Johns Hopkins University, Baltimore, Maryland, USA. 1. Better appreciate the challenges faced in managing treatment of patients with ovarian cancer.

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1 The Oncologist Relapsed Ovarian Cancer: Challenges and Management Strategies for a Chronic Disease DEBORAH K. ARMSTRONG Johns Hopkins University, Baltimore, Maryland, USA Key Words. Chronic disease Ovarian neoplasms Platinum Quality of life Recurrent Topotecan LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Better appreciate the challenges faced in managing treatment of patients with ovarian cancer. 2. Describe the factors that impact on the design of long-term treatment strategies for patients with d ovarian cancer. 3. Describe important disease management issues, including when to initiate treatment, which treatments to consider and why, and patient education. CME ABSTRACT Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com Advances in the treatment and early detection of ovarian cancer have led to gains in 5-year survival rates, with 52% of women diagnosed between 1992 and 1997 surviving 5 years or longer, compared with 41% of women diagnosed between 1983 and Although approximately 10%-15% of patients achieve and maintain complete responses to therapy, the remaining patients have persistent disease or eventually. These patients will generally undergo a series of treatments, each associated with progressively shorter treatment-free intervals. Nevertheless, median survival of patients with recurrent ovarian cancer ranges from months, demonstrating the chronic natural history of the disease. Advances in the treatment of ovarian cancer over the past decade have led to these improvements and have prompted oncologists to now view the management of patients with ovarian cancer as an ongoing, long-term challenge. This shift in approach has raised important new questions regarding patient management, including the need to define trigger points for initiating or changing treatment (e.g., sequential increases in serum cancer antigen 125 levels, appearance of symptoms, or cumulative toxicities), anticipation of impending treatment decision points, recognition that the overtreatment of patients early in the disease process may adversely affect future treatment opportunities, and a renewed emphasis on patient education and participation in decision-making. This review will discuss these important patient management issues and will conclude with case studies illustrating two distinct treatment strategies (planning and sequencing) for the long-term management of patients with ovarian cancer. The Oncologist 2002;7(suppl 5):20-28 INTRODUCTION The 5-year survival of patients diagnosed with ovarian cancer has continued to improve over the past several decades, with more than half of the patients diagnosed between 1992 and 1997 expected to live 5 years or more [1]. These gains have been attributed, in large part, to broader Correspondence: Deborah K. Armstrong, M.D., Johns Hopkins University, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting Blaustein Cancer Research Building, Room 190, 1650 Orleans Street, Baltimore, Maryland , USA. Telephone: ; Fax: ; darmstro@jhmi.edu Received August 12, 2002; accepted for publication August 15, AlphaMed Press /2002/$5.00/0 The Oncologist 2002;7(suppl 5):

2 Armstrong 21 Table 1. Key considerations in long-term patient management Identify triggers for treatment initiation (surveillance options) Anticipate clinical turning points Treatment sequencing and selection Align therapy with patient needs Patient education and participation in decision process access to expert surgical care, improvements in chemotherapy, and (to a lesser extent) to cancer screening. Of the patients who present with advanced disease (approximately 60%), approximately 10%-15% achieve long-term remission; however, the remainder tend to undergo a progression of treatments [2]. Thus, for the oncologist, a great deal of effort will be invested in the management and treatment of patients in. The chronic nature of d ovarian cancer has important implications for both oncologists and patients alike, including repercussions concerning treatment planning and patient education (e.g., setting realistic expectations). This review will discuss these important patient management issues and will conclude with case studies illustrating two distinct treatment approaches (planning and sequencing) to the long-term management of patients with d ovarian cancer. CHALLENGES IN OVARIAN CANCER A number of important questions have emerged as a consequence of the need to plan for the long-term care of patients with ovarian cancer, many of which revolve around treatment planning (Table 1). Although >50% of patients treated with first-line therapy achieve a clinical complete response, half of these responders will be positive for disease on second-look laparotomy. A further percentage of patients (50%) who are negative on second-look laparotomy will eventually [3], leaving a small proportion of patients initially diagnosed achieving long-term remission. These findings underscore the importance of disease surveillance and of defining the point at which the tumor has d and reinstitution of therapy is appropriate. Disease Surveillance and Relapse Definition Surveillance options for monitoring disease activity include second-look laparotomy, physical examination (pelvic exam), serum cancer antigen 125 (CA-125) levels, and radiographic, magnetic resonance, or computed tomography imaging. Of these, a physical examination that includes a thorough pelvic exam is perhaps the most cost-effective surveillance option. Additionally, CA-125, a serum marker of the presence and severity of ovarian cancer, can be monitored at intervals. However, there can be a poor correlation between disease burden and CA-125 concentration in some relapsing patients. Additionally, abnormally elevated or rising CA-125 levels may predate the onset of symptoms by many months or even years. Finally, patients often undergo or request imaging as a means of monitoring for disease recurrence. Although myriad tools are available to monitor disease activity, the timing of treatment initiation can be confounded by a number of factors, including interpretation of CA-125 findings, ambiguous test results, and a lack of consensus for when has occurred. Relapse is defined by some clinicians as a sequential increase in serum CA-125 or levels greater than some arbitrary value such as 100 U/ml. Although serum CA-125 is often used to guide treatment decisions, patients may remain asymptomatic for extended periods despite exhibiting very high CA-125 levels. Additionally, some patients experience a symptomatic recurrence without suggestive changes in CA-125 marker levels or confirmatory imaging. In such cases, a combination of positive surveillance findings may confirm initial suspicions; alternatively, the patient may require further rigorous follow-up. Traditional clinical measures of include disease progression, usually defined as a 25% or greater increase in tumor size, appearance of new lesions, or death. Applying this definition to patients enrolled in clinical trials (e.g., Gynecologic Oncology Group Study 111), approximately 7% of patients will progress within the initial 3 months of receiving cisplatin/paclitaxel, while 13%-14% of patients will progress within 6 months of randomization (Fig. 1) [4]. Proportion surviving progression free Patients, n Progressionfree Median Relative Treatment Failure Total survival, mo risk Cisplatin/Paclitaxel Time after study entry, months Figure 1. Progression-free survival in patients with advanced ovarian cancer treated with cisplatin and paclitaxel in Gynecologic Oncology Group Study 111. Relative risk versus patients treated with cisplatin plus cyclophosphamide.

3 22 Long-Term Management of Ovarian Cancer In Study 111, the average patient experienced clearly defined progression within approximately 18 months of randomization to cisplatin/paclitaxel therapy [4]. Clearly defined progression triggers a decision for further treatment based on factors including the time interval since completion of initial chemotherapy. The observation of variable patient responses based on the duration of this interval has led to a definition of d patients based on the predicted platinum sensitivity of the tumor. Patients who progress on first-line therapy or within 3 months of treatment are considered to be platinum refractory. Patients who respond to primary treatment and within 6 months are considered platinum resistant, whereas those who more than 6 months after completion of initial therapy are characterized as platinum sensitive. Considerations in Recurrent Ovarian Cancer On disease progression or confirmation of disease, patients may obtain a clinical