20.5%) topotecan patients and in 15/114 (14%) paclitaxel patients. Disease stabilization for at least eight weeks was reported in 20% of topotecan patients and in 33% of paclitaxel patients. Patients with a platinum-free interval of more than six months had the highest response rates in both the topotecan and paclitaxel groups.

Two large noncomparative phase II studies have been published [7, 10]. Patients enrolled in the Creemers study (n = 111) were treated with topotecan1 after initial platinum-based (nontaxane) therapy had failed [7]. Patients enrolled in study 033 (n = 139) received topotecan after the failure of first- or second-line therapy with cisplatin or carboplatin and paclitaxel (alone or in combination) [10]. Overall efficacy was modest, with 15/92 (16.3%) evaluable patients responding in the Creemers study and 19/139 (13.7%) patients responding in study 033. However, many of these patients were platinum-refractory and therefore had a poor prognosis at the start of topotecan therapy.

Kudelka and colleagues also evaluated the efficacy and safety of topotecan in patients with platinum-refractory relapsed ovarian cancer (n = 30) [8]. Responses were reported in 4/30 (13%) patients, although two patients withdrew from the study after the first course of topotecan. The median duration of response was 8.9 months.

More recently, the Gynecologic Oncology Group conducted a noncomparative phase II trial of topotecan in patients with relapsed platinum-sensitive ovarian cancer with a progression-free interval of six months (unpublished manuscript). Among the 46 patients evaluable for response, there were two complete remissions and 13 partial remissions, for an overall response rate of 32.6%. Stable disease was noted in 22/46 (47.8%) patients.

Topotecan is generally well tolerated, with a predictable and manageable side-effect profile. Dose-limiting toxicity is hematologic but is reversible, noncumulative, and infrequently associated with serious sequelae [6, 7, 10]. Grade 4 neutropenia (<500 cells/mm³) was most common during course 1 of treatment (60% of patients) and occurred in 40% of all courses, with a median duration of seven days. Grade 4 thrombocytopenia (<25,000/mm³) occurred in 27% of patients and in 9% of courses, with a median duration of five days. Red blood cells and platelet transfusions were administered in 22% and 4% of courses, respectively. Because of the noncumulative nature of hematologic toxicity, patients were generally managed with dose reduction and/or schedule delay without the need for hematopoietic colony-stimulating factors. Recently, it has become more common to utilize erythropoietin for the prevention and management of symptomatic anemia, which may avoid the need for red cell transfusion.

The majority of nonhematologic side effects reported in ovarian cancer patients treated with topotecan were mild (grade 1 or 2). The most frequently reported nonhematologic side effects were related to the gastrointestinal system and included nausea, vomiting, and diarrhea. Prophylactic antiemetics were not routinely used in patients treated with topotecan. Gastrointestinal and other nonhematologic side effects occurring with topotecan were not dose-limiting. Fatigue has also been reported, partly as a consequence of anemia, and is probably underreported in most clinical studies because of its subjective nature. Development or worsening of peripheral neuropathy has not been consistently observed—an important benefit in a patient population with a high frequency of preexisting neuropathy related to prior chemotherapy.

It should be noted that the dosing cycle of topotecan (daily for five days every three weeks) is inconvenient for some patients and their families, such as those who must travel great distances for their treatment. In the relapsed setting, patient preferences are important considerations when selecting a treatment, and the schedule for topotecan can be a significant quality-of-life issue. However, because of the lack of acute toxicity associated with topotecan and the short duration of infusion, it is often possible to arrange home-based therapy for days 2 through 5 of each cycle, after an initial clinical evaluation on day 1. The availability of oral topotecan, which is currently under investigation, may help overcome some of the inconveniences associated with the intravenous regimen.

	Extending the Platinum-Free Interval with Topotecan

Top Abstract Introduction Definitions of Platinum... Importance of the Platinum-Free... Topotecan Safety and Efficacy... Extending the Platinum-Free... Conclusions References

 
The natural history of ovarian cancer is characterized by the subsequent development of broad cross-resistance to various chemotherapy agents. This resistance may develop from changes in drug-host metabolism, from the expansion of tumor cells to sites that are poorly responsive to chemotherapy, and/or from biochemical changes at the cellular or subcellular level. The availability of novel non-cross-resistant agents, such as topotecan, allows clinicians the opportunity to extend the platinum-free interval at the first relapse, increase the likelihood of response to platinum reinduction at the second relapse, and even overcome or delay acquired platinum resistance in some patients. The rationale for using topotecan includes its novel mechanism of action, its comparable efficacy compared with paclitaxel in patients with recurrent drug-sensitive disease, and its noncumulative well-characterized toxicity profile based on a large clinical trial experience.

Mechanism of Action
Topotecan has a novel mechanism of action distinct from platinum compounds, taxanes, alkylating agents, and other agents previously used in the treatment of ovarian cancer. Topoisomerase I is an enzyme that is critical for cell growth and proliferation. It catalyzes the cutting and mending of a single DNA strand and is required for DNA replication, DNA repair, and gene expression [26]. Topotecan exerts its cytotoxic effect by disrupting the DNA breakage-resealing process that occurs during replication, resulting in tumor cell death.

