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© 2001 American Society for Clinical Oncology Recurrent Epithelial Ovarian Carcinoma: A Randomized Phase III Study of Pegylated Liposomal Doxorubicin Versus TopotecanByFrom the Texas Oncology, Professional Association, Dallas, TX; Rocky Mountain Cancer Center, Boulder Valley Oncology, Boulder, CO; Hospital General de Asturias, Oviedo, Spain; Derbyshire Royal Infirmary; Royal Marsden Hospital, London; and and Aberdeen Royal Infirmary, Aberdeen, United Kingdom. Address reprint requests to Alan N. Gordon, MD, Division of Gynecology, Texas Oncology P.A., 3535 Worth St, Suite S-200, Dallas, TX 75246; email: alan.gordon{at}usoncology.com
PURPOSE: To compare the efficacy and safety of pegylated liposomal doxorubicin (PLD) and topotecan in patients with epithelial ovarian carcinoma that recurred after or didn’t respond to first-line, platinum-based chemotherapy. PATIENTS AND METHODS: Patients with measurable and assessable disease were randomized to receive either PLD 50 mg/m2 as a 1-hour infusion every 4 weeks or topotecan 1.5 mg/m2/d for 5 consecutive days every 3 weeks. Patients were stratified prospectively for platinum sensitivity and for the presence or absence of bulky disease. RESULTS: A total of 474 patients were treated (239 PLD and 235 topotecan). They comprised the intent-to-treat population. The overall progression-free survival rates were similar between the two arms (P = .095). The overall response rates for PLD and topotecan were 19.7% and 17.0%, respectively (P = .390). Median overall survival times were 60 weeks for PLD and 56.7 weeks for topotecan. Data analyzed in platinum-sensitive patients demonstrated a statistically significant benefit from PLD for progression-free survival (P = .037), with medians of 28.9 for PLD versus 23.3 weeks for topotecan. For overall survival, PLD was significantly superior to topotecan (P = .008), with a median of 108 weeks versus 71.1 weeks. The platinum-refractory subgroup demonstrated a nonstatistically significant survival trend in favor of topotecan (P = .455). Severe hematologic toxicity was more common with topotecan and was more likely to be associated with dosage modification, or growth factor or blood product utilization. CONCLUSION: The comparable efficacy, favorable safety profile, and convenient dosing support the role of PLD as a valuable treatment option in this patient population.
OVARIAN CARCINOMA is the leading cause of cancer deaths of the female reproductive system.1 For 2000, ovarian cancer estimates projected approximately 23,100 new diagnoses and 14,000 deaths.2 Early-stage ovarian carcinoma is generally asymptomatic; therefore, the majority of women are diagnosed with advanced-stage disease (International Federation of Gynecology and Obstetrics stage III or IV).3 This is unfortunate, since stage inversely correlates with survival. Five-year survival rates for women with stage III or IV disease range from less than 5% to 20%.4 Although most patients demonstrate a complete response (CR) to surgery and first-line chemotherapy, 50% to 75% of advanced-stage patients have persistent or recurrent disease.5 Palliation and optimizing quality of life are the primary treatment goals for patients with recurrence, as the probability of cure for this population is remote. The Gynecologic Oncology Group trial 111, in which patients with advanced ovarian cancer were randomly assigned to receive cisplatin with either cyclophosphamide or paclitaxel, led to a new standard for front-line treatment of advanced ovarian carcinoma. The results of this trial supported the use of paclitaxel in combination with a platinum compound, and an independent, intergroup study confirmed these findings.6,7 With the inclusion of paclitaxel in front-line therapy, agents lacking cross-resistance to both paclitaxel and platinum compounds are needed for patients with recurrent or refractory disease. Topotecan, oral etoposide, and gemcitabine are three agents that have demonstrated responses in patients who have undergone unsuccessful first-line combination platinum and paclitaxel therapy.8-10 Of these, only topotecan is an approved agent for recurrent ovarian carcinoma. Topotecan has demonstrated response rates ranging from 13% to 33%, depending on platinum sensitivity.8,11-14 Patients with recurrent ovarian carcinoma are typically divided into two groups with differing prognoses. Patients with progression on primary therapy or after a treatment-free interval of less than 6 months are considered platinum-resistant; those who relapse or develop progression after a treatment-free interval of greater than 6 months after completion of therapy are platinum-sensitive. Platinum-sensitive patients are more likely to demonstrate a response to subsequent chemotherapy; therefore, they have a more favorable prognosis.5,15 In addition, several studies have demonstrated that the response rate improves with longer platinum-free periods, thus providing evidence that nonplatinum-based compounds may be efficacious in the subgroup of platinum-sensitive patients.14,16-18 To date, no data have established the superiority of platinum compounds or paclitaxel over other agents in platinum-sensitive patients.18 Given these findings, nonplatinum chemotherapeutic options for recurrent ovarian carcinoma are needed.
Pegylated liposomal doxorubicin is an emerging option for patients with recurrent ovarian carcinoma. It received Food and Drug Administration approval for patients refractory to paclitaxel and platinum-based chemotherapy in June 1999. Although doxorubicin has been associated with poor responses in recurrent ovarian cancer, pegylated liposomal doxorubicin is active.19-21 In addition to potential differences in efficacy, encapsulation of doxorubicin in pegylated liposomes attenuates the toxicities attributed to peak doxorubicin plasma levels (specifically, nausea, vomiting, and cardiotoxicity).21 Furthermore, this formulation drastically alters the pharmacokinetic profile of doxorubicin. The surface of the pegylated liposome is coated with methoxypolyethylene glycol polymers, which prevent liposomal detection and destruction by the reticuloendothelial system.22 The pegylated liposomes are small ( A phase II study assessed the efficacy of pegylated liposomal doxorubicin in 89 patients with recurrent ovarian cancer who were unsuccessfully treated with platinum and paclitaxel therapy.21 Of these 89 patients, 82 were refractory to both platinum and paclitaxel therapy. The overall response rates were 16.9% and 18.3% in the intent-to-treat population and in the platinum/paclitaxel–refractory patients, respectively (one CR and 14 partial responses [PRs]). The median times to progression were 19.3 weeks and 17 weeks for the intent-to-treat patients and the platinum/paclitaxel–refractory patients, respectively. Pegylated liposomal doxorubicin was generally well tolerated. The majority of adverse events were grade 3 severity or lower. Stomatitis, palmar-plantar erythrodysesthesia (PPE), and skin lesions were common and easily managed with dosing modification. Given the need for effective chemotherapy and because of the promising phase I/II results seen with pegylated liposomal doxorubicin, this randomized comparison of pegylated liposomal doxorubicin to topotecan in recurrent epithelial ovarian carcinoma patients was performed. The primary end point was a comparison of time to progression between the patients treated with pegylated liposomal doxorubicin and those treated with topotecan. Secondary end points included overall survival, response rate, time to response, duration of response, and safety and toxicity following treatment with either pegylated liposomal doxorubicin or topotecan.
Study Design This phase III, randomized, multicenter, open-label, comparative study of pegylated liposomal doxorubicin versus topotecan in women with histologically proven recurrent epithelial ovarian carcinoma began in May 1997. All investigators were required to obtain approval from an institutional review board, and all patients provided signed informed consent. Eligible patients were randomized in a 1:1 fashion to receive pegylated liposomal doxorubicin or topotecan. Enrollment was closed on March 3, 1999, after 474 patients had been treated. This article describes the results for these patients.
Eligibility Criteria Treatment with either drug was to be temporarily suspended or discontinued under any of the following conditions: disease progression, serious or intolerable adverse events precluding further treatment, inability to tolerate study drug despite dose modification, LVEF less than 45% or a 20% decrease from baseline, or patient’s decision to withdraw participation. Any patient requiring radiation was removed from treatment.
Treatment Plan The dose of pegylated liposomal doxorubicin was modified for PPE, hematologic toxicity, elevated bilirubin, and stomatitis. These side effects primarily resulted from prolonged intervals and/or decreased doses as previously described.21 The dose was reduced by 25% for all other grade 3 and 4 events until resolution to grade 2 or lower. In the event of severe neutropenia during any cycle with topotecan, the dose of topotecan was to be reduced by 0.25 mg/m2 for subsequent courses. Alternatively, before reducing the topotecan dose, granulocyte colony-stimulating factor could be administered starting from day 6 of the course at the discretion of the treating physician. No dose adjustment was required for patients with mild renal impairment (creatinine clearance, 40 to 60 mL/min); however, dose reduction to 0.75 mg/m2 was recommended in cases of moderate renal impairment (creatinine clearance, 20 to 39 mL/min). Prophylactic cytokine administration was not recommended during the first cycle of either study drug. However, growth factor support was allowed in subsequent cycles for any patient with grade 4 neutropenia lasting more than 7 days or failure of absolute neutrophil count to recover within 22 days. All patients who developed febrile neutropenia were also eligible for prophylactic growth factor administration in the next cycles.
Patient Stratification
Assessment of Response
Response to study drug was based on objective tumor assessments. A CR was defined as complete disappearance of all measurable and assessable disease, no new lesions, and no disease-related symptoms. A PR was documented in patients with a Safety analyses were performed on all patients who received at least one partial infusion of the study drug. Toxicity was graded using the National Cancer Institute common toxicity criteria. Adverse events were evaluated by the following grading scale: mild, grade 1; moderate, grade 2; severe, grade 3; or life-threatening, grade 4. The impact of therapy on the patients’ well-being was assessed by self-administration of the validated European Organization for Research and Treatment of Cancer Quality of Life questionnaire (QLQ-C30).31 The QLQ-C30 encompasses six domains (physical functioning, role functioning, cognitive functioning, emotional functioning, social functioning, and global quality of life), as well as eight symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, and diarrhea). All patients completed a QLQ-C30 questionnaire before study entry, during every cycle, and 4 weeks after the last treatment dose. To evaluate the impact of treatments on both length of survival and quality of life, a methodology called quality-adjusted time without symptoms and toxicity32 was used.
Statistical Analysis About 82% of patients completed the health-related quality-of-life (HQL) questionnaire at study entry. Owing to the difference in cycle length (4 weeks for pegylated liposomal doxorubicin and 3 weeks for topotecan), week 12 was the first time point after study entry at which HQL was assessed in both treatment groups at the same time. By 12 weeks, less than 50% of patients in either treatment group remained in the study with HQL data. Although this may have limited the analysis, it still left approximately 100 patients in each arm for comparison. Disease progression and death were the main reasons for discontinuing the HQL assessment. A total of 350 assessable patients, 175 patients in each treatment group, were to be randomized to ensure with a probability of 80% that the lower 95% one-sided confidence limit of the hazard ratio of topotecan to pegylated liposomal doxorubicin would not fall below 0.757. Two additional factors influenced the number of patients enrolled. First, two interim analyses were planned, necessitating enrollment of approximately 5% more patients. Second, it was anticipated that up to 20% of randomized patients might not be assessable for efficacy end points; thus, the number of patients to be randomized was up to 460, depending on the assessibility rate. This study was designed with 80% power to demonstrate statistical equivalence between the two treatment groups.
Patient Characteristics Between May 1997 and March 1999, 481 patients were randomized at 104 sites in the United States and Europe. Seven of these patients did not receive the study drug. Thus, a total of 474 patients were randomized and received at least a partial dose of pegylated liposomal doxorubicin (239 patients) or topotecan (235 patients). The efficacy and safety analyses described in this report were performed on these 474 patients (the intent-to-treat population). At the time of this analysis, 189 patients (103 receiving pegylated liposomal doxorubicin and 86 receiving topotecan) were still alive, and four pegylated liposomal doxorubicin patients and one topotecan patient were still being treated. Protocol deviations included: (1) failure to meet entry criteria (seven receiving pegylated liposomal doxorubicin, two receiving topotecan); (2) patients who continued on study after first clinically significant change in LVEF (13 receiving pegylated liposomal doxorubicin); (3) patients who continued treatment after documented disease progression (40 receiving pegylated liposomal doxorubicin, 42 receiving topotecan); and (4) patients who completed fewer than eight cycles of treatment but were deemed protocol-completed by the investigator (20 receiving topotecan). Tables 1 and 2 describe the demographic data and baseline disease characteristics for the intent-to-treat study population. The two treatment groups were well-matched in terms of demographic variables and disease status at study entry, and both groups were similar in platinum sensitivity and presence of bulky disease.
Drug Administration Treatment compliance with pegylated liposomal doxorubicin and topotecan administration was assessed. Details of study drug administration are provided in Table 3. The mean cycle dose and cycle length for each treatment group were close to those specified in the protocol, indicating good compliance in following the dosing guidelines.
Responses and Survival PFS for the two treatment groups showed a trend favoring pegylated liposomal doxorubicin, but it did not achieve statistical significance (P = .095) (Fig 1). No significant differences between the two treatment groups for confirmed objective response rates were identified (P = .390): 19.7% of pegylated liposomal doxorubicin patients and 17.0% of topotecan patients achieved a confirmed objective response (CR or PR). An independent radiologic review of the scans revealed 10 responders who were reclassified as unconfirmed responders; however, seven patients were reclassified as confirmed responders for an overall response rate of 18.4% to pegylated liposomal doxorubicin (44 of 239). Review of the topotecan patients reclassified seven responders as unconfirmed but also reclassified five patients as confirmed responders for a response rate of 16.2% (38 of 235). The difference in response rates remained insignificant. All of the reclassified patients except for one were partial responders. Overall survival (time to death) was also similar (P = .341) with medians of 60 weeks for pegylated liposomal doxorubicin and 56.7 weeks for topotecan (Fig 2).
Patients were prospectively stratified by bulky disease and platinum sensitivity, and an analysis of these subgroups was conducted. There were no differences in any outcome parameter when patients were stratified by bulky disease. Both treatment groups demonstrated a higher objective response among the platinum-sensitive patients compared with the platinum-resistant patients (Table 4). A large percentage of patients with stable disease was seen in both treatment groups.
The subset analysis of platinum-resistant patients showed trends in favor of topotecan for PFS (P = .733), with medians of 9.1 and 13.6 weeks (Fig 3). A similar trend was seen in overall survival (P = .455), with medians of 35.6 weeks for pegylated liposomal doxorubicin and 41.3 weeks for topotecan (Fig 4). Objective response rates of 6.5% for topotecan and 12.3% for pegylated liposomal doxorubicin were not significantly different (P = .118).
However, when data were analyzed for the platinum-sensitive group, differences between the two treatment groups emerged. Although the platinum-sensitive subgroups demonstrated similar response rates (28.4% pegylated liposomal doxorubicin, 28.8% topotecan; P = .964), there was a significant difference in favor of pegylated liposomal doxorubicin for PFS (P = .037), with medians of 28.9 and 23.3 weeks (Fig 5). Most notably, there also was a significant difference in overall survival favoring pegylated liposomal doxorubicin, with medians of 108 versus 71.1 weeks (P = .008) (Fig 6).
Toxicity Almost all patients reported adverse events. The proportion of grade 1, 2, and 3 adverse events was similar between the two groups; however, a greater percentage of patients in the topotecan group experienced grade 4 adverse events (71.1% v 17.2%) (Fig 7). The toxicity profiles of the two agents were different (Table 5). Generally, the toxicity attributed to pegylated liposomal doxorubicin was mild to moderate in severity. The most common adverse events associated with pegylated liposomal doxorubicin were PPE, which occurred in 49% of patients, and stomatitis, which occurred in 40% of patients. Grade 3 PPE events occurred in 22%, and grade 4 occurred in 0.8% of patients. PPE was managed primarily by dose reduction or delay, and it necessitated discontinuation of therapy in only nine patients (3.8%). Only 7.9% and 0.4% of patients experienced grade 3 or grade 4 stomatitis, respectively.
Hematologic toxicity was more frequent and usually grade 3 or 4 in the topotecan-treated patients. The majority of patients in the topotecan group (90.2%) experienced hematologic adverse events, and two thirds of these events were grades 3 and 4. The hematologic toxicity in the topotecan arm resulted in a greater utilization of hematopoietic growth factors (granulocyte or granulocyte-macrophage colony-stimulating factor, 29.1% v 4.6%; erythropoietin, 23.1% v 6.3%), blood transfusions (57.8% v 14.9%), and dosing modifications (78.3% v 57.3%) when compared with the pegylated liposomal doxorubicin arm. A number of patients treated with topotecan experienced clinical sequelae related to the hematologic toxicity. Nine patients (3.8%) experienced treatment-related sepsis (three of whom died), two experienced sepsis of an unknown relationship to study drug (one of whom died), two withdrew from the study because of sepsis, and two additional patients experienced treatment-related neutropenic fever. No patients who received pegylated liposomal doxorubicin experienced treatment-related sepsis or neutropenic fever. Pegylated liposomal doxorubicin required fewer dose modifications than did topotecan (Table 6). The leading causes of dose modification were PPE in the pegylated liposomal doxorubicin group (25.2% of doses) and hematologic toxicity in the topotecan group (43.3% of doses). The number of patients who withdrew from the study because of adverse events was similar (43 pegylated liposomal doxorubicin patients and 37 topotecan patients). The most common reasons for termination were PPE in the pegylated liposomal doxorubicin arm and sepsis and leukopenia/neutropenia in the topotecan arm. Three treatment-related deaths were associated with topotecan. All three patients died from complications resulting from neutropenia and sepsis. There were no instances of treatment-related death in patients treated with pegylated liposomal doxorubicin.
No patient in either group demonstrated signs or symptoms of congestive heart failure. There were few changes in LVEF in the 132 patients treated with pegylated liposomal doxorubicin who had a baseline and at least one postdose LVEF evaluation by multiple gated aquisition or echocardiogram. Sixty-one patients received cumulative pegylated liposomal doxorubicin doses of more than 300 mg/m2, and 14 received doses exceeding 450 mg/m2. Three of the 61 patients demonstrated a  20% absolute decrease in LVEF from baseline, and three had a postbaseline LVEF of less than 45% (two began the study with LVEF < 45%). None of these patients demonstrated clinical signs or symptoms of congestive heart failure. There was no evidence of a relationship between cumulative pegylated liposomal doxorubicin dose and change from baseline for LVEF.
Health-Related Quality of Life
The choices for effective treatment of recurrent ovarian carcinoma are limited. Options include chemotherapy, hormonal therapy, intraperitoneal chemotherapy, secondary cytoreductive surgery, radiotherapy, and high-dose chemotherapy with stem-cell support. Response rates to chemotherapy or hormonal therapy are modest: ifosfamide, 20%33; hexamethylmelamine, 14%34; oral etoposide, 26%35; gemcitabine, 19%36,37; vinorelbine, 20%38; and hormonal therapy, 10% to 15%.4 Response rates tended to be higher in platinum-sensitive subgroups.8,16,39 Typically, combination therapy in recurrent disease has not proved to be more effective than single agents and is associated with increased toxicity.4 In addition to modest response rates, the duration of response and survival are limited. Median survival times are 6 to 16 months.8,38,39 Given these factors, cure is not a goal for these patients. Palliation and improved quality of life are among the most important considerations when choosing chemotherapy for these recurrent patients. Data show that pegylated liposomal doxorubicin and topotecan, an established, efficacious agent for recurrent ovarian carcinoma, demonstrate equivalence in efficacy measures. While endpoints such as PFS response rates, duration of response, and overall survival were similar between the two groups, subgroup analyses of platinum-sensitive patients demonstrated that pegylated liposomal doxorubicin was associated with a statistically significant increase in PFS (P = .037) and overall survival (P = .008). The significant survival advantage reported for the pegylated liposomal doxorubicin patients with platinum-sensitive disease merits further investigation. One possible explanation may be due to other therapies that patients received after being removed from the study. Patients who initially received topotecan may not have subsequently received pegylated liposomal doxorubicin because it had not yet been approved for use in epithelial ovarian cancer. Unfortunately, subsequent therapy was not collected prospectively, and it is unknown as to what therapies were administered after the failure of initial therapy. It is possible that pegylated liposomal doxorubicin, with its decreased marrow toxicity, allowed more subsequent doses of marrow-toxic drugs. In addition, it has been postulated that pegylated liposomal doxorubicin may prevent the development of multidrug resistance.40,41 The difference of 5.6 weeks in progression-free intervals resulted in an overall survival difference of 37 weeks in the platinum-sensitive patients. This improvement, compared with the platinum-resistant patients, was probably due to the greater probability of platinum-sensitive patients to respond to further therapy.8,16,39 Given the similarities in efficacy, the toxicity profile and resulting tolerability are of paramount importance when selecting therapy for recurrence. In this study, nearly all patients experienced adverse events; however, the patients who received topotecan experienced more grade 4 toxicities (71.1% v 17.2%) than did the patients who received pegylated liposomal doxorubicin. A large percentage of patients in both groups required dosage modifications. However, pegylated liposomal doxorubicin required fewer dose modifications when compared with topotecan (57.3% v 78.3%), including dose delays, interrupted doses, and reduced doses. Topotecan and pegylated liposomal doxorubicin were administered at their Food and Drug Administration–approved doses and schedules. Severe (grade 3 or 4 or fatal) hematologic toxicities were more common in the topotecan arm, and they were more often associated with morbidity and, in a few cases, mortality. Specifically, grades 3 and 4 neutropenia, anemia, thrombocytopenia, and leukopenia were all significantly more common with topotecan (P < .007). In other studies, grade 4 neutropenia has been noted in 79% to 94% of topotecan-treated patients.8,13,39 In this investigation, hematologic toxicity in the topotecan group was associated with a higher utilization of growth factor support and blood-product transfusions. Doses lower than the Food and Drug Administration–approved 1.5–mg/m2 dose have led to reduced rates of hematologic toxicity without any apparent decrease in efficacy; however, the hematologic toxicity is still greater than that with pegylated liposomal doxorubicin in the current study.42 The significant costs associated with hematologic supportive care must be considered when choosing therapy for recurrent disease. Pegylated liposomal doxorubicin was generally well tolerated. The most common treatment-related adverse events observed in the pegylated liposomal doxorubicin group were stomatitis and PPE. Stomatitis tended to be mild. Only 5.3% of dose modifications were due to stomatitis. Chemotherapy-induced PPE has been documented with a number of agents: fluorouracil, doxorubicin, vinorelbine, cytarabine, and capecitabine.43,44 PPE, also called hand-foot syndrome, is a cutaneous reaction typically involving the palms of the hands and soles of the feet. The reaction typically begins with a 3- to 5-day period during which the patient experiences paresthesias of the extremities. This is followed by edema and erythema that can be complicated by severe pain and cracking of the skin. Discontinuation of the agent results in desquamation of the affected areas followed by re-epithelialization. Severe PPE can be prevented and managed by early recognition and dose modification, either by decreasing the dose or lengthening the dosing interval.19,21,45 Dose modification can allow continued treatment without recurrence of the PPE. Although there is no definitive evidence that pharmacologic therapy is effective in managing PPE, various approaches have been used, including topical dimethyl sulfoxide or pyridoxine.45,46 PPE associated with pegylated liposomal doxorubicin generally develops 1 to 3 weeks after repeated dosing.47 Although the cause of PPE is not known, it is theorized that the long half-life and the small size of the liposomes result in localization of drug in the skin.47 Although PPE occurred in 49% of patients in this study, only 22% (53 of 239) and 0.8% (two of 239) of patients experienced grade 3 or 4 toxicity, respectively. The primary approach to preventing PPE involved observation for early signs of toxicity. Careful questioning of the patients for early signs of PPE may have contributed to the relatively small percentage of patients who experienced grade 3 or 4 PPE and the small percentage of patients who discontinued pegylated liposomal doxorubicin owing to PPE by allowing early intervention before severe toxicity occurred. The tolerability of pegylated liposomal doxorubicin makes it an ideal agent for long-term dosing in responsive patients. The lack of hematologic toxicity may enable pegylated liposomal doxorubicin to be combined with other agents for possible incorporation into front-line therapy. Additionally, pegylated liposomal doxorubicin is dosed less frequently than is topotecan, which results in improved convenience for the patient and a reduction in resource use. The favorable safety profile, combined with overall comparable efficacy with an established agent and a significant survival benefit for platinum-sensitive patients, supports the role of pegylated liposomal doxorubicin for patients with ovarian cancer who have undergone unsuccessful first-line platinum-containing chemotherapy.
Support for this project was provided by ALZA Corp, Mountain View, CA.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
100 nm in diameter) and can pass through endothelial gaps or leaky membranes commonly associated with tumors.
0.5 cm, lesion(s) on scan with either diameter smaller than the distance between cuts, palpable lesion(s) with either diameter 
, pegylated liposomal doxorubicin; 
, topotecan.