benefit from a number of second-line or salvage therapies, including topotecan (Hycamtin ; GlaxoSmithKline; Philadelphia, PA), liposomal doxorubicin, gemcitabine, oral etoposide, paclitaxel, docetaxel, and platinum. However, because available agents for second-line and salvage treatment are rarely curative, the goals of treatment shift to providing disease control (i.e., extended survival) and symptom palliation with a generally well-tolerated regimen and an emphasis on patient quality of life. A number of factors impact the decision to treat recurring disease, including the potential for platinum sensitivity, number of prior treatment regimens, and potential cumulative Table 2. Characteristics of active agents in recurrent ovarian cancer a toxicities of therapy, as well as patient or disease factors, such as performance status, volume of disease, and presence of ascites and gastrointestinal symptoms. Each of these considerations will be reviewed in turn. Platinum-Free Interval According to current dogma in ovarian cancer treatment, the potential for patient sensitivity to platinum is perhaps the most important factor in planning subsequent treatment. Tumor response rates are directly related to the platinum-free interval among all of the novel agents currently used in second-line therapy [5-8]. For instance, the range of antitumor responses in platinum-sensitive patients receiving topotecan is 19%-33% [9, 10], compared with 12%-19% for patients who are platinum resistant [9, 11] (Table 2) [5, 7-21]. A comparable pattern of responses has been observed with other novel agents in patients with recurrent ovarian cancer [5, 7, 8, 14-21]. As a result of these findings, an important goal of treatment is to extend the platinum-free interval for all patients, regardless of platinum sensitivity. One explanation for the consistent relationship between tumor response and platinum- or treatment-free interval is tumor resistance (e.g., P-glycoprotein-mediated multidrug resistance). As noted previously, the majority of patients following an initial response to therapy and develop disease that is more drug resistant than at first-line therapy. Tumor resistance in ovarian cancer may be acquired or intrinsic. In acquired resistance, tumors become resistant to treatment under the selective pressure of a specific agent. However, acquired resistance is frequently unstable and can be lost over Agent Mechanism of action Overall response rates Cumulative toxicity Topotecan [9-13] Topoisomerase I inhibition ORR: 13%-33% None Plat-sens: 33% Plat-res: 12%-19% Liposomal doxorubicin [14, 15] Nucleic acid synthesis inhibition ORR: 17%-20% PPE Plat-sens: 28% Plat-res: 12%-17% Gemcitabine [16-19] Nucleoside analogue ORR: 13%-22% None Etoposide [20] Topoisomerase II inhibition ORR: 30% Secondary leukemias Plat-sens: 34% Plat-res: 27% Paclitaxel [21] Microtubule inhibitor ORR: 7%-20% Peripheral neuropathy Plat-sens: 20% Plat-res: 7%-17% Carboplatin [5, 7, 8] DNA cross-linking Plat-sens: 28% Thrombocytopenia Plat-res: 10% a Single agent. Abbreviations: ORR = overall response rate; Plat-sens = platinum-sensitive; Plat-res = platinum-resistant; PPE = palmar-plantar erythrodysesthesia.

4 Armstrong 23 time [22]. Therefore, the longer the treatment-free interval, the greater the chance for tumors to lose acquired resistance. In cases in which patients develop resistance to a specific agent (e.g., cisplatin), the application of a non-cross-resistant agent (e.g., topotecan) may offer an opportunity for tumor response. Because many of the agents used in second-line and salvage settings have disparate mechanisms of action and are non-cross-resistant with platinum and/or paclitaxel, there are a variety of options to offer patients. Moreover, the use of a nonplatinum agent at first, for instance, can lower the probability that tumors will become increasingly resistant to platinum retreatment. The results of a study by Kavanagh et al. [6] suggest that extending the platinum-free interval improves patient outcomes by increasing the sensitivity of tumors to subsequent reintroduction of platinum. In that study, the use of an agent not cross-resistant with platinum (taxane) at sensitized patients disease to the reintroduction of carboplatin. Another potential benefit of extending the platinum-free interval is avoiding potential cumulative toxicities. Cumulative Toxicities Treatment-related toxicities increase with increasing numbers of treatments. Because the treatment-free intervals progressively narrow or disappear with the introduction of each new therapy, planning for cumulative toxicity takes on greater significance as the number of salvage regimens increases. For instance, the reintroduction of platinum at first may lead to cumulative myelosuppression (particularly thrombocytopenia) and neurotoxicity. Thus, patients receiving platinum at first may enter further therapies with compromised bone marrow reserves and consequently may not achieve maximal clinical benefits from these other active therapies. Potentially suboptimal tumor responses may be attributed to the administration of lower, potentially subtherapeutic dose levels or because of dose omissions (see Dunton et al. in this issue for an in-depth review of cumulative toxicity, pp [23]). Likewise, the use of or need for blood product support may result in a delay in initiating subsequent courses of therapy or reductions in subsequent dose levels. In summary, although in clinical practice all patients entering on therapy for ovarian cancer have hope for complete response and long-term remission, clinicians and their patients should be realistic about the low probability of achieving these outcomes. As a result, caution should be exercised that subsequent rounds of intervention are not jeopardized through the pursuit of overly aggressive treatment at first. Patient/Disease Factors For newly diagnosed patients, a number of patient and disease factors are important in the rational design of a treatment plan, including disease stage, volume of residual disease following cytoreductive surgery, performance status, sites of metastases (e.g., liver), presence of ascites, and tumor histology. Of these prognostic factors, disease stage, residual tumor burden, and performance status have been the best studied. Survival is inversely related to disease stage; patients with stage I, II, III, and IV ovarian cancer have median 5-year survival rates of approximately 93%, 70%, 37%, and 25%, respectively [24]. Thus, in patients with advanced inoperable tumors, chemotherapy with a good tolerability profile may be used to control symptoms. In these patients and in those who undergo optimal debulking surgery (approximately 60%), platinum-based therapy with paclitaxel is the standard first-line approach. Intuitively, optimal versus suboptimal (residual disease 1 cm) cytoreduction represents another important prognostic factor in the survival of patients with ovarian cancer. Patients with minimal residual disease have a greater probability of achieving a remission following systemic chemotherapy, have a longer time to, and live longer than patients with large-volume, bulky residual disease. In one study of patients with stage IV disease, the overall median survival for optimally debulked patients was 32 months, compared with 16 months for suboptimally debulked patients [25]. In a similar study in patients with stage IV disease, median survival for optimally cytoreduced patients was 38 months, compared with 10 months for suboptimal residual disease [26]. Other studies have demonstrated the importance of surgical debulking as an independent prognostic indicator for survival [24, 27, 28]. However, the potential benefits of surgical debulking and the prognostic importance of disease volume have not been prospectively studied in recurrent disease. Performance status is another useful prognostic indicator of survival in patients with advanced ovarian cancer. In a study by Bristow et al. [26], overall median survival was highly correlated with performance status (p = 0.002). The prognostic value of performance status has also been demonstrated in other studies [29]. Patient Education Educating patients regarding the natural history of their disease and the treatment options available empowers them to partner with their physician in the decision-making process and to better meet the challenges of the disease. Because it is likely that patients will receive a series of three to five treatment regimens over the course of the disease, proactive planning and shared decision-making are vital to ensure the best possible outcome. Additionally, proactive planning allows for the use of a treatment regimen that offers the greatest efficacy benefit while balancing considerations for patient lifestyle and potential cumulative toxicities.

5 24 Long-Term Management of Ovarian Cancer Consideration should also be made for scheduling chemotherapy into the patient s daily routine; that is, discussing with the patient issues concerning when she is better able to comply with treatments and to tolerate certain toxicities. Additionally, educating patients on the toxicities associated with each regimen and toxicity interventions and management are vital to ensuring that therapeutic dose levels are administered in a timely manner and maintained throughout the recommended duration of treatment. Another critical aspect of education involves the early establishment of realistic expectations for patients. Although only a small percentage of patients will achieve long-term disease remission, the vast majority will experience a series of treatments, remissions, and recurrences. Additionally, patients should be informed about the possibility of achieving a late clinical benefit despite a lack of early evidence that a clinical response will be achieved (i.e., reduction or normalization of CA-125 levels). Further, educating patients on the benefits of stable disease is an important lesson in the context of this chronic disease. The clinical value of stable disease in ovarian cancer has been established [30]. Survival among patients who achieved stable disease was statistically comparable with those who experienced a partial response to topotecan. Thus, stable disease may offer equal clinical benefit compared with partial tumor responses in patients with d ovarian cancer. In the context of maintaining stable disease, the choice of an agent that can be administered at disease progression (i.e., no cumulative toxicities) would be desirable. TREATMENT STRATEGIES IN OVARIAN CANCER First-line MANAGEMENT Treatment strategies will be presented that summarize two approaches in the long-term management of patients with d ovarian cancer. The first strategy offers a review of a commonly practiced treatment sequence, whereas the second strategy provides an alternate sequence plan with greater recognition of the chronic nature of d ovarian cancer. As shown in Figure 2, the commonly practiced treatment sequence Agent Platinum* begins with carboplatin or cisplatin plus paclitaxel as first-line therapy. Paclitaxel The median progression-free interval (PFI) in stage III/IV ovarian Topotecan cancer patients receiving platinum Doxorubicin (cisplatin/carboplatin) with pacli- Etoposide taxel ranges from approximately months [4, 31, 32]. Because most patients respond well to platinum and paclitaxel in first-line therapy as measured by objective response rates and PFI, the median or average patient is considered platinum sensitive and usually is re-treated with platinum and taxane therapy at first. Response rates of up to 84%-91% have been reported at first [33, 34]; however, the time to progression generally shortens with consecutive therapies. Provided the patient continues to respond to treatment, each successive response or disease remission is typically shorter in duration than the previous one. Following each disease recurrence, the patient will continue to receive a series of new treatments, including, but not limited to, oral etoposide at second, liposomal doxorubicin at third, topotecan at fourth, and gemcitabine at fifth. However, cumulative toxicities associated with most, but not all, of these treatment choices may lead to a diminution in the number of downstream options (Dunton et al. [23]). For instance, retreatment with platinum and paclitaxel at first can result in cumulative neurotoxicity and myelosuppression, which may limit the available treatment options on subsequent s. In the treatment strategy proposed in Figure 2, etoposide is recommended at second, with the goal of extending the platinum-free interval. However, although etoposide is convenient and generally well tolerated, it has also been associated with an increased risk for secondary leukemias. Upon on etoposide, patients continue on therapy with liposomal doxorubicin. Although liposomal doxorubicin affords patients the opportunity to further extend the platinum-free interval, cumulative palmar-plantar erythrodysesthesia (PPE) often limits the number of cycles administered. Severe (grade 3/4) PPE occurs in up to 23% of liposomal doxorubicin-treated patients and is managed by dose reduction, delay, or discontinuation of therapy [15]. Viewed as a whole, this treatment sequence can be seriously debilitating to the overall health and well-being of the patient. 1st 2nd 3rd 4th 5th Figure 2. Treatment matrix illustrating a widely followed treatment plan in patients with advanced ovarian cancer. Gemcitabine * Includes carboplatin or cisplatin. Liopsomal doxorubicin. Oral.

6 Armstrong 25 Figure 3. Treatment matrix illustrating an attractive alternative to retreatment with platinum/taxane at first that incorporates topotecan as secondline therapy. According to the sequence illustrated in Figure 2, the patient will typically receive topotecan at fourth. However, significant disadvantages to withholding topotecan until fourth are the more demanding dosing schedule and bone marrow toxicity. The standard regimen of 1.5 mg/m 2 /day Agent Platinum* Paclitaxel Topotecan Doxorubicin Etoposide Gemcitabine for 5 consecutive days of every 21-day cycle is more demanding of the patient at a time when she is less likely to be able to tolerate therapy, irrespective of how active the agent is in managing the disease. Moreover, whereas the bone marrow toxicity associated with topotecan is noncumulative and can decrease over subsequent courses of therapy [35], it arrives at a time when the patient has undergone a series of myelosuppressive treatments and enters on treatment with depleted bone marrow reserves. Finally, the patient receives gemcitabine at fifth. Gemcitabine is convenient and, like topotecan, has no cumulative toxicity. However, gemcitabine demonstrates a lower activity level than other agents in patients with recurrent ovarian cancer. In summary, the cumulative toxicities incurred with the treatment schema illustrated in Figure 2 may adversely affect patient outcomes, including quality of life. Because this strategy does not adequately recognize the chronic nature of d ovarian cancer, alternate approaches to the long-term management of patients should be pursued. An attractive but unproven alternate approach to that described in the first strategy is depicted in Figure 3. As illustrated in this matrix, initial therapy continues to include carboplatin or cisplatin plus paclitaxel. However, rather than re-treating the patient with platinum and a taxane at first, the patient receives topotecan. The efficacy of topotecan is comparable to that of single-agent platinum in this setting. Topotecan yields overall response rates of 13%-33% and a PFI of approximately months, depending on the degree of platinum sensitivity (Herzog pp 3-10 [37]) [9-13, 36]. An additional 23%-48% of patients achieve stable disease, which has also been associated with significant patient benefits (i.e., improved survival) [9, 10, 12, 13, 30, 36]. The rationale for moving topotecan forward in the treatment sequence is several-fold. First, there is a lack of cumulative toxicity associated with topotecan. Although the main toxicity associated with topotecan is myelosuppression, it is First-line * Includes carboplatin or cisplatin. Liposomal doxorubicin. Oral. 1st 2nd 3rd 4th short-lived, noncumulative, and manageable. Furthermore, the platelet toxicity associated with topotecan wanes in severity over the duration of treatment [35]. Additionally, as might be expected, the severity of myelosuppression with topotecan correlates with the number of prior treatments and is worsened in patients who are heavily pretreated (Fig. 4) [38]. Therefore, the best opportunity to use topotecan is at first, when patients are less heavily pretreated. Patients are also better able to comply with topotecan therapy when they are less heavily pretreated. Because myelosuppression is noncumulative and short-lived, the use of topotecan at first should not diminish downstream opportunities with platinum, etoposide, liposomal doxorubicin, gemcitabine, or paclitaxel (Fig. 3). Because topotecan demonstrates a lack of cumulative toxicity, the agent can be used to treat patients until disease progression, allowing patients to extend the treatment benefits of topotecan. The long-term benefits of topotecan treatment have been established in patients with ovarian cancer treated over the long term [39]. Finally, patients may benefit from an extension in the platinum-free intervals in terms of the tumor response rates that can be achieved with further platinum treatment. Notably, topotecan has a distinct mechanism of action and has not shown cross-resistance with platinum or paclitaxel. In a study by ten Bokkel Huinink et al. [21], topotecan was active in platinum- and paclitaxel-resistant tumors, with an overall response rate of 20%. The non-cross-resistance of topotecan to first-line therapy and data indicating that extending the platinum-free interval facilitates platinum reintroduction suggest that this agent is a good candidate for treatment of patients at first. In this alternate sequence, after on topotecan therapy, the patient receives platinum rather than the oral etoposide recommended in the initial strategy. Tumor responses have been observed in patients re-treated with platinum following topotecan therapy [21]. Additionally, according to this sequence (and the first sequence), liposomal 5th??

7 26 Long-Term Management of Ovarian Cancer Figure 4. Influence of prior treatments on the severity of myelosuppression in Grade 4 neutropenia topotecan-treated patients. Reprinted with permission [38] doxorubicin is reserved for treatment of third, thus delaying the onset of cumulative PPE. However, the relative convenience of once-monthly administration of liposomal doxorubicin is an important factor in selecting salvage agents. Finally, etoposide is recommended at fourth because of its convenience and because secondary leukemia is less of an issue later in the disease course, whereas taxane retreatment or gemcitabine is selected for fifth due to unique mechanisms of action and good tolerability, albeit with less proven efficacy. % of patients % of patients SUMMARY AND CONCLUSIONS The chronic natural history of d ovarian cancer has important implications for both oncologists and patients in terms of treatment planning and patient education (Table 3). To optimize the management of patients over the long term, clinicians should recognize that ovarian cancer and the patient s response to treatment take a variable course that requires tailoring disease management to individual patient needs. Additionally, clear definitions and consensus guidelines are needed to provide oncologists with the necessary information to anticipate impending decision points in the natural history of the disease. These tools will help guide the oncologist and the patient through the treatment decision process. Also driving treatment decisions is the desire to manage treatment-associated toxicities and extend the platinum-free interval, with a focus on monitoring for potential cumulative toxicity in these sometimes heavily treated patients. Finally, the education of patients takes on greater importance, including apprising them of the benefits of stable disease and partial tumor responses, and maintaining realistic expectations for lasting disease remission and survival. A greater appreciation of these challenges and issues will augment our ability to offer the best possible n of regimens Febrile neutropenia n of regimens Grade 3/4 thrombocytopenia % of patients % of patients Table 3. Guidelines for treatment planning n of regimens Platelet transfusions n of regimens Extend the platinum- or treatment-free intervals as long as possible Use sequential non-cross-resistant therapies to maximize options available for future treatments Be cognizant of any potential cumulative toxicities with sequential treatments Set realistic expectations for patients, including education on the benefits of stable disease and partial tumor response Always consider clinical trials, particularly in patients who rapidly progress on standard therapies treatment strategy that maximizes clinical end points in patients with ovarian cancer. ACKNOWLEDGMENT This work was supported by an unrestricted educational grant by GlaxoSmithKline, Philadelphia, Pennsylvania. Deborah K. Armstrong is a lecture for GlaxoSmithKline and Aventis, and receives research support from Aventis. REFERENCES 1 Jemal A, Thomas A, Murray T et al. Cancer statistics, CA Cancer J Clin 2002;52: Ozols RF, Schwartz PE, Eifel PJ. Ovarian cancer, fallopian tube carcinoma, and peritoneal carcinoma. In: DeVita Jr. VT,

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9 28 Long-Term Management of Ovarian Cancer 33 Rose PG, Fusco N, Fluellen L et al. Second-line therapy with paclitaxel and carboplatin for recurrent disease following first-line therapy with paclitaxel and platinum in ovarian or peritoneal carcinoma. J Clin Oncol 1998;16: Gronlund B, Hogdall C, Hansen HH et al. Results of reinduction therapy with paclitaxel and carboplatin in recurrent epithelial ovarian cancer. Gynecol Oncol 2001;83: Goldwasser F, Buthaud X, Gross M et al. Decreased topotecan platelet toxicity with successive topotecan treatment cycles in advanced ovarian cancer patients. Anticancer Drugs 1999;10: Swisher EM, Mutch DG, Rader JS et al. Topotecan in platinum- and paclitaxel-resistant ovarian cancer. Gynecol Oncol 1997;66: Herzog TJ. Update on the role of topotecan in the treatment of recurrent ovarian cancer. The Oncologist 2002;7(suppl 5): Armstrong D, O Reilly S. Clinical guidelines for managing topotecan-related hematologic toxicity. The Oncologist 1998;3: Möbus V, Pfaff PN, Volm T et al. Long time therapy with topotecan in patients with recurrence of ovarian carcinoma. Anticancer Res 2001;21: SELECTED READING McGuire WP, Hoskins WJ, Brady MF et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1-6. McGuire WP, Blessing JA, Bookman MA et al. Topotecan has substantial antitumor activity as first-line salvage therapy in platinum-sensitive epithelial ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2000;18: Kudelka AP, Tresukosol D, Edwards CL et al. Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 1996;14: Gordon AN, Fleagle JT, Guthrie D et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 2001;19: 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: