PETER G. ROSE. Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio, USA

Transcription

1 The Oncologist Gynecologic Oncology Pegylated Liposomal Doxorubicin: Optimizing the Dosing Schedule in Ovarian Cancer PETER G. ROSE ABSTRACT Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio, USA Key Words. Doxorubicin Liposomes Ovarian neoplasms Drug administration schedules The need for effective, well-tolerated, and convenient therapies for patients with advanced ovarian cancer has led researchers to continually refine chemotherapeutic regimens to balance efficacy with safety and tolerability in order to maintain or improve patient quality of life. In this article, we review current strategies for the optimal dosing of pegylated liposomal doxorubicin (DOXIL ; Tibotec Therapeutics, a division of Ortho Biotech Products, L.P., Bridgewater, NJ, Caelyx, Schering-Plough Corporation, Kenilworth, NJ, in relapsed ovarian cancer. Pegylated liposomal doxorubicin has demonstrated efficacy in the treatment of recurrent/resistant ovarian cancer in several clinical trials utilizing a dose of 50 mg/m 2 every 4 weeks. The most common adverse events associated with pegylated liposomal doxorubicin treatment in these studies hand-foot syndrome (HFS, also known as INTRODUCTION Ovarian cancer remains the leading cause of death among gynecologic malignancies in the U.S. [1]. In 2005, it is estimated that 22,220 new cases of ovarian cancer will be diagnosed, and 16,210 women will die of the disease [1]. Because early-stage ovarian cancer is generally asymptomatic, most women (70%-75%) present with advancedstage (i.e., stage III/IV) disease [2]. Survival is highly dependent on and inversely correlated with the stage of disease at the initiation of treatment, with women who are diagnosed early having the best prognosis. palmar-plantar erythrodysesthesia) and stomatitis are schedule and dose dependent, respectively, and do not typically lead to discontinuation of therapy. Several phase II and retrospective studies support the use of pegylated liposomal doxorubicin 40 mg/m 2 every 4 weeks (dose intensity of 10 mg/m 2 weekly) to optimize clinical efficacy and minimize the occurrence of schedule- and doserelated adverse events in patients with recurrent/relapsed ovarian cancer. Further reductions in dose intensity are necessary for use in combined chemotherapy regimens. Antitumor activity was maintained, with reduced incidences of HFS and stomatitis. Given the chronic course of ovarian cancer, the improved tolerability profile of pegylated liposomal doxorubicin 40 mg/m 2 combined with a convenient once-monthly dosing schedule may translate into an improved quality of life for patients with ovarian cancer. The Oncologist 2005;10: The standard of care for the management of ovarian cancer includes surgery for staging and cytoreduction (debulking) and chemotherapy with a platinum/taxane combination. While approximately 85% of patients respond to surgery and first-line chemotherapy, 50%-75% of patients with advanced ovarian cancer will experience recurrent disease [3, 4]. In these patients, the goals of second-line chemotherapy include palliation of symptoms, preservation of quality of life, and prolongation of progression-free survival. Selection of a second-line agent is generally based on initial tumor response to platinum-based chemotherapy. In Correspondence: Peter G. Rose, M.D., Cleveland Clinic Taussig Cancer Center, 9500 Euclid Avenue, A-81, Cleveland, Ohio 44195, USA. Telephone: ; Fax: ; rosep@ccf.org Received August 23, 2004; accepted for publication December 10, AlphaMed Press /2005/$12.00/0 The Oncologist 2005;10:

2 Rose 206 patients initially responsive to platinum-based therapy (i.e., those with an initial response lasting >6 months), rechallenge with a platinum agent is an option [5-7]. Response rate improves with a longer treatment-free interval, which has led some to suggest that the use of nonplatinum compounds also may be of benefit in platinum-sensitive patients [6-10]. However, in a population with a long treatment-free interval (>12 months), Cantu and colleagues demonstrated an improved progression-free interval and survival in patients treated with platinum-based chemotherapy compared with paclitaxel [11]. Recent results from the International Collaborative Ovarian Neoplasm 4 (ICON4)/ Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) OVAR-2.2 trial suggest that platinum/taxane combination therapy may improve progression-free and overall survival versus platinum therapy alone in patients with platinumsensitive relapsed ovarian cancer [12]. The ICON4/AGO- OVAR-2.2 trial, however, has several limitations that should be considered: A) data were pooled from two parallel trials with three separate protocols, B) follow-up was incomplete in terms of agents received after failure of second-line therapy, and C) several patients did not receive a taxane first line. Despite these potential limitations, ICON4/AGO-OVAR-2.2 shows a survival advantage in a relapsed solid tumor patient population, suggesting a change in current treatment strategy second-line therapy has the potential to increase patient survival. While further investigation and confirmation of these results may be necessary (e.g., evaluation of other platinum-based doublet regimens in patients with platinum-sensitive ovarian cancer, such as carboplatin/pegylated liposomal doxorubicin or carboplatin/gemcitabine), the results of ICON4/AGO-OVAR- 2.2 should be considered when treating patients with platinum-sensitive disease. The Gynecologic Oncology Group is currently planning to examine this issue further. Patients with platinum-resistant disease (progression or recurrence within 6 months of primary therapy) have traditionally been treated with an agent that does not exhibit crossresistance with platinum compounds (i.e., agents with different mechanisms of action) [13]. Agents demonstrating activity in this setting include pegylated liposomal doxorubicin (DOXIL ; Tibotec Therapeutics, a division of Ortho Biotech Products, L.P., Bridgewater, NJ, Caelyx, Schering-Plough Corporation, Kenilworth, NJ, [14-16], topotecan [17, 18], oral etoposide [19], gemcitabine [20], and vinorelbine [21]. Response rates reported with these agents in patients with platinum-resistant ovarian cancer have ranged from 12%- 27%. However, a recent French Cooperative Group (GINECO) retrospective study demonstrating higher responses and survival for patients treated with platinum combinations, even when relapse occurred within 6 months, has challenged this concept [22]. Overall survival of women with platinum- and taxaneresistant ovarian cancer has been estimated based on a retrospective analysis of 111 patients treated in one or more of four nonrandomized phase II trials conducted by the Gynecologic Cancer Program of the Cleveland Clinic [23]. Duration of survival in patients with platinum/taxane-resistant disease was defined as the time from documentation of both platinum and taxane resistance until death. Median overall survival was 6 months (range, 1-37 months); 32% of patients survived <4 months, and almost three-quarters of patients (73%) died in <12 months. Because many of these patients will likely receive only one agent in this relapsed setting, these statistics highlight the importance of selecting the most effective and well-tolerated agent for patients with resistant ovarian cancer. The need for effective, convenient, and well-tolerated therapies for patients with advanced ovarian cancer has led researchers to continually refine chemotherapeutic dosing regimens in an effort to balance efficacy with safety and tolerability. In this article, we review current strategies for the optimal dosing of pegylated liposomal doxorubicin in relapsed ovarian cancer by highlighting the differences from conventional doxorubicin dosing, and by comparing the results seen in clinical trials of patients with ovarian cancer treated with different dosages (and consequently, different dose intensities) of pegylated liposomal doxorubicin. Pegylated Liposomal Doxorubicin Pegylated liposomal doxorubicin is a unique formulation of conventional doxorubicin in which a polyethylene glycol layer surrounds the doxorubicin-containing liposome as the result of a process termed pegylation. Pegylation protects the liposomes from detection by the reticuloendothelial system and increases the plasma half-life compared with conventional doxorubicin [24, 25]. The size of these drugcontaining vesicles allows the liposomes to extravasate through the leaky tumor vasculature. This property, combined with its longer half-life, promotes targeted drug delivery to the tumor site [24]. Pegylated liposomal doxorubicin has been investigated in a variety of cancer types, including breast cancer, gynecologic malignancies, multiple myeloma, non-hodgkin s lymphoma, gastrointestinal malignancies, and non-small cell lung cancer. In the U.S., pegylated liposomal doxorubicin is approved by the Food and Drug Administration (FDA) for the treatment of metastatic ovarian cancer in patients with disease refractory to both paclitaxel- and platinum-based chemotherapy regimens [26]. Guidelines from the National Institute for Clinical Excellence advocate

3 207 Optimal Dosing of Pegylated Liposomal Doxorubicin pegylated liposomal doxorubicin as the drug of choice for many patients with advanced ovarian cancer for whom first-line chemotherapy has failed [27]. Pegylated liposomal doxorubicin is also approved in the European Union, Canada, and Israel for the treatment of metastatic breast cancer in patients who are at increased cardiac risk. It is important to note that pegylated liposomal doxorubicin should not be substituted for conventional doxorubicin on a milligram per milligram basis, as conventional doxorubicin is administered at doses of mg/m 2 every 3 weeks, while the current FDA-recommended dose of pegylated liposomal doxorubicin is 50 mg/m 2 every 4 weeks. This difference in dosing is due to the substantial changes in the functional properties of a drug (i.e., increased half-life, ability to evade the immune system) that occur with liposomal encapsulation. Moreover, different liposomal formulations of doxorubicin can vary in terms of the chemical composition and physical properties of the liposomes themselves, and thus should not be used as a direct substitute for pegylated liposomal doxorubicin either. Pegylated Liposomal Doxorubicin in Recurrent/Relapsed Ovarian Cancer Pegylated liposomal doxorubicin has demonstrated efficacy as a single agent in the treatment of recurrent/relapsed ovarian cancer in several clinical trials [14-16]. The first of these was a phase II study of 35 patients with platinum- and paclitaxel-refractory ovarian cancer who received pegylated liposomal doxorubicin 50 mg/m 2 every 3 weeks, resulting in a dose intensity of 16.7 mg/m 2 per week. In the event of grade 3/4 toxicities, the dose was reduced to 40 mg/m 2 (or a dose intensity of 13.3 mg/m 2 per week), while the presence of persistent (lasting >3 weeks) grade 1/2 adverse events resulted in an increase in the dosing interval to every 4 weeks [14]. The overall response rate was 25.7% (one complete response [CRs] and eight partial responses [PRs]); however, 13 (37.1%) patients experienced grade 3/4 skin and mucosal toxicities that often necessitated dose modifications. In a second phase II study, 89 patients with platinum- and paclitaxel-refractory ovarian cancer were treated with pegylated liposomal doxorubicin at a slightly lower dose intensity: 50 mg/m 2 every 4 weeks, or 12.5 mg/m 2 weekly [15]. Tumor response was observed in 16.9% of patients, with one CR and 14 PRs. Dose delays, reductions, or interruptions occurred in 39 (43.8%) patients, over half of which were required due to adverse events (i.e., hematologic toxicity, HFS [hand-foot syndrome], or stomatitis). The most common treatmentrelated adverse events were asthenia and HFS, both of which occurred in 41.6% of patients (severity grades 1, 2, or 3). A subsequent phase III trial was conducted by Gordon and colleagues to compare the safety and efficacy of pegylated liposomal doxorubicin with that of topotecan in 474 patients with relapsed ovarian cancer that recurred after or failed to respond to first-line, platinum-based chemotherapy [16]. Patients were randomly assigned to treatment with pegylated liposomal doxorubicin 50 mg/m 2 every 4 weeks (given as a 1-hour infusion) or topotecan 1.5 mg/m 2 /day for 5 consecutive days every 3 weeks (given as a 30-minute infusion) for up to 1 year. Patients were stratified prospectively based on platinum sensitivity and presence/absence of bulky disease. Based on the results of an end-of-study analysis, similar overall response rates and median progression-free and overall survival were observed in both treatment groups. In patients with platinum-sensitive disease, women treated with pegylated liposomal doxorubicin had a significantly longer median progression-free (p =.037) and overall survival (p =.008) compared with those treated with topotecan. Survival data from a long-term follow-up analysis of this phase III study were presented at the 2003 European Cancer Conference [28]. This analysis revealed that overall survival was significantly longer in patients randomized to treatment with pegylated liposomal doxorubicin compared with topotecan (hazard ratio [HR] = 0.82; 95% confidence interval [CI]: , p =.05), with an 18% reduction in the risk of death. In the subset of patients with platinumsensitive disease, the significant difference in overall survival observed during the interim analysis was maintained (updated results: HR = 0.63; 95% CI: , p =.002), with a 37% reduction in the risk of death favoring patients randomized to pegylated liposomal doxorubicin. The proportion of patients experiencing grade 1, 2, and 3 adverse events was similar between the two treatment groups; however, fewer patients treated with pegylated liposomal doxorubicin reported grade 4 adverse events (17.2% versus 71.1% with topotecan) [16]. Differences were also observed with respect to the nature of toxicities: the most common grade 3/4 nonhematological toxicities associated with pegylated liposomal doxorubicin were HFS (23%) and stomatitis (8%), while hematologic toxicity was the most common event among topotecan-treated patients (Table 1). Significantly fewer patients receiving pegylated liposomal doxorubicin required dose modifications (57.3% versus 78.3% of those receiving topotecan; p <.001). The toxicities associated with pegylated liposomal doxorubicin are managed by delaying or reducing the dose, with no apparent loss of antitumor activity. Several studies have suggested that pegylated liposomal doxorubicin administered at a dose of 40 mg/m 2 every 4 weeks (for an overall dose intensity of 10 mg/m 2 per week) rather than 50 mg/m 2 every 4 weeks (overall dose intensity, 12.5 mg/m 2 per week) results in a substantially reduced incidence of HFS [29-32] and stomatitis [29-31], without a loss of clinical efficacy.

4 Rose 208 Table 1. Grade 3/4 toxicities associated with pegylated liposomal doxorubicin or topotecan [16] Patients, n (%) Pegylated liposomal Adverse event doxorubicin Topotecan (n = 239) (n = 235) Neutropenia 29 (12) 180 (77) Anemia 13 (5) 66 (28) Thrombocytopenia 3 (1) 80 (34) Leukopenia 24 (10) 117 (50) Alopecia 3 (1) 14 (6) HFS 55 (23) 0 (0) Stomatitis 20 (8) 1 (0.4) Abbreviation: HFS = hand-foot syndrome. Further investigation has shown that the incidence of HFS is schedule dependent, with shorter dosing intervals leading to increased frequency and severity of occurrence [33]. In contrast, the incidence of stomatitis is dose related, occurring with greater incidence and severity in patients receiving pegylated liposomal doxorubicin doses of mg/m 2. These findings suggest that reducing the dose intensity of pegylated liposomal doxorubicin may be used in an effort to maintain efficacy and optimize tolerability. Clinical evidence exists to provide the rationale for a modified dosing schedule of pegylated liposomal doxorubicin 40 mg/m 2 every 4 weeks in patients with recurrent/relapsed ovarian cancer. Dose and Schedule of Pegylated Liposomal Doxorubicin: What Is Optimal Dose Intensity? Most prospective clinical trials with pegylated liposomal doxorubicin have utilized a dose of 50 mg/m 2 every 4 weeks [14-16]. However, when the phase III trial results of Gordon and colleagues are viewed in terms of the median dosage received (50 mg/m 2 per day) and overall median cycle length (30 days), the median dose intensity is 11.6 mg/m 2 per week [16]. This suggests that the overall effective dose and dose intensity for pegylated liposomal doxorubicin are less than 50 mg/m 2 every 28 days and 12.5 mg/m 2 per week, respectively. Further evidence that reduced dose intensity provides comparable efficacy and results in fewer side effects comes from studies in which clinicians have empirically reduced the dose of pegylated liposomal doxorubicin in their clinical practice to 40 mg/m 2 every 4 weeks (an intensity of 10 mg/m 2 per week) to reduce the risk of HFS and stomatitis, because this dose is effective and better tolerated than 50 mg/m 2 every 4 weeks (i.e., reduced incidence of HFS and stomatitis) in patients with recurrent ovarian cancer [29-31]. In the largest of these studies, Rose and colleagues conducted a retrospective analysis comparing the efficacy and safety of pegylated liposomal doxorubicin at an initial dose of 40 mg/m 2 or 50 mg/m 2 every 4 weeks (10 mg/m 2 or 12.5 mg/m 2 weekly, respectively) in patients with platinumrefractory ovarian, peritoneal, or tubal carcinoma (Table 2) [29]. A total of 78 patients were identified (38 treated with 40 mg/m 2 and 40 treated with 50 mg/m 2 ). No differences were noted between dose groups with respect to patient age, performance status, the proportion of patients who were also paclitaxel resistant, or tumor bulk. Response rates were similar for patients receiving pegylated liposomal doxorubicin 40 mg/m 2 every 4 weeks and 50 mg/m 2 every 4 weeks (13.5% versus 7.7%, respectively; p =.7) [29]. Median progression-free survival was the same (4 months), and median overall survival was similar for both dose groups (7 months versus 10 months, respectively; p =.25). However, a significant difference was observed in the proportion of patients requiring dose reductions: 27.5% of patients required a reduction at the 50-mg/m 2 dose, compared with none of the patients treated at the 40-mg/m 2 dose (p <.001). Dose delays occurred in twice as many patients treated with the 50-mg/m 2 dose versus the 40-mg/m 2 dose (14 patients [32%] versus 7 patients [16%], respectively; p =.14). These results support the hypothesis that reducing the dose intensity of pegylated liposomal doxorubicin to Table 2. Clinical experience in advanced ovarian cancer with pegylated liposomal doxorubicin at doses of 40 mg/m 2 every 4 weeks Pegylated liposomal Response TTP, months Dose reductions Dose delays Study/Population n doxorubicin dose rate (%) (range) % of patients % of patients Rose, 2001; platinum-resistant OC [29] mg/m 2 q 4 weeks (1-20) mg/m 2 q 4 weeks (1-21) Campos, 2001; recurrent OC, 40% mg/m 2 q 4 weeks ( ) 8 (% of cycles) 3 (% of cycles) of patients with platinum/paclitaxelresistant disease [30] Markman, 2000; platinum/ mg/m 2 q 4 weeks 9.0 Not reported 12.0 Not reported paclitaxel-refractory OC [31] Abbreviations: OC = ovarian cancer; TTP = time to progression

5 209 Optimal Dosing of Pegylated Liposomal Doxorubicin 10 mg/m 2 per week (i.e., 40 mg/m 2 every 4 weeks) achieves similar efficacy and better tolerability compared with that of the 12.5-mg/m 2 per week (i.e., 50 mg/m 2 every 4 weeks) regimen. However, these findings should be interpreted with caution, as this was not a prospective study, nor was it powered to address the issue of equivalent efficacy. Campos and colleagues also conducted a retrospective analysis of patients who received pegylated liposomal doxorubicin at a dose of 40 mg/m 2 every 4 weeks (10 mg/m 2 weekly; Table 2) [30]. All patients (n = 72) had recurrent ovarian cancer and a history of platinum/paclitaxel therapy; 40% of patients had tumors that were resistant to both platinum and paclitaxel. Despite the high platinum and paclitaxel resistance of the population, the overall response rate (defined as clinical or radiologic evidence of response with reduction in CA-125 >50%) was 27%, and the time to progression was 5.3 months (range, months). Toxicities were generally mild and self-limiting [30]. Seven dose delays (3%) and 20 dose reductions (8%) were required in 265 cycles of treatment. Hematologic toxicity was generally mild, with few patients experiencing grade 3/4 neutropenia (n = 1), thrombocytopenia (n = 1), and anemia (n = 8). Other toxicities included grade 3 cutaneous toxicity in six patients (8%) and grade 3/4 mucositis in three patients (4%; Table 3). These results are consistent with those of Rose and colleagues and support the use of the 40-mg/m 2 dose to decrease dose intensity in order to reduce toxicity while maintaining efficacy. A single prospective phase II clinical trial has examined the use of pegylated liposomal doxorubicin 40 mg/m 2 every 4 weeks (10 mg/m 2 weekly; Table 2) [31]. Conducted by Markman and colleagues, this study included 49 patients with platinum/paclitaxel-refractory ovarian and fallopian tube cancers or primary peritoneal carcinoma who had received a median of two prior treatment regimens (range, 1-6 regimens). All patients received pegylated liposomal doxorubicin 40 mg/m 2 every 4 weeks for a maximum of 12 treatment cycles. Of the 44 patients evaluated, four patients (9%) demonstrated objective and subjective evidence of a response. Pegylated liposomal doxorubicin was generally well tolerated, with Table 3. Incidence of grade 3/4 hand-foot syndrome (HFS) and stomatitis with pegylated liposomal doxorubicin 40 mg/m 2 every 4 weeks HFS n (%) of patients Stomatitis/mucositis Study Grade 3 Grade 4 Grade 3 Grade 4 Rose, 2001 [29] 0 (0) 0 (0) 0 (0) 0 (0) Campos, 2001 [30] 6 (8) 0 (0) 1 (1) 2 (3) Markman, 2000 [31] 0 (0) 0 (0) 0 (0) 0 (0) treatment-related toxicities necessitating dose reductions in six patients (12%). No episodes of grade 4 neutropenia or grade 3/4 thrombocytopenia, HFS, or stomatitis were observed. Grade 2 HFS and stomatitis were observed in six patients (12%) and four patients (8%), respectively. These findings further extend those of previous investigators, suggesting that the tolerability profile of pegylated liposomal doxorubicin is improved with the use of a reduced dose-intensity treatment schedule (40 mg/m 2 every 4 weeks, or 10 mg/m 2 weekly). A retrospective chart review was performed by Kim and colleagues to evaluate the skin toxicity associated with pegylated liposomal doxorubicin administered at a dose of 40 mg/m 2 every 4 to 6 weeks in 90 patients with gynecologic malignancies [32]. Efficacy results have not been reported. A total of 33 of 90 (37%) patients reported skin reactions, but only one patient had grade 3 skin toxicity and none had grade 4 skin toxicity. In those patients with skin reactions who continued treatment, 93% did not experience subsequent skin toxicity following dose reduction. The authors concluded that severe skin toxicity is less frequent with the 40-mg/m 2 dose, and when reactions do occur, they respond to dose reduction and do not limit treatment duration. Although conducted in patients with metastatic breast cancer, another retrospective analysis by Perez and colleagues provides further evidence that pegylated liposomal doxorubicin is effective and well tolerated at doses of less than 50 mg/m 2 every 4 weeks [34]. In this analysis, a total of 40 patients received a median initial pegylated liposomal doxorubicin dose of 42.5 mg/m 2 (range, mg/m 2 ), which translates to a dose intensity of 10.6 mg/m 2 per week. Results suggest that efficacy was maintained, as demonstrated by a clinical benefit rate (i.e., patients with PR or stable disease) of 43%. The median time to progression was 4 months, and median overall survival was 20 months. There were no grade 4 toxicities reported. Grade 3 mucositis and HFS occurred in one patient each. Taken together, the results of these studies suggest that pegylated liposomal doxorubicin is effective in the treatment of ovarian cancer when given at doses ranging from mg/m 2 every 4 weeks, which equates to an overall dose intensity of mg/m 2 per week. Furthermore, it appears that 12.5 mg/m 2 per week may be approaching the upper limit of the dose intensity scale, as regimens utilizing doses of greater intensity have resulted in more toxicity [14]. A prospective phase III study would be required to adequately compare the relative efficacy and tolerability of pegylated liposomal doxorubicin at dosage schedules of 40 mg/m 2 and 50 mg/m 2 every 4 weeks. The results of a phase II trial recently presented at the 2004 Annual Meeting of the American Society of Clinical Oncology further support the concept that pegylated liposomal doxorubicin is effective and well tolerated at a dose

6 Rose 210 intensity of 10 mg/m 2 weekly in patients with ovarian cancer [35]. Patients (n = 68) in this study were heavily pretreated and received a biweekly dose schedule of pegylated liposomal doxorubicin 20 mg/m 2 every 14 days (dose intensity, 10 mg/m 2 weekly). Of those patients evaluable for efficacy (n = 36), seven (19%) achieved a response to therapy. This dose schedule was well tolerated, with only three patients experiencing grade 3 HFS, and no incidences of grade 4 HFS. The authors concluded that despite being heavily pretreated, the dose schedule seemed to be effective and well tolerated in these patients. Currently, the dosage approved by the FDA for use in patients with platinum/paclitaxel-refractory ovarian cancer is 50 mg/m 2 every 4 weeks [26]. However, based on the available literature, it appears that pegylated liposomal doxorubicin 40 mg/m 2 every 4 weeks (or a dose intensity of 10 mg/m 2 weekly) is a viable therapeutic option, with an improved tolerability profile over that of the currently approved dosage. Optimizing the Dose of Pegylated Liposomal Doxorubicin as Part of a Combination Regimen The combined use of agents with nonoverlapping toxicities has long been explored in an effort to improve response rates Table 4. Pegylated liposomal doxorubicin: dose intensity in combined regimens and survival times without increasing toxicity. The results of the ICON4/AGO-OVAR-2.2 trial suggest that this combined treatment approach with a platinum-based doublet shows a survival advantage in patients with relapsed/refractory ovarian cancer [12], which represents a change in the treatment paradigm: prolongation of survival in the second-line setting. One platinum-based doublet that is worthy of consideration in patients with platinum-sensitive ovarian cancer is carboplatin and pegylated liposomal doxorubicin. This combination has been studied in several clinical trials, the results of which are summarized in Table 4. Pegylated liposomal doxorubicin was studied in combination with carboplatin in a GINECO phase II trial in patients with advanced ovarian cancer in late relapse (treatment-free interval >6 months) who were treated with one or two previous platinum- and taxane-based regimens (n = 105) [36]. Based on the results of a previous phase I study, patients were treated with carboplatin at an area under the concentration time curve (AUC) of 5 on day 1 and pegylated liposomal doxorubicin 30 mg/m 2 on day 1 every 4 weeks (dose intensity, 7.5 mg/m 2 weekly). An overall response rate of 63% was observed, with a CR rate of 38%. Median progression-free survival was 9 months, and median overall survival was 33 months. When stratified by therapy-free interval, PLD dose intensity Study/Population Maximum tolerated dose (mg/m 2 per week) Toxicity ORR Ferrero, 2004 (n = 105); Pegylated liposomal doxorubicin 7.5 Grade 3/4 toxicities primarily 63.0% advanced OC in late relapse 30 mg/m 2 on day 1 + carboplatin hematologic; necessitated dose (>6 months) and 1 or 2 prior AUC 5 on day 1 every 4 weeks reductions in 27% of patients platinum regimens [36] Vorobiof, 2004 (n = 32); Pegylated liposomal doxorubicin 12.5 Grade 3/4 toxicities primarily 62.5% relapsed platinum-sensitive 50 mg/m 2 + carboplatin AUC 5 hematologic; grade 3 HFS in OC (DFI >6 months) [37] every 4 weeks two patients D Agostino, 2002 (n = 23); Pegylated liposomal doxorubicin 11.7 Severe leukopenia and/or 21.7% relapsed OC, 18/23 patients 35 mg/m 2 on day 1 + gemcitabine thrombocytopenia (25%) with platinum/paclitaxel- 800 mg/m 2 on days 1 and 8 every refractory/resistant disease [38] 28 days Tobias, 2000 (n = 17); recurrent Pegylated liposomal doxorubicin 6.25 Grade 4 thrombocytopenia (n = 1); 43.0% or persistent OC (platinum 25 mg/m 2 on day 1 + gemcitabine no other hematologic toxicities sensitivity unknown) [39] 650 mg/m 2 on days 1 and 8 every noted 28 days Holloway, 2004 (n = 25); Pegylated liposomal doxorubicin 8.3 Grade 3/4 toxicities mostly 64.0% current OC, 17/25 patients 25 mg/m 2 on day 1 + gemcitabine hematologic; HFS in three with platinum-sensitive 650 mg/m 2 on days 1 and 8 patients disease [40] every 21 days Campos, 2003 (n = 40); Pegylated liposomal doxorubicin 7.9 Grade 3/4 neutropenia (n = 16); 29.0% recurrent Müllerian tumors, 30 mg/m 2 on day 1 every 21 days grade 3/4 HFS (n = 21) 10/40 patients with platinum/ + paclitaxel 70 mg/m 2 weekly taxane-resistant disease [41] Abbreviations: AUC = area under the curve; DFI = disease-free interval; HFS = hand-foot syndrome; OC = ovarian cancer; ORR = objective response rate; PLD = pegylated liposomal doxorubicin

7 211 Optimal Dosing of Pegylated Liposomal Doxorubicin median progression-free survival (p =.001) and overall survival (p =.006) were significantly longer in patients with a therapy-free interval 12 months compared with those with a therapy-free interval <12 months. The most common toxicities with this combination were hematologic in nature, with no reports of grade 3/4 HFS. Although it is difficult to compare results from studies with dissimilar patient populations and study designs, Ferrero and colleagues performed an indirect comparison between their results and those reported from the ICON4/AGO- OVAR-2.2 trial [12] to place their results in the context of current clinical practice [36]. Patients in the GINECO study were a more difficult-to-treat population, as all had been treated with at least one prior platinum- and taxane-based regimen. This population represents the majority of patients in the U.S. with relapsed ovarian cancer, as first-line standard of care is platinum/taxane combination therapy. Despite having poorer characteristics, patients treated with carboplatin and pegylated liposomal doxorubicin in the GINECO study had similar response and survival rates compared with patients treated with platinum/paclitaxel in the ICON4/AGO-OVAR- 2.2 study. In terms of tolerability, the rates of grade 2 alopecia and neurotoxicity were lower with the carboplatin and pegylated liposomal doxorubicin combination. The platinum-based doublet of carboplatin and pegylated liposomal doxorubicin has been studied further in a prospective, multicenter phase II study in 32 patients with relapsed, platinum-sensitive ovarian cancer (disease-free interval >6 months) [37]. The dosage regimen used in this study, which was based on prior phase I trials, stretches the dose intensity of pegylated liposomal doxorubicin, particularly as combination therapy. Patients in the study received carboplatin AUC 5 and pegylated liposomal doxorubicin 50 mg/m 2 every 4 weeks (dose intensity, 12.5 mg/m 2 weekly). Response was similar to that observed in the GINECO study, with an overall response rate of 62.5% and a CR rate of 37.5%. At the time of analysis, median time to treatment failure and overall survival were >287 days (range, days) and >436 days (range, days), respectively. Toxicities were manageable in an outpatient setting: 50% of patients experienced HFS during therapy, but grade 3 HFS occurred in only 6% of patients, and there was no grade 4 HFS reported. The results from this study further support those of the GINECO study, providing rationale for the use of carboplatin and pegylated liposomal doxorubicin doublet therapy in patients with relapsed platinum-sensitive ovarian cancer. Although a higher dose of pegylated liposomal doxorubicin was used in the present study compared with the GINECO study, similar response rates were observed, suggesting that a lower dose intensity of pegylated liposomal doxorubicin may be used in this combination without compromising efficacy. Pegylated liposomal doxorubicin also has been studied in combination with other nonplatinum agents, such as gemcitabine, in patients with relapsed ovarian cancer (Table 4). A phase I study was conducted to determine the maximum tolerated doses of combined treatment with pegylated liposomal doxorubicin and gemcitabine in patients with relapsed ovarian cancer [38]. The majority of patients (18/23) had platinum/paclitaxel-refractory/resistant disease. Initially, pegylated liposomal doxorubicin was administered at a dose of 20 mg/m 2 on day 1 in combination with gemcitabine 600 mg/m 2 on days 1 and 8 every 21 days. Planned dose levels were 20/800 mg/m 2 ; 20/1,000 mg/m 2 ; 30/800 mg/m 2 ; 30/1,000 mg/m 2 ; 35/800 mg/m 2, and 35/1,000 mg/m 2 for pegylated liposomal doxorubicin and gemcitabine, respectively. The maximum tolerated dose was pegylated liposomal doxorubicin 35 mg/m 2 plus gemcitabine 800 mg/m 2 every 21 days (pegylated liposomal doxorubicin dose intensity, 11.7 mg/m 2 per week), with febrile neutropenia and thrombocytopenia as the dose-limiting toxicities. Nonhematologic toxicities were mild and manageable. Among the 23 patients evaluated, five patients had PRs (21.7%; 95% CI: ), five had stable disease (21.7%, 95% CI: ) and 13 had progressive disease (56.6%, 95% CI: ). In another phase I dose-evaluation study conducted by Tobias and colleagues, patients with recurrent or persistent ovarian cancer received gemcitabine 800 mg/m 2 on days 1 and 8 and pegylated liposomal doxorubicin 30 mg/m 2 on day 1 every 28 days [39]. Patients were entered at escalating doses until dose-limiting toxicities occurred, defined as either grade 4 hematologic or grade 3/4 nonhematologic toxicities. A total of 17 patients were enrolled (platinum sensitivity unknown), all of whom had received at least one prior platinum-containing regimen, with a median of 2.5 prior regimens (range, 1-8 regimens). In the first dose cohort, three patients experienced grade 3/4 hematologic toxicities, precluding the day-8 gemcitabine dose. The gemcitabine dose was reduced to 650 mg/m 2 ; however, the occurrence of grade 3 stomatitis in the two patients treated at this dose level resulted in further modification of the combined regimen. Eight patients were subsequently treated with gemcitabine 650 mg/m 2 on days 1 and 8 in combination with pegylated liposomal doxorubicin 25 mg/m 2 every 28 days (mean dose intensity, 6.25 mg/m 2 per week). The reduction in pegylated liposomal doxorubicin dose intensity resulted in improved tolerability. At this dose level, one patient developed grade 4 thrombocytopenia, but no other cases of grade 4 hematologic or grade 3/4 nonhematologic toxicities occurred. In this heavily pretreated population, the response rate was 43%; five patients had a CR, one had a PR, five had stable disease, and three had progressive disease. This combination was further evaluated in a phase II study conducted by Holloway and colleagues in which patients

8 Rose 212 received gemcitabine 650 mg/m 2 on days 1 and 8 and pegylated liposomal doxorubicin 25 mg/m 2 on day 1 every 21 days (pegylated liposomal doxorubicin dose intensity, 8.3 mg/m 2 weekly) [40]. Most patients enrolled in this study (17/25) had platinumsensitive disease. Toxicities were manageable, and an overall response rate of 64% was observed. Taken together with the results of the phase I studies described above, these findings indicate that combination chemotherapy with pegylated liposomal doxorubicin and gemcitabine is effective for ovarian cancer, even in patients whose prognosis is extremely poor. Combined treatment with pegylated liposomal doxorubicin and paclitaxel has been examined in patients with recurrent müllerian gynecologic tumors (Table 4) [41]. In this phase II study, 40 patients initially received pegylated liposomal doxorubicin 30 mg/m 2 every 21 days plus paclitaxel 70 mg/m 2 weekly for 18 weeks. The median platinum-free interval was 7 months; two patients were paclitaxel naïve, and 10 patients had platinum/taxane-resistant disease. Four patients had a CR to treatment, and an additional seven patients experienced PRs, for an overall objective response rate of 29% among the 38 evaluable patients. As expected, the response rate was considerably higher (54%) among the 13 women whose tumors had recurred more than 6 months after prior platinum-based treatment. With respect to tolerability, pegylated liposomal doxorubicin and paclitaxel were administered at 77% (7.65 mg/m 2 per week) and 95% (66.4 mg/m 2 per week) of their intended weekly dose intensities, respectively. Of note, the majority of pegylated liposomal doxorubicin dose reductions were due to the occurrence of HFS. Clearly, the administration of chemotherapeutic agents in combination requires the use of lower doses than typically used with either agent alone. The results of these studies suggest that combined schedules utilizing a dose intensity of <12 mg/m 2 per week of pegylated liposomal doxorubicin are associated with more favorable tolerability profiles. Vorobiof and colleagues stretched the dose intensity of pegylated liposomal doxorubicin (12.5 mg/m 2 weekly) in combination with carboplatin without a noticeable increase in efficacy compared with that observed in the GINECO study using a lower dose intensity (7.5 mg/m 2 weekly). SUMMARY AND CONCLUSIONS Data suggest that nearly three quarters of patients with platinum-resistant ovarian cancer die in less than 12 months from documented platinum and taxane resistance [23]. Therefore, it is extremely important to select the most effective and well-tolerated agent for patients with resistant ovarian cancer. Clinical trials have documented that pegylated liposomal doxorubicin is effective and well tolerated as single-agent therapy for patients with relapsed ovarian cancer, even in patients with platinum- and paclitaxel-resistant disease [14-16]. Moreover, long-term follow-up of a phase III randomized trial demonstrated that overall survival was significantly longer in patients randomized to treatment with pegylated liposomal doxorubicin compared with topotecan, with an 18% reduction in the risk of death [28]. The most common adverse events associated with pegylated liposomal doxorubicin treatment HFS and stomatitis are schedule and dose dependent, respectively, and do not typically lead to discontinuation of therapy. Researchers have investigated the use of various doses and schedules of pegylated liposomal doxorubicin in an effort to improve tolerability while maintaining antitumor efficacy. The optimal level of dose intensity appears to range from 10 mg/m 2 to 12.5 mg/m 2 per week (given at doses of mg/m 2 every 4 weeks) when used as single-agent therapy, as dosing schedules utilizing a greater dose intensity have demonstrated substantially higher rates of toxicity. In addition, the use of pegylated liposomal doxorubicin in combined treatment regimens (specifically, with carboplatin, gemcitabine, or paclitaxel) is best accomplished by reducing the dose intensity of both agents to avoid toxicities while maintaining or improving antitumor efficacy. Pegylated liposomal doxorubicin has shown particular promise in combination with carboplatin in patients with platinum-sensitive ovarian cancer, with overall response rates of 63% and CR rates of 38%. In conclusion, pegylated liposomal doxorubicin is currently indicated at a dose of 50 mg/m 2 every 4 weeks; however, the literature supports the use of 40 mg/m 2 every 4 weeks (or a dose intensity of 10 mg/m 2 per week) to optimize clinical efficacy and minimize the occurrence of schedule- and dose-related adverse events in patients with recurrent/relapsed ovarian cancer [29-32, 35]. Given the chronic course of ovarian cancer, the improved safety profile of pegylated liposomal doxorubicin 40 mg/m 2 combined with a convenient once-monthly dosing schedule may translate into an improved quality of life for patients with advanced ovarian cancer. REFERENCES 1 Jemal A, Murray T, Ward E et al. Cancer statistics, CA Cancer J Clin 2005;55: Memarzadeh S, Berek JS. Advances in the management of epithelial ovarian cancer. J Reprod Med 2001;46: Ozols RF, Schwartz PE, Eifel PJ. Ovarian cancer, fallopian tube carcinoma, and peritoneal carcinoma. In: DeVita VT, Hellman S, Rosenberg RA, eds. 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10 Rose Perez AT, Domenech GH, Frankel C et al. Pegylated liposomal doxorubicin (Doxil ) for metastatic breast cancer: the Cancer Research Network, Inc., experience. Cancer Invest 2002;20(suppl 2): Sehouli J, Katsares I, Oskay-Oezcelik G et al. Biweekly schedule of pegylated liposomal doxorubicin (PLD) induces low rates of skin toxicities: results of a phase-ii trial in heavily pretreated patients with relapsed ovarian cancer (ROC). Proc Am Soc Clin Oncol 2004;23:467s. 36 Ferrero JM, Weber B, Lepille D et al. Carboplatin (PA) and pegylated liposomal doxorubicin (CA; PACA regimen) in patients with advanced ovarian cancer in late relapse (>6 months) (AOCLR): results of a GINECO phase II trial. Proc Am Soc Clin Oncol 2004;23:454s. 37 Vorobiof DA, Rapoport BL, Slabber CF et al. Phase 2 study of combination therapy with liposomal doxorubicin and carboplatin in patients with relapsed, platinum sensitive ovarian cancer. Proc Am Soc Clin Oncol 2004;23:471s. 38 D Agostino G, Ferrandina G, Garganese G et al. Phase I study of gemcitabine and liposomal doxorubicin in relapsed ovarian cancer. Oncology 2002;62: Tobias D, Runowicz C, Mandeli J et al. A phase I trial of gemcitabine and Doxil for recurrent epithelial ovarian cancer. Proc Am Soc Clin Oncol 2000;19:392a. 40 Holloway RW, Finkler NJ, Nye LP et al. Doxil and gemcitabine combination therapy for recurrent ovarian cancer: results of a phase II trial. Proc Am Soc Clin Oncol 2004;23:471s. 41 Campos SM, Matulonis UA, Penson RT et al. Phase II study of liposomal doxorubicin and weekly paclitaxel for recurrent Mullerian tumors. Gynecol Oncol 2003;90: ADDITIONAL READING Gabizon AA. Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy. Cancer Invest 2001;19: Harries M, Gore M. Part II: chemotherapy for epithelial ovarian cancer treatment of recurrent disease. Lancet Oncol 2002;3: Stebbing J, Gaya A. Pegylated liposomal doxorubicin (Caelyx) in recurrent ovarian cancer. Cancer Treat Rev 2002;28: