|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2000 American Society for Clinical Oncology Phase II Study of Liposomal Doxorubicin in Platinum- and Paclitaxel-Refractory Epithelial Ovarian CancerFrom the Physicians Reliance Network, Dallas, TX; Women’s and Infants Hospital, Providence, RI; University Hospitals, Cleveland, OH; The Sarah Cannon Cancer Center, Nashville, TN; Arizona Cancer Center, Tucson, AZ; Capital District Hematology Oncology, Latham, NY; and Alza Corporation, Palo Alto, CA. Address reprint requests to Alan N. Gordon, MD, Texas Oncology, PA, 3535 Worth St, Suite S-200, Dallas, TX 7524; email alan.gordon @usoncology.com.
PURPOSE: Stealth liposomal doxorubicin (Alzal Corp, Palo Alto, CA) has a slower clearance rate than free doxorubicin, resulting in sustained serum levels. Liposomal encapsulation also leads to increased concentration of drug in tumor tissue. Meta-analysis of previous studies has shown that doxorubicin has activity in epithelial ovarian cancer. The current study was developed to examine the activity of Stealth liposomal doxorubicin in platinum- and paclitaxel-refractory ovarian cancer. PATIENTS AND METHODS: Patients had epithelial ovarian cancer that either progressed on or recurred within 6 months of completion of platinum and paclitaxel chemotherapy. All patients had measurable disease. Stealth liposomal doxorubicin was administered at 50 mg/m2 every 4 weeks as a 1-hour infusion. RESULTS: Eighty-nine patients were treated and included in an intent-to-treat analysis. There were 82 patients who were platinum and paclitaxel refractory and met all study criteria. There was one complete response and 14 partial responses, for a total response rate of 16.9% (95% confidence interval [CI], 9.1% to 24.6%). For platinum- and paclitaxel-refractory patients, the response rate was 18.3% (95% CI, 9.9% to 26.7%). Median time to progression was 19.3 weeks for the entire population. Ten patients (11.2%) withdrew because of adverse events related to the drug (palmar-plantar erythrodysesthesia [PPE], n = 3; asthenia, n = 2; cardiac, n = 2; neutropenia, n = 1; stomatitis, n = 1; and edema, n = 1). There were no drug-related fatal events. There were only eight grade 4 adverse events attributable to the drug. Stomatitis, PPE, and skin lesions were managed with dose reductions and delays in most cases. CONCLUSION: Stealth liposomal doxorubicin has activity in refractory epithelial ovarian cancer. PPE and stomatitis can usually be managed by dose adjustment. The ease of administration makes this an attractive agent.
OVARIAN CANCER represents the leading cause of death from gynecologic malignancies in the United States and Western Europe. Approximately 25,200 new cases and 14,500 deaths as a result of the disease are estimates for the United States for 1999.1 The vast majority of patients initially present with advanced-stage disease, which contributes to the high mortality rates.2 Despite aggressive cytoreduction and multiagent chemotherapy, most patients eventually relapse and die from progressive disease. Paclitaxel was found to have activity in patients with platinum-resistant recurrent epithelial ovarian cancer.3 The subsequent introduction of paclitaxel into front-line therapy has resulted in significantly improved progression-free survival and overall survival when compared with the previous standard of cyclophosphamide- and platinum-based therapy.4 However, most patients will still eventually develop recurrence and die of disease, despite front-line therapy with paclitaxel and a platinum agent. Several agents have demonstrated activity after failure of paclitaxel-containing regimens.5-7 Response rates have been in the 10% to 30% range and have generally been of modest duration. Typically, even lower response rates have been seen in patients who have initially been refractory to front-line chemotherapy or developed recurrence within 6 months of completing chemotherapy.5,6 There is still a need for newer, non–cross-resistant agents to be tried in cases of failure after front-line platinum- and paclitaxel-based therapy. Doxorubicin has shown modest activity in early trials against epithelial ovarian cancer.8 Several trials compared the then standard cyclophosphamide and platinum therapy with and without the addition of doxorubicin.9-12 Independently, all failed to show any significant improvement with the addition of doxorubicin. In all of the studies, a higher incidence of complications was also noted because of the addition of the third agent. Recently, a meta-analysis of these randomized trials was able to demonstrate a modest but significant 7% improvement in survival in the doxorubicin-containing arms.13 This analysis has rekindled interest in the possible use of doxorubicin in ovarian carcinoma. Liposomal encapsulation of doxorubicin results in significantly altered pharmacokinetics for the drug. Infusion of liposomal doxorubicin results in plasma area under the curve levels that are greater than that found from infusion of conventional doxorubicin.14 However, the volume of distribution is limited to the vascular volume and the plasma clearance is markedly reduced, resulting in prolonged sustained serum levels similar to a prolonged infusion of doxorubicin.14,15 The use of a pegylated (polyethylene glycol–coated form of liposome known as Stealth) liposomal doxorubicin (Doxil; Alza Corporation, Palo Alto, CA) results in even further advantages. The Stealth liposome prevents significant uptake and release of doxorubicin by the spleen and reticuloendothelial system.16 The size of the liposome also tends to prevent leakage out of the vascular system, however, in areas where capillaries may have leaky membranes, such as tumors. The liposomes are able to leak out, and subsequent disruption by macrophages leads to local release of doxorubicin.16 The accumulation of doxorubicin in tumors has been demonstrated in biopsy specimens of Kaposi’s sarcoma that had been treated with Stealth liposomal doxorubicin.17 In initial phase I studies, an 8-month partial response was seen in a patient who had advanced ovarian cancer that had been unresponsive to several different chemotherapy regimens.18 An early phase II salvage study of single-agent liposomal doxorubicin was conducted, and a 26% response rate was seen in a group of heavily pretreated patients.19 To more fully evaluate the activity of liposomal doxorubicin in epithelial ovarian cancer, a phase II study was developed. In the present report, we describe the results of a phase II study of liposomal doxorubicin in patients with recurrent ovarian cancer that were either refractory or resistant to paclitaxel- and platinum-based therapy.
Eligibility Criteria Patients were required to have histologically proven epithelial ovarian cancer with measurable disease defined as a bidimensionally measurable lesion(s) with clearly defined margins on x-ray with at least one diameter  0.5 cm, or on computed tomography scan or MRI with both diameters more than the distance between cuts, or palpation with both diameters 2 cm. Initially, no more than two prior regimens were allowed. A later amendment allowed for at least two but no more than three prior regimens to include patients who had failed topotecan therapy. Patients were to have been taxane- and platinum-refractory defined as progression on chemotherapy or within 6 months of completion. A Karnofsky performance status of 60% was required along with age 18 years. Patients were required to have adequate bone marrow function defined as platelets 100,000/µL, hemoglobin 9 g/dL, and an absolute neutrophil count (ANC) 1,500 cells/µL. Adequate renal function was defined as creatinine  2.5 mg/dL, adequate liver function (AST and ALT two times the upper limit of normal, alkaline phosphatase two times the upper limit of normal unless caused by tumor, and bilirubin the upper limit of normal). All patients were required to undergo left ventricular ejection fraction by a multigated angiogram (MUGA) scan and have a value 50% within 30 days of the first dose of the study drug. Patients were to be disease-free from prior malignancies for 5 years, with the exception of basal cell carcinoma of the skin or carcinoma-in-situ of the cervix. An informed consent was required, and the protocol received approval from all local institutional review boards.
Patients were to be excluded in the event of pregnancy or breast feeding or if they had a life expectancy of
Study Design On day 1 of each cycle, patients would receive liposomal doxorubicin at a dose of 50 mg/m2. Liposomal doxorubicin was supplied in vials containing 20 mg of doxorubicin hydrochloride at a concentration of 2 mg/mL. Vials were stored in a refrigerator between 2°C and 8oC. Doses of less than 90 mg were to be diluted in 250 mL of dextrose 5% in water, and doses more than 90 mg were to be diluted in 500 mL of dextrose 5% in water. Diluted liposomal doxorubicin was to be kept refrigerated between 2°C and 8°C and administered within 8 hours of mixing. The drug was administered by intravenous infusion over 1 hour. Infusion could be given through a peripheral or a central line. Cycles were planned for 28-day intervals. After administration of chemotherapy, weekly CBCs were obtained and patients were monitored for adverse events. Before each new cycle, a complete interval history and physical examination along with a repeat CBC, serum chemistries, and a CA-125 were performed. Repeat radiologic assessments were obtained after every two cycles or 8 weeks. If a total anthracycline dose of 300 mg/m2 was reached, a MUGA scan was repeated, and this would be repeated after every additional 100-mg/m2 additional dose. At the completion of treatment, 4 weeks after the last dose, patients again would undergo a complete physical examination, CBC, repeat serum chemistries, CA-125, and urinalysis. Liposomal doxorubicin was to be administered every 4 weeks for six cycles or until disease progression or dose-limiting toxicity occurred. Patients who were receiving clinical benefit after six cycles were allowed to continue therapy. Therapy was to be suspended or discontinued if disease progression occurred or if the patient could not tolerate therapy despite dose adjustment. Patients who required radiation therapy were removed from treatment during radiation or 30 days thereafter but could be retreated. If the left ventricular injection fraction declined to less than 45% or decreased by 20% from the baseline value, treatment was to be suspended. Any patient wishing to withdraw could do so at anytime. The use of prophylactic cytokines was not allowed. However, patients developing prolonged grade 4 neutropenia (ANC < 500/µL lasting for more than 7 days, failure of the ANC to recover within 22 days, or because of febrile neutropenia) were allowed to receive cytokines with subsequent therapy. Patients who developed grade 4 thrombocytopenia would be treated on resolution to grade 1 and were to have a 25% dose reduction in subsequent cycles. An increase in total bilirubin up to 3 mg/dL would require a subsequent 25% dose reduction. Increases over 3 mg/dL that were secondary to liposomal doxorubicin would require discontinuation of therapy. For most other grade 3 and 4 events, a 25% dose reduction of liposomal doxorubicin was recommended. Guidelines for dose delays and reductions were developed for palmar-plantar erythrodysesthesia (PPE) or stomatitis (Table 1).
Response classifications were based on the same methodology as a baseline. A complete response was defined as a complete disappearance of all measurable and assessable disease. No new disease or disease-related symptoms were allowed. A partial response required a 50% or greater decrease in the sum of the products of all bidimensionally measurable lesions. There was to be no progression of any assessable disease and no new lesions. All responses had to be confirmed by a second measurement 4 weeks later. Progressive disease was defined as a 50% or greater increase in the sum of the products of bidimensionally measurable lesions. The reappearance of any lesion or clear worsening of assessable disease or the appearance of any new lesion was also considered progressive disease. All other patients were classified as stable disease. Accrual was conducted in two stages to allow for early termination because of lack of efficacy. Initially, 25 assessable patients were to enroll, and if three or fewer responders were detected, further study of liposomal doxorubicin would be terminated. The chance of the drug being rejected (having a less than 22% rate of activity) would have been less than 5%. If at least four responders were seen in stage I, 20 additional patients would be evaluated. If more than eight of 53 assessable patients were determined to have a response, the probability of a response rate of at least 22% had an alpha of 0.0457, with a power of 85%.
Ninety patients enrolled in the study as of February 2, 1998. Eighty-nine patients received liposomal doxorubicin therapy and are included in intent-to-treat analysis. One enrolled patient withdrew before receiving any study medication. There were seven patients (7.7%) who were not included in the group of patients who were double refractory to platinum and paclitaxel. Three of these patients did not have measurable or histopathologically confirmed disease at baseline, and four patients did not meet the strict definition of double refractory. Thirty-three (37.1%) of the 89 patients had also failed prior treatment with topotecan. The patient demographics are listed in Table 2. The median age was 61 years (range, 38 to 85 years), and the median performance status was 90% (range, 60% to 100%). The median number of prior chemotherapy regimens was two. Carboplatin was used in 76 patients (85.4%), and cisplatin was given to 40 patients (44.9%).
Within the intent-to-treat population, there was one complete and 14 partial responders, for an overall response rate of 16.9% (95% confidence interval, 9.1% to 24.6%). All responders had received two or more cycles and were refractory to both platinum and paclitaxel. Therefore, the response rate was 18.3% (95% confidence interval, 9.9% to 26.7%) for the platinum/paclitaxel refractory patients. One additional patient had a partial response; however, this was not confirmed within the 1-month period, and she was therefore classified as a nonresponder. Nineteen patients failed to have an evaluation for response, and 17 of these patients had fewer than two cycles. All of these patients were considered nonresponders. Response rates are listed in Table 3. Patients who failed to complete a response evaluation (n = 19) or received less than one cycle were considered to have progressive disease. The response rates of the 82 double-refractory patients were analyzed by time of progression from previous therapy. There was a 15% response rate (six of 40 patients) in patients who progressed while on treatment compared with a 17.6% response rate (three of 17 patients) in those who progressed 3 months after completing treatment and a 24% response rate (six of 25 patients) in those who progressed from 3 months to within 6 months after prior platinum-based therapy. Although there does seem to be a trend, this is not statistically significant. There were six responses (including the one complete responder) in the 33 patients who were classified as triple refractory (refractory to platinum, taxane, and topotecan), for a response rate of 18.2%.
The median time to response was 15.4 weeks (range, 3.3 to 32.9 weeks). The median duration of response was 24.1 weeks (range, 4.6+ to 48.3 weeks). Median time to progression for the intent-to-treat population was 19.3 weeks (range, 0.7 to 86 weeks); whereas for the platinum/paclitaxel-refractory population, the median time to progression was 17 weeks (range, 0.7 to 71.6 weeks). There were 36 assessable patients (57.1%) who were classified as having stable disease as their best response. These patients had long periods of treatment before documentation of progressive disease, with a median of 21.9+ weeks of therapy. There were 389 cycles of treatment for 89 patients, giving an average of 4.4 cycles per patient. Seventeen patients (19.1%) received fewer than two cycles of liposomal doxorubicin. The mean cumulative dose was 211.16 mg/m2 (median, 150 mg/m2), with a range from 50 mg/m2 to 808.4 mg/m2. Twenty-eight patients (31.5%) received more than 300 mg/m2, and nine (10.1%) received more than 450 mg/m2. Thirty-nine patients (43.8%) required some form of dose delay, reduction, or interruption, affecting 118 (30.3%) of the total cycles. Adverse events or toxicity accounted for just over half (54.2%) of these dose modifications. Hematologic toxicity accounted for 28 cycles, PPE accounted for 25 cycles and stomatitis for six cycles. Four cycles (3.4%) were interrupted because of an infusion reaction, and one cycle was modified because of laboratory toxicity. Fifty-two cycles were altered for other reasons, which generally was continuation of a previous dose reduction or delay. In most cases of dose modification caused by hematologic toxicity or PPE, doses were delayed by 1 or 2 weeks, with only more severe cases requiring dose reduction (as outlined in the management schema, Table 1). This allowed most patients to receive close to the full dose (mean dose was 49.67 mg/m2), although the median cycle length was 30 days compared with a specified 28-day cycle. Fifteen patients (16.9%) terminated the study because of adverse events, and one (1.1%) patient was lost to the follow-up. Forty-two patients (47.2%) terminated the study because of progression of disease. Eighteen patients (20.2%) terminated the study because of various other reasons. Of the 15 patients who discontinued because of adverse events, five had events that were believed to be unrelated to the study drug and 10 withdrew because of events that were felt to be related to the drug. These included grade 3 PPE (three patients), grade 3 asthenia (two patients), grade 4 neutropenia (one patient), and grade 4 stomatitis (one patient). One additional patient developed severe edema of the hands and feet. Two patients discontinued therapy because of adverse cardiac events (one grade 1 and one grade 3). A 50-year-old patient with no cardiac history had a baseline ejection fraction of 72%; after six cycles, she had a decrease in ejection fraction to 59% without any cardiac signs or symptoms and was removed from the study by the investigator. An 86-year-old patient with no cardiac history had a baseline ejection fraction of 53%; an echocardiogram 2 weeks after cycle 2 showed a decrease to 45%, with mild to moderate left ventricular function. One week later, she had an episode of dyspnea and orthopnea and was removed from study. She died from progressive disease 18 days later without any further cardiac symptoms. Forty-six patients (51.7%) died either on study or during the follow-up period; 45 of the deaths were a result of disease progression, and one was attributed to a complication of surgery to relieve a bowel obstruction. There were no treatment-related deaths. All patients reported at least one adverse event. The percentage of patients with adverse events and those believed to be related to the study drug are listed in Table 4. Asthenia and PPE were the two most common adverse events related to the study drug and were seen in 41.6% of the patients. Skin toxicity extending beyond the palmar-plantar areas was experienced by some patients, primarily stomatitis (34.8%) and rash (29.2%). Although nausea was the most common adverse event reported in 50 of the patients (60.7%), it was felt to be related to liposomal doxorubicin use in only 34 patients (38.2%). There were no reports of total alopecia, with mild hair thinning reported by eight patients (9%). Overall, grade 4 adverse events were seen in 18 patients (20.2%), and grade 3 events were noticed in 63 patients (70.8%). Of all adverse events, only eight grade 4 (0.9%) and 80 grade 3 (9%) events were believed to be caused by liposomal doxorubicin. Hematologic toxicity was generally of short duration and easily managed. Stomatitis, PPE, and skin lesions were managed by dose reductions and delays as needed. Only one patient, an 86-year-old woman who entered the study with a left ventricular ejection fraction of 53%, experienced grade 3 left ventricular dysfunction (discussed above), and this patient also had a 15% decrease in ejection fraction. Overall, three patients had an asymptomatic 20% decrease in ejection fraction; one patient had discontinued after two cycles because of PPE and was found on study at completion, one patient had completed nine cycles (450 mg/m2) and was found on follow-up study, and the previously described 50-year-old patient with no cardiac history completed six cycles. A 79-year-old patient, with no prior cardiac history and a baseline ejection fraction of 80%, received a single cycle of liposomal doxorubicin. Two weeks later she developed a small bowel obstruction with ascites later developed angina with pulmonary edema and clinical congestive heart failure with positive sputum cultures for Klebsiella pneumoniae. Because of the timing, an association with liposomal doxorubicin could not be excluded for this grade 2 toxicity. No patient in the study had received prior anthracycline therapy.
Paclitaxel and platinum combination therapy have become standard first-line therapy for ovarian cancer after the report of McGuire et al4 and confirmation by the European Organization for Research and Treatment of Cancer Intergroup study.20 Despite the high response rates to first-line therapy, the majority of patients will eventually relapse. There continues to be a need for new effective non–cross-resistant agents to be used as second-line therapy for failure or recurrence after paclitaxel and platinum. Topotecan has demonstrated an overall response rate of 13.7%, with a response rate of 12.4% in platinum-resistant patients.5 Oral etoposide also has been shown to be active, with a 26.8% response rate in platinum-resistant patients.6 Gemcitabine also has been reported to have activity with response rates of 13% and 13.9% in two separate studies.7,21 However, some of the patients in these studies were platinum-sensitive making it difficult to determine the response rate to gemcitabine in platinum-resistant patients. The present study has demonstrated an overall response rate of 16.9% and a response rate of 18.3% in the platinum/paclitaxel-refractory patient population. It is difficult to make direct comparisons of response rates across nonrandomized phase II studies. However, this is similar to the 26.8% response rate in the assessable patients and 20.8% response rate (11 of 53 patients) in the intent-to-treat population for oral etoposide reported by Rose et al6 and is slightly higher than those results reported for topotecan5 or gemcitabine.7,21 Only confirmed responses were included as responders in the present series. This is important because as many as 10% of apparent responses were lost after review in the phase II topotecan study reported by Bookman et al.5 The 18.3% response rate in the platinum/paclitaxel-refractory population in the present series is after an independent outside review and is similar to the 20% confirmed response rate previously reported for liposomal doxorubicin in a salvage setting.19 The current study also has demonstrated activity in patients who were triple refractory, with an 18.2% response rate in patients refractory to platinum, paclitaxel, and topotecan. It should also be noted that 57.1% of patients were classified as having stable disease after a median of 29.1 weeks of therapy. This compares favorably with a stable disease rate of 27.3% lasting at least 8 weeks reported for topotecan.5 The median time to response of 15.4 weeks would require continuation of chemotherapy for at least four cycles in the absence of toxicity or disease progression. A similar need is seen in therapy with topotecan, with a median time to response of 12.1 weeks.5 The median duration of response and time to progression of 24.1 weeks and 19.3 weeks, respectively, are similar to those reported for topotecan (18.1 and 12.1 weeks, respectively)5 and for etoposide in platinum-resistant patients (17.2 and 22.8 weeks, respectively).6 The median progression-free interval of 19.3 weeks in the current study is also similar to the 5.7-month progression-free interval reported by Muggia et al19 in a salvage setting. A randomized phase III study comparing liposomal doxorubicin with topotecan is currently being completed. However, the activity of liposomal doxorubicin seems to be similar to that reported for other active agents. All patients reported adverse events. However, only 18 patients (20.2%) experienced a grade 4 adverse event, and 63 (70.8%) experienced a grade 3 adverse event. Only eight (0.9%) of grade 4 and 80 (9%) of grade 3 events were felt to be related to the liposomal doxorubicin. PPE and asthenia accounted for the two most common side effects attributable to liposomal doxorubicin, each occurring in 37 patients (41.6%). No patient exhibited grade 4 PPE or asthenia, and only three patients withdrew from the study because of PPE and two patients because of grade 3 asthenia. Stomatitis and other cutaneous reactions were frequently seen and felt to be secondary to liposomal doxorubicin, but grade 4 changes were uncommon. One patient did withdraw because of stomatitis, and one patient withdrew because of severe edema of the hands and feet. PPE, stomatitis, and other cutaneous reactions were usually handled by increasing cycle length or dose reduction, which occurred in 31 cycles (8%) in the current series. Muggia et al19 also found increasing cycle length or dose reduction usually allowed patients to continue therapy. Liposomal doxorubicin was well tolerated, as 28 patients (31.5%) received over 300 mg/m2, and nine patients (10.1%) received over 450 mg/m2, and the average dose per cycle was 49.57 mg/m2 (cycle length was usually increased before dose reductions were used). Neutropenia caused by liposomal doxorubicin was seen in 33 patients (37.1%), but only four cases were grade 4. There was only one case of febrile neutropenia. Only 28 cycles (7%) required a dose modification because of neutropenia. There was only one instance of grade 4 thrombocytopenia, and no deaths attributable to the study drug occurred during the present study. This contrasts sharply with the degree of neutropenia associated with topotecan. Bookman et al5 reported that grade 4 neutropenia occurred in 82% of patients or 34% of courses. He also reported infectious complication in 6% of courses, although there were no deaths attributable to topotecan, and grade 4 thrombocytopenia in 30% of patients or 9% of courses.5 Rose et al6 also reported that hematologic toxicity occurred frequently with oral etoposide. Grade 4 neutropenia occurred in 25% of patients, grade 4 thrombocytopenia occurred in 4%, and three treatment-related deaths occurred (two from neutropenic sepsis and one from thrombocytopenic bleeding). Hematologic toxicity was also the dominant toxicity for gemcitabine, with 5% of patients exhibiting grade 4 neutropenia and 5% exhibiting grade 4 thrombocytopenia.7 Cardiac toxicity was also uncommon, with only two patients exhibiting an asymptomatic decrease in ejection fraction. The toxicity profile of liposomal doxorubicin is clearly different from standard doxorubicin with a safer profile and decreased hematologic toxicity. Liposomal doxorubicin will make a valuable addition to the armamentarium against epithelial ovarian cancer. The 16.9% response rate in the intent-to-treat population and 18.3% response rate in the population that were refractory to both platinum and paclitaxel is equivalent to the response rates reported for other agents.5,6 The 1-hour infusion schedule every 4 weeks makes this agent easy to administer, and because it is not a vesicant, a central line is not required. The absence of total alopecia and low incidence of nausea and vomiting also make this an attractive agent for administration in this palliative setting. Although PPE occurred in 41.6% of cases, few patients withdrew because of PPE, and most patients were able to continue through the use of dose delays or reductions. The ability to continue therapy without cumulative toxicity in responding and stable patients makes this an attractive agent in recurrent ovarian cancer. Its activity and lack of cross-resistance with platinum and paclitaxel also make it a candidate for incorporation into front-line therapy.
The following investigators and their institutions also participated in the study: Bob Cogbum, St Vincent Infirmary Medical Center; Groesbeck Preer Parham, University of Arkansas for Medical Sciences, Little Rock, AR; Robert Coleman, The University of Texas Southwestern Medical School, Dallas, TX; Salvatore A Del Prete, Hematology Oncology, P.C., Stamford, CT; Louis Fehrenbacher, Kaiser Permanente Medical Center, Vallejo; David Irwin, Alta Bates Comprehensive Cancer Center, Berkeley; Michael Kosty, Scripps Clinic, La Jolla; Edward Wolin, Cedars-Sinai Comprehensive Cancer Center, Los Angeles; Sharon Yee, Arcadia, CA; John T. Fleagle, Rocky Mountain Cancer Center Boulder Valley Oncology, Boulder; David Garfield, Rocky Mountain Cancer Centers, Denver, CO; David Goldberg, Atlanta; Melvin Moore, Decatur, GA; Sarah Lincoln, Rush Presbyterian St Lukes Medical Center, Chicago, IL; John Malfetano, Albany Medical College of Union University, Albany, NY; Vinay Malviya, Southfield, MI; Janes Orr, Patty Berg Cancer Center, Fort Myers, FL; and William A. Peters, Seattle, WA.
Supported by Alza Corporation, Palo Alto, CA.
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1999. CA Cancer J Clin 49: 8-31, 1999 2. Ozols RF, Rubin SC, Thomas GM, et al: Epithelial ovarian cancer, in Hoskins WJ, Perez CA, Young RC (eds): Principles and Practice of Gynecologic Oncology. Philadelphia, PA, Lippincott-Raven, 1997, pp 919-986 3. McGuire WP, Rowinsky EK, Rosenshein NB, et al: Taxol: A unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 111: 273-279, 1989
4.
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 334: 1-6, 1996 5. Bookman M, Malmstrom H, Bolis G, et al: Topotecan for the treatment of advanced epithelial ovarian cancer: An open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol 16: 3345-3352, 1998[Abstract] 6. Rose PG, Blessing JA, Mayer AR, et al: Prolonged oral etoposide as second line therapy for platinum-resistant and platinum sensitive ovarian carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 16: 405-410, 1998[Abstract] 7. Shapiro JD, Millaward MJ, Rischin D, et al: Activity of gemcitabine in patients with advanced ovarian cancer: Responses seen following platinum and paclitaxel. Gynecol Oncol 63: 89-93, 1996[Medline]
8.
A’Hern RP, Gore ME: Impact of doxorubicin on survival in advanced ovarian cancer. J Clin Oncol 13: 726-732, 1995 9. Omura GA, Bundy BN, Berek JS, et al: Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 7: 4457-4465, 1989 10. Gruppo Interregionale Cooperativo Oncologico Ginecologia: Randomized comparison of cisplatin with cyclophosphamide and cisplatin and cyclophosphamide with doxorubicin in advance ovarian cancer. Lancet 2: 353-359, 1987[Medline] 11. Bertelsen K, Jakobsen A, Anderson JE, et al: A randomized study of cyclophosphamide and cisplatin with or without doxorubicin in advanced ovarian cancer. Gynecol Oncol 28: 161-169, 1987[Medline]
12.
Conte PF, Bruzzone M, Chiara S, et al: A randomized trial comparing cisplatin plus cyclophosphamide versus cisplatin, doxorubicin, and cyclophosphamide in advanced ovarian cancer. J Clin Oncol 4: 965-971, 1986 13. Ovarian Cancer Meta-Analysis Project: Cyclophosphamide plus cisplatin versus cyclophosphamide, doxorubicin, and cisplatin chemotherapy of ovarian carcinoma: A meta-analysis. JClin Oncol 9: 1668-1674, 1991[Abstract] 14. Rahman A, Treat J, Roh JK, et al: A phase I clinical trial and pharmacokinetic evaluation of liposome encapsulated doxorubicin. J Clin Oncol 8: 1093-1100, 1990[Abstract] 15. Gabizon A, Catane R, Uziely B, et al: Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer 54: 987-992, 1994 16. Harrington KJ, Gooden CSR, Mohammedtaghi S, et al: Biodistribution and pharmacokinetics of IN-111 labeled Stealth liposomes in patients with solid tumors. Proc Am Soc Clin Oncol 15: 477, 1996 (abstr 1511) 17. Northfelt DW: Stealth liposomal doxorubicin (Doxil) delivers more doxorubicin to AIDS-Kaposi’s sarcoma lesions than to normal skin. Proc Am Soc Clin Oncol 13: 51, 1994 (abstr 5)
18.
Uziely B, Jeffers S, Isacson R, et al: Liposomal doxorubicin (Doxil): Antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 13: 1777-1785, 1995
19.
Muggia FM, Hainsworth JD, Jeffers S, et al: Phase II study of liposomal doxorubicin in refractory ovarian cancer: Antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 15: 987-993, 1997 20. Stuart G, Bertleson K, Mangioni C, et al: Updated analysis shows a highly significant improved overall survival (OS) for cisplatin-paclitaxel as first line treatment of advanced ovarian cancer: Mature results of the EORTC-GCCG, NOCOVA, NCIC CTG and Scottish intergroup trial. Proc Am Soc Clin Oncol 17: 361, 1998 (abstr 1394)
21.
Friedlander M, Millward MJ, Bell D, et al: A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer. Ann Oncol 9: 1343-1345, 1998 Submitted July 29, 1999; accepted May 1, 2000. This article has been cited by other articles:
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
INTRODUCTION
