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© 2002 American Society for Clinical Oncology Phase II Trial of the Pegylated Liposomal Doxorubicin in Previously Treated Metastatic Endometrial Cancer: A Gynecologic Oncology Group StudyByFrom the Department of Medicine, Kaplan Cancer Center, New York University Medical Center, New York, and Gynecologic Oncology Group, Roswell Park Cancer Institute, Buffalo, NY; Division of Gynecologic Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA; and Riverside Methodist Hospital, Columbus, OH. Address reprint requests to Gynecologic Oncology Group Administrative Office, 4 Penn Center, Suite 1020, 1600 John F. Kennedy Blvd, Philadelphia, PA 19103.
PURPOSE: To determine whether pegylated liposomal doxorubicin (PLD) has antitumor activity in pretreated patients with persistent or recurrent endometrial carcinoma and to define the nature and degree of toxicity of PLD. PATIENTS AND METHODS: Women with histologically documented recurrent or persistent measurable endometrial carcinoma and with failure of one prior treatment regardless of prior anthracycline therapy were enrolled. PLD was administered intravenously over a 1-hour period at a dose of 50 mg/m2 every 4 weeks; the dosage was modified in accordance with observed toxicity. RESULTS: Of 46 patients entered, 42 were assessable for response, as three were declared ineligible on central pathology review and one was not assessable for response. Forty had received prior chemotherapy, 11 hormonal therapy, and 29 radiation therapy. Doxorubicin had been given to 32 patients, carboplatin with paclitaxel to six, carboplatin to one, and fluorouracil to one. Four patients had partial responses lasting 1.1, 2.1, 3.3, and 5.4 months; the overall response rate was 9.5% (95% confidence interval, 2.7% to 22.6%). Three of these responses (in liver and in lymph node) occurred in patients who had progressed after doxorubicin with either paclitaxel or cisplatin. The median number of courses was 2.5 (range, one to 14). Toxicity was generally mild: only 25 patients experienced leukopenia, with a median WBC count of 2,900 (range, 800 to 3,900) at nadir. The only grade 4 toxicities were one episode each of esophagitis, hematuria, and vomiting. The median overall survival was 8.2 months. CONCLUSION: PLD has only limited activity in pretreated advanced, recurrent endometrial cancer, but further trials in anthracycline-naive patients and in previously untreated patients are ongoing. Its toxicity profile should permit its use in combination with myelosuppressive drugs.
MOST PATIENTS with endometrial cancer present with localized stages amenable to treatment with surgery. A small percentage of these women have unfavorable features that place them at increased risk for local or distant recurrences. An even smaller percentage are found to have advanced disease with distant metastases when initially diagnosed. Several decades ago, progestational agents were noted to be effective, particularly against pulmonary metastases.1 Unfortunately, patients responding to such treatments are those with well-differentiated tumors that are least likely to metastasize. Postoperative radiation therapy has been found to decrease recurrences in a subset of patients with stage I endometrial cancer2 but not alter their survival. Systemic chemotherapy has been explored in an effort to improve the outcome of those patients with poorly differentiated tumors that have recurred or are destined to metastasize. However, the role of cytotoxic agents remains uncertain because of both efficacy and toxicity considerations. Doxorubicin has been the most frequently studied cytotoxic drug in endometrial cancer, after demonstration of its activity when given alone and in combination.3,4 The Gynecologic Oncology Group (GOG) subsequently established that response rates and progression-free survival after doxorubicin plus cisplatin were superior to those achieved by doxorubicin as a single agent.5 More recently, paclitaxel was established as another active drug (Lincoln et al, manuscript submitted for publication),6 and the results of a study by the GOG comparing doxorubicin plus cisplatin versus doxorubicin plus paclitaxel were recently reported.7 Unfortunately, the therapeutic achievements of these combinations remain modest with regard to improving survival, and the toxicities of the regimens often pose an obstacle for initial or continued treatment with these cytotoxic drugs. Pegylated liposomal doxorubicin (PLD; doxorubicin HCl liposome injection [Doxil, Alza Pharmaceuticals, Palo Alto, CA]) has been documented to have a markedly different pharmacology and toxicity spectrum in relation to the free drug.8 It also has been shown to have antitumor activity against platinum- and paclitaxel-resistant ovarian cancer9 and against previously untreated breast cancer.10 Activity in patients who had previously received doxorubicin suggests that one might overcome resistance with this liposomal formulation.11 This could occur if the amount delivered to the tumor were to be considerably greater than that provided by the free drug or if continued exposure were to result in some advantage in overcoming MDR1 P-glycoprotein–mediated drug efflux as a cause of resistance. Moreover, PLD has the potential advantage of allowing repeated administration with a lesser likelihood of cumulative cardiotoxicity12,13 and, therefore, a greater acceptability by older patients with cardiac risk factors. Accordingly, the GOG initiated a study of PLD in patients with persistent or recurrent endometrial cancer for whom one treatment protocol of higher priority had failed.
Eligible patients had to have histologically confirmed persistent or recurrent endometrial carcinoma and the presence of measurable disease. All epithelial cell types were eligible. The GOG performance status was to be 0, 1, or 2. At least 3 weeks had to elapse from prior therapy, and recovery had to take place from any recent treatment. Patients were required to have adequate organ function as evidenced by WBC count  3,000/µL, granulocyte count 1,500/µL, platelet count 100,000/µL, creatinine level  2.0 mg/100 mL, bilirubin level 1.5 times the institutional normal, and AST and alkaline phosphatase three times the institutional normal. A normal left ventricular ejection fraction by radionuclide multiple-gated acquisition (MUGA) scan was required. Patients had to have received one and only one prior chemotherapy regimen or to have qualified for one prior study for recurrent endometrial cancer. Prior treatment with doxorubicin was allowed, as long as the cumulative dose level was 350 mg/m2. Therefore, patients who entered and completed GOG Protocol 163 (doxorubicin/cisplatin versus doxorubicin/paclitaxel) were eligible to enter this study. No patient could have had a previous or concomitant malignancy with the exception of nonmelanoma skin cancer. Written informed consent was obtained from all patients before entry onto the study, fulfilling all institutional, state, and federal regulations. Pretherapy evaluation included history and physical examination, performance status, tumor measurement(s), complete blood cell count with differential and platelet count, serum creatinine, bilirubin, AST and alkaline phosphatase, chest roentgenogram, ECG MUGA radionuclide heart scan, urinalysis, and serum CA-125 level. Complete blood cell count, differential, and platelet count were repeated weekly, and hematologic toxicity grading was based on nadir counts. The MUGA scan and ECG were repeated when a cumulative dose of 300 mg/m2 was reached, and they were repeated every other cycle of therapy. Blood chemistry analyses were repeated every 4 weeks except for the chest roentgenogram and the CA-125 test, which were repeated if results were initially abnormal. Other tests were repeated as clinically indicated. PLD was administered as a 1-hour infusion at the initial dose of 50 mg/m2 every 4 weeks. Premedication including dexamethasone 20 mg intravenously, together with diphenhydramine 50 mg and cimetidine 300 mg, was recommended during the first and subsequent courses. Subsequent courses of PLD were not administered until the granulocyte count was greater than 1,500/µL, the platelet count was greater than 100,000/µL, and the patient had recovered fully from any nonhematologic toxicity. Dose modification by 25% was based on nadir grade 4 platelets or neutrophils, or any grade 3 or greater nonhematologic toxicity (expected to be primarily skin or mucosal toxicities). Patients were assessable for response after receiving PLD and being observed for at least 4 weeks. Objective responses were defined by standard GOG criteria.14
After at least three objective responses were recorded during the entry of the first 24 patients, the second-stage accrual was opened and completed with 46 entries. Three patients were ineligible: one patient (who actually exhibited a partial response) was disqualified because of a synchronous ovarian primary, and one each with wrong pathology and wrong primary site. One patient was assessable only for toxicity. Thus 42 patients were assessable for response.
Patient Characteristics
Treatment Outcome and Responses The median number of courses was 2.5 (range, one to 14). Four patients achieved a partial response, out of 42 assessable patients (9.5%). Response duration was 1.1, 2.1, 3.3, and 5.4 months. Three of the responses occurred in the 32 patients who had previously received doxorubicin, one of whom had completed seven cycles in GOG 163. The 95% confidence interval for the true response rate in these pretreated patients is 2.7% to 22.6%. One partial response was observed among the eight patients pretreated with nondoxorubicin combination chemotherapy. Table 2 shows the characteristics of the four responders. The number of courses received by responding patients was two, three, 10, and 14. The short response was observed in a patient who preferred to discontinue therapy after only two courses. Twenty-nine percent experienced stable disease for at least two cycles, and the median overall survival was 8.2 months. It is noteworthy that four patients developed brain metastases (two including the cerebellum) during the course of therapy, and four additional patients developed vertebral metastases with neurologic complications in two. One patient had resection of lung metastases, and another had a complete response to subsequent megestrol acetate in a vaginal recurrence arising in a previously radiated field. These two patients were still alive and had no evidence of disease at 32 and 43 months since study entry, respectively. Five other patients went on to receive additional chemotherapy, with stable disease as best response in one patient receiving paclitaxel.
Adverse Effects Forty-three patients were assessable for toxicity (Table 3). There were no treatment-related deaths. Fourteen patients had subsequent MUGA scans, and seven of these had three or more additional determinations. One patient, age 64, experienced a 25% decrease in ejection fraction (from 68% to 51%). She had received five courses of doxorubicin in GOG 163 (combined with paclitaxel 150 mg/m2 per course) prior to 200 mg/m2 of PLD, and two other patients also had a decrease in their left ventricular ejection fraction (22% and 24%, respectively). These two patients had received two and five doses of doxorubicin-containing therapy and then received two and eight courses of PLD, respectively. The pulmonary toxicity represented dyspnea, and the two grade 3 neurologic toxicities were fatigue and weakness. Neutropenia was the most common hematologic toxicity, thrombocytopenia being confined to only nine patients with grade 1 changes. Among nonhematologic toxicities, dermatologic problems were most common, and severe gastrointestinal toxicities were rare.
Dose reductions were required in six patients. These occurred at the second doses in three patients and at the third, fifth, and sixth doses in the others. Seven patients discontinued drug treatment because of side effects, and two others (one of whom was a responder) refused further treatment for no clear reason. The given reasons for discontinuation of therapy include stomatitis in two instances and loss of appetite, weakness, fatigue, abdominal pain with dyspnea, and a decrease in ejection fraction in one instance each. Thus, except for mucosal toxicity, other reasons were quite variable.
When patients with endometrial cancer manifest recurrent or metastatic disease, endocrine therapy and/or chemotherapy is usually administered. Toxicity considerations often preclude using chemotherapy such as doxorubicin alone or with cisplatin or paclitaxel. Therefore, efforts continue in identifying active drugs or drug combinations that may have advantages over current chemotherapy regimens. Recent studies have defined better the indications and limitations of hormonal therapy and have identified poor-risk entities such as papillary serous and clear-cell histologies. In GOG studies, response rates of 25% or less for medroxyprogesterone acetate, and of 10% for tamoxifen, with median durations of survival varying between 7 and 11 months, have been observed. Alternating sequences of both of these drugs are under study. Against this background, the results achieved in the current study with PLD are of interest in two respects: (1) some antitumor activity was observed despite prior cytotoxic therapy (including prior doxorubicin in most patients), and (2) the toxicity profile should allow testing of PLD-containing combinations even with myelosuppressive drugs. Four instances of severe (grade 3) skin toxicity may reflect the slightly higher dose intensity (12.5 mg/m2/wk) than is commonly used (10 mg/m2/wk). Additional clinical findings in these patients receiving second-line therapy for endometrial cancer deserve comment. Prolonged treatment may predispose to observing new complications of the disease, such as the four patients with brain metastases and four others with involvement of the vertebral column. Encountering these complications may be the result of either lengthening survival with metastatic disease, or the greater medical surveillance provided to patients receiving treatment, or both. Furthermore, the occurrence of cerebellar metastases in two patients may indicate an unusual tropism of endometrial cancer for this site: three instances of cerebellar metastases were recorded among 10 patients with endometrial cancer metastatic to the CNS.15 By contrast, in a literature review of ovarian cancer metastatic to the brain, only seven (8.7%) of 80 had cerebellar metastasis.16 In summary, PLD had only limited antitumor activity in this extensively pretreated population with endometrial cancer, but minimal myelosuppression, even in patients who had received radiation. This should facilitate the study of combinations with other active agents, such as taxanes or platinum compounds.
APPENDIX The following Gynecologic Oncology Group institutions participated in this study:University of Alabama at Birmingham, Duke University Medical Center, Abington Memorial Hospital, University of Rochester Medical Center, University of Southern California Medical Center at Los Angeles, University of Mississippi Medical Center, Georgetown University Hospital, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University Medical Center, State University of New York Downstate Medical Center, Cleveland Clinic Foundation, University of Oklahoma Health Sciences Center, Cooper Hospital University Medical Center, Columbus Cancer Council, University of Chicago, Tacoma General Hospital, Thomas Jefferson University Hospital, Case Western Reserve University, Long Island Jewish Medical Center, Tampa Bay Cancer Consortium, and Carolina Gynecologic Oncology.
Supported by National Cancer Institute grant no. CA 27469 to the Gynecologic Oncology Group Administrative Office and grant no. CA 37517 to the Gynecologic Oncology Group Statistical Office.
1. Thigpen JT, Brady M, Alvarez RD, et al: Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial cancer: A dose-response study by the Gynecologic Oncology Group. J Clin Oncol 17: 1736-1744, 1999 2. Look KY: Who benefits from radiotherapy treatment of endometrial cancer and at what price? Lancet 355: 1381-1382, 2000 (editorial)[CrossRef][Medline] 3. Thigpen JT, Blessing JA, DiSaia PJ, et al: A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 12: 1408-1414, 1994[Abstract] 4. Muggia FM, Perloff M, Chia GA, et al: Adriamycin (NSC 123127) in combination with cyclophosphamide (NSC 262710): A phase I/II evaluation. Cancer Chemother Rep 58: 919-926, 1974[Medline] 5. Thigpen JT, Blessing JA, Homesley H, et al: Phase III trial of doxorubicin +/- cisplatin in advanced or recurrent endometrial carcinoma: A Gynecologic Oncology Group (GOG) study. Proc Am Soc Clin Oncol 12: 261, 1993 (abstr 830) 6. Ball HG, Blessing JA, Lentz SS, et al: A phase II trial of Taxol in advanced and recurrent adenocarcinoma of the endometrium: A Gynecologic Oncology Group study. Gynecol Oncol 56: 120, 1995 (abstr 42) 7. Fleming GF, Brunetto VL, Bentley R, et al: Randomized trial of doxorubicin (DOX) plus cisplatin (CIS) versus DOX plus paclitaxel (TAX) plus granulocyte colony-stimulating factor (G-CSF) in patients with advanced or recurrent endometrial cancer: A report on Gynecologic Oncology Group (GOG) Protocol 163. Proc Am Soc Clin Oncol 119: 379a, 2000 (abstr 1498)
8.
Uziely B, Jeffers S, Isaacson R, et al: Liposomal doxorubicin: Antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 13: 1777-1785, 1995
9.
Muggia FM, Hainsworth J, Jeffers S, et al: Phase II study of Doxil in refractory ovarian cancer: Antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 15: 987-983, 1997 10. Ranson MR, Carmichael J, O’Byrne K, et al: Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: Results of a multicenter phase II trial. J Clin Oncol 15: 3185-3191, 1997[Abstract] 11. Gabizon A, Uziely B, Lotem M, et al: Doxil in patients with pretreated metastatic breast cancer (MBC): A dose-schedule findings study with pharmacokinetics. Proc Am Soc Clin Oncol 16: 147, 1997 (abstr 516)
12.
Berry G, Billingham M, Alderman H, et al: The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi’s sarcoma treated with pegylated liposomal doxorubicin. Ann Oncol 9: 711-716, 1998
13.
Safra T, Muggia F, Jeffers S, et al: Pegylated liposomal doxorubicin (Doxil): Reduced clinical cardiomyopathy in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 11: 1029-1033, 2000 14. Blessing JA: Design, analysis and interpretation of chemotherapy trials in gynecologic cancer, in Deppe G (ed): Chemotherapy of Gynecologic Cancer ( ed 2 ). New York, NY, Alan R Liss Inc, Scientific and Medical Publications, 1990, pp 63-97 15. Cormio G, Lissoni A, Losa G, et al: Brain metastases from endometrial carcinoma. Gynecol Oncol 61: 40-43, 1996[CrossRef][Medline] 16. Sood A, Kumar L, Sood R, et al: Epithelial ovarian carcinoma metastatic to the central nervous system: A report on two cases with review of literature. Gynecol Oncol 62: 113-118, 1996[CrossRef][Medline] Submitted August 31, 2001; accepted January 14, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