The general mechanisms of antineoplastic drug resistance include decreased drug accumulation, altered drug metabolism, altered drug targets, and enhanced DNA repair capacity [27]. Preclinical studies have suggested that mechanisms of resistance for the latter category (increased repair of drug-induced DNA damage) may be circumvented by pharmacologic manipulations [27]. Topoisomerases may be the final common cytotoxic pathway for several different classes of antineoplastic drugs (including platinum compounds). Drugs that act through topoisomerases prevent the re-ligation of DNA as a consequence of cleavable complex formation. Through this mechanism, topotecan can potentially interfere with repair from cisplatin-induced DNA damage (a major mechanism of cisplatin resistance) [28, 29]. Based on preclinical data, several investigators have also suggested that the combination of topotecan and cisplatin could produce synergistic cytotoxicity, and phase I trials have already been conducted [30, 31].

Efficacy in Relation to Platinum Sensitivity
As described earlier, topotecan has demonstrated activity across all categories of platinum sensitivity (refractory, resistant, sensitive) in patients with relapsed or recurrent ovarian cancer and in patients who were resistant or refractory to paclitaxel (Table 3) [6-8, 10]. Response rates to topotecan in patients with platinum-sensitive disease ranged from 19% to 32%, with median time to progression or progression-free intervals among all patients ranging from 11 weeks to almost 11 months.

Second-line therapy with topotecan, rather than platinum, could theoretically maximize the effectiveness of both agents. Responses to topotecan are highest when used in first-relapse, drug-sensitive disease; responses to platinum therapy are highest when the platinum-free interval is extended. Conversely, second-line therapy with platinum prior to topotecan can promote the development of drug resistance and reduce the subsequent likelihood of response to topotecan.

Noncumulative Toxicity Profile
In addition to efficacy, a number of safety-related factors must be considered when selecting a second-line regimen in relapsed ovarian cancer, including quality of life, the type and degree of prior platinum- and taxane-induced toxicities, and patient preferences about their treatment [1, 2]. Recent guidelines developed at a consensus conference of the National Institutes of Health state that the goals of follow-up and treatment of relapsed ovarian cancer need to incorporate quality-of-life considerations as an integral part of treatment [12].

Approximately one-third of patients treated with platinum-taxane regimens still have persistent neuropathy at the time of relapse. Patients with cumulative peripheral neuropathy may suffer a significant loss of manual dexterity, balance, and coordination that interferes with daily activities and reduces quality of life. It is important to avoid potentially neuropathic agents in this population. As described earlier, topotecan has a predictable, manageable, and noncumulative side effect profile and is unlikely to add to the cumulative nonhematologic toxicities caused by prior therapy, including peripheral neuropathy and renal toxicity. The majority of nonhematologic side effects reported in ovarian cancer patients during topotecan clinical trials were mild and not dose-limiting.

Retreatment with platinum compounds in relapsed ovarian cancer may be compromised by cumulative toxicities, especially in heavily pretreated patients, older patients, and patients with preexisting nephrotoxicity. Administration of topotecan to patients with multiple prior therapies may require dose delays or dose reductions because of diminished bone marrow reserves (from carboplatin) or renal impairment (from cisplatin). Earlier utilization of topotecan may reduce the likelihood of dose-limiting hematologic toxicities.

	Conclusions

Top Abstract Introduction Definitions of Platinum... Importance of the Platinum-Free... Topotecan Safety and Efficacy... Extending the Platinum-Free... Conclusions References

 
Despite high overall clinical response rates achieved with combination platinum-taxane therapy (up to 80%), including a high proportion of complete responses, most patients subsequently relapse and develop drug-resistant disease [2]. Thus, the primary goal of therapy in relapsed ovarian cancer is to extend survival by maximizing all available therapies while minimizing side effects and preserving quality of life.

The choice of therapy for relapsed ovarian cancer is typically based on the timing and characteristics of the relapse and the extent of prior treatment. Current guidelines recognize the importance of platinum sensitivity with regard to prognosis and likelihood of response to retreatment [12]. Although there is no definitive "drug of choice" for ovarian cancer at first relapse, topotecan represents a logical alternative to platinum-based therapy in patients with platinum-sensitive disease who are not able to participate in clinical trials. Further prolongation of the platinum-free interval through early use of topotecan and other nonplatinum reagents can maximize the therapeutic utility of each drug while enabling clinicians to better manage individual toxicity profiles, thereby optimizing quality of life for patients with recurrent disease.

	References

Top Abstract Introduction Definitions of Platinum... Importance of the Platinum-Free... Topotecan Safety and Efficacy... Extending the Platinum-Free... Conclusions References

 

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This Article Abstract Full Text (PDF) eLetters: Submit a response to this article 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Bookman, M. A. Search for Related Content PubMed PubMed Citation Articles by Bookman, M. A.