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Phase 2 Trial of Nonpegylated Doxorubicin (Myocet) as Second-Line Treatment in Advanced or Recurrent Endometrial Cancer

Di Legge, Alessia MD; Trivellizzi, Ilaria Nausica MD; Moruzzi, Maria Cristina MD; Pesce, Adele MD; Scambia, Giovanni MD; Lorusso, Domenica MD

International Journal of Gynecological Cancer: November 2011 - Volume 21 - Issue 8 - p 1446-1451
doi: 10.1097/IGC.0b013e31822d754e
Uterine Cancer

Background: Advanced or recurrent endometrial cancer is associated with a poor prognosis, and results obtained with systemic therapy are far from being impressive. Myocet is an interesting formulation of citrate conjugated doxorubicin encapsulated in nonpegylated liposomes. This phase 2 study was designed to evaluate the objective response rate and the toxicity profile of Myocet in women with advanced or recurrent endometrial cancer.

Methods: Patients with diagnosis of advanced or recurrent endometrial cancer failing 1 previous carboplatin-paclitaxel chemotherapy were enrolled. Myocet was administered at the dose of 60 mg/m2 intravenously on day 1 every 4 weeks.

Results: Eighteen patients were enrolled in our institution from September 2007 to January 2010. No complete or partial response was observed. Stable disease was registered in 5 patients (27.5%). Median time to progression was 9 weeks. Median time to death was 24 weeks. Grade 3/4 anemia was reported in 2 patients (11%). Grade 3/4 neutropenia was observed in 16.5% and 44% of patients, respectively. The major nonhematologic toxicities (grades 3/4) were fatigue (22%), nausea, and vomiting (5.5%).

Conclusions: Myocet presents no activity, and only few stabilizations of disease of limited duration in this recurrent endometrial carcinoma population previously treated with platinum-taxane chemotherapy are reported.

Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome, Italy.

Received March 31, 2011, and in revised form June 28, 2011.

Accepted for publication July 12, 2011.

Address correspondence and reprint requests to Domenica Lorusso, MD, Department of Gynecologic Oncology, Catholic University of the Sacred Heart, Largo Agostino Gemelli 8, IT-00168 Rome, Italy. E-mail:

The authors have no conflicts of interest to declare.

Endometrial carcinoma is the most common invasive malignancy of the female genital tract and is the fourth most common cancer in women.1 Most patients present with early-stage disease, have a good prognosis, and can be cured with surgery. On the other hand, patients with advanced or recurrent disease have a worse prognosis, and results obtained with systemic therapy are far from being impressive.

Currently, the standard of care for women with locally advanced or metastatic disease is chemotherapy. The results of Gynecologic Oncology Group 122 (GOG-122) support the use of systemic chemotherapy with cisplatin and doxorubicin associated with a 29% reduction of the risk of disease progression (hazard ratio, 0.71; 95% confidence interval, 0.55-0.91) and a 32% reduction in the risk of death (hazard ratio, 0.68; 95% confidence interval, 0.52-0.89) when compared with whole abdominal radiation in patients with stage III to IV endometrial cancer with no more than 2 cm of postoperative residual disease.2 Moreover, recent evidence of the literature supports the use of adjuvant chemotherapy in combination with radiotherapy also in high-risk early-stage endometrial cancer in which the combined treatment appears associated with a 55% reduction of risk of recurrence and a 49% reduction of risk of cancer-specific survival with respect to radiotherapy alone.3 These results herald a change in treatment patterns for women with advanced- and early-stage high-risk disease and strongly support the use of adjuvant chemotherapy in this malignancy. After the publication of GOG-177 results,4 the combination of cisplatin, doxorubicin, and paclitaxel became the standard treatment of advanced disease, but the modest therapeutic achievement of this combination in terms of survival in conjunction with the elevated toxicity of the regimen has identified, even in absence of phase 3 results, carboplatin-paclitaxel as the most used chemotherapy regimen in endometrial cancer.

Despite this modified approach to the adjuvant treatment of high-risk disease, the median survival of women with advanced endometrial cancer is only 15 months; therefore, it is essential to identify new drugs with limited toxicity for the treatment of endometrial cancer relapses.

Many drugs such as ifosfamide, topotecan, pegylated liposomal doxorubicin, docetaxel, and medroxyprogesterone acetate have been found to have activity of interest as single agents in the treatment of advanced disease (Table 1). Recently, phase 2 trials have evaluated new agents such as epothilones and phosphoinositide 3-kinase/AKT inhibitors showing response rates ranging between 7% and 12%.6-15



In particular, pegylated liposomal doxorubicin (Caelyx, Doxil), a liposome-encapsulated form of adryamicin with modified pharmacokinetic and toxic properties, is often used as second-line treatment of recurrent endometrial cancer, but despite its promising effectiveness as single agent5,16 or in combination with carboplatin,17,18 its typical mucocutaneous toxicity often represents a limitation to widespread use.

Myocet (TLC D-99) is an interesting formulation of citrate conjugated doxorubicin encapsulated in nonpegylated liposomes, which modify the pharmacokinetic properties of the drug ameliorating its adverse effect profile and potentiating the effectiveness of doxorubicin. The drug has been studied in gynecologic malignancies, such as ovarian and endometrial cancer, and, at present, is licensed for metastatic breast cancer treatment.19,20 Given the activity of Myocet in endometrial cancer cell lines, this phase 2 study was designed to evaluate the activity and the toxicity profile of Myocet in women with advanced or recurrent endometrial cancer.

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Eligibility Criteria and Baseline Assessment

Patients with diagnosis of advanced or recurrent endometrial cancer failing 1 previous carboplatin-paclitaxel chemotherapy line, older than 18 years, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater, and life expectancy of at least 12 weeks were eligible. Previous radiotherapy was allowed, but for efficacy evaluation with RECIST (Response Evaluation Criteria In Solid Tumors) criteria,21 disease outside a previously irradiated field was required at baseline radiological assessment.

Exclusion criteria were prior or concurrent malignancy (except for nonmelanoma skin cancer and in situ carcinoma of the uterine cervix, if adequately treated), more than 1 previous chemotherapy line, inadequate bone marrow function (white blood cells, <4000/μL; absolute neutrophil count, <1500/μL; or platelets, <100,000/μL), abnormal renal function (total serum creatinine level, >1.5 the upper normal limit), abnormal liver function (serum aspartate and alanine aminotransferases, >1.5 the upper normal limit), heart disease (heart failure, heart attack in the previous 6 months, atrioventricular block of any degree, serious arrhythmia), and central nervous system metastasis.

The protocol was approved by the ethics committee of the Catholic University of Rome. Written informed consent was obtained from each enrolled patient, before study entry.

Baseline evaluation included a complete physical examination and history, neurological assessment, complete blood count, and biochemistry with CA-125 determination, electrocardiogram, echocardiogram, chest abdominopelvic computed tomography scan or nuclear magnetic resonance, abdominopelvic ultrasonography, bone scan with skeletal x-ray if indicated, and other examination at the investigators' discretion.

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Myocet was administered at the dose of 60 mg/m2 intravenously (IV) on day 1 of a 28-day cycle. Premedication, with dexamethasone 20 mg IV, diphenhydramine 50 mg orally or IV, and ranitidine 150 mg orally or 50 mg IV (or another equivalent histamine 2 blocker), was administered 30 minutes before administration of Myocet. Subsequent cycle was administered when the absolute neutrophil count reached 1500/μL or greater, and when platelets recovered to 100,000/μL or higher.

Dose reduction of 20% was required for the following: first occurrence of febrile neutropenia; documented grade 4 neutropenia lasting for 5 days or more, thrombocytopenia grade 3, or hemoglobin less than 7 g/dL; and grade 2 or greater hepatic, renal, and/or mucocutaneous toxicity.

Treatment was discontinued if left ventricular ejection fraction less than 45% or if greater than 20% decrease from the baseline was documented and in any case of nonhematologic toxicity greater than grade 3 (excluding alopecia and/or nausea/vomiting).

Delays for more than 2 weeks with respect to scheduled date of treatment determined discontinuation of study. Patients did not receive prophylactic growth factors (filgrastim or pegfilgrastim) unless they experienced recurrent febrile neutropenia and/or recurrent documented grade 4 neutropenia that persisted for more than 5 days despite dose reduction. Patients were allowed to receive erythropoietin for management of anemia after documentation of hemoglobin less than 9 g/dL. Eligible patients received study treatment until disease progression or intolerable toxicity occurred.

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Assessment of Response

The primary aim of the study was the evaluation of the objective response rate to experimental treatment. A secondary end point was the description of treatment tolerability. Time to progression, defined as the time from the date of enrollment to the date of the first progression, and time to death, defined as the time between the date of enrollment and the date of death, were also described. Clinical evaluation of response, including serum CA-125, was tested on day 1 of each cycle; computed tomography scan was planned every 2 cycles, and response evaluated according to the RECIST criteria.21 In case of complete or partial response or stable disease after 6 cycles of chemotherapy, treatment prosecution was allowed at the discretion of the physician.

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Assessment of Toxicity

Toxicity was graded according to National Cancer Institute Common Toxicity Criteria, version 4.0.22 Physical examination and vital signs were recorded before each cycle of chemotherapy. Complete blood counts were performed at baseline and weekly. Laboratory examinations (serum aspartate and alanine aminotransferases, total serum proteins, albumin, bilirubinemia, alkaline phosphatase, lactate dehydrogenase, creatininemia, blood urea nitrogen, glycemia, uricemia, serum electrolytes) were planned at baseline and then repeated before each cycle. Electrocardiographic monitoring was performed at each cycle; echocardiography with left ventricular ejection fraction assessment was planned every 3 cycles.

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Statistical Analysis

The study used a 2-stage Simon23 accrual design with an early stopping rule in the event of insufficient activity demonstrated by the treatment. The percentage of objective response in patients with advanced or recurrent endometrial cancer who failed a previous platin-based chemotherapy treatment is around 10% to 15%. The hypothesis is that Myocet might obtain a response rate of 25% in patients with disease in not previously irradiated fields. During the first stage of accrual, 18 patients were to be entered and evaluated. If at least 3 responses were observed, a second phase of the study was to be initiated that would increase accrual to 43 patients. The regimen would be considered active if at least 7 responses were observed among 43 patients evaluable (α = 0.05; β = 0.20).24

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From September 2007 to January 2010, 18 patients were enrolled in our institution. The median age was 66 years (range, 50-82 years). Main baseline characteristics of the enrolled patients are reported in Table 2. Fifteen patients had a good ECOG performance status (0 or 1), whereas 3 had ECOG performance status of 2. Four patients had metastatic disease progressing after first-line carboplatin-paclitaxel chemotherapy (platinum-free interval [PFI], >5 months; range, 2-6 months). In 10 patients with recurrent disease, 6 had received as adjuvant treatment carboplatin-paclitaxel-based chemotherapy and pelvic radiotherapy (45 Gy) followed by brachytherapy (25 Gy), but in all cases, the relapse occurred outside the previously irradiated field (PFI, >8 months; range, 6-12 months). All patients (100%) had received prior chemotherapy with carboplatin and paclitaxel, in particular 4 patients (22%) with the weekly and 14 with the triweekly schedule (77%).



Seven patients experienced local recurrences (lymph nodes, n = 4; pelvic peritoneum, n = 3). Seven patients experienced distant recurrence (lung, n = 2; liver, n = 2; bone, n = 1). In the remaining, recurrence was mixed. No patient underwent secondary surgery before starting treatment.

All patients were assessable for response (Table 3); no complete or partial responses were observed. Stable disease was registered in 5 patients (27.5%); 4 of the 5 stable diseases were seen in women with endometrioid carcinomas; only 1 patient was seen with "glassy cells" tumor. All patients had received prior chemotherapy with carboplatin (area under the curve, 5) and paclitaxel (175 mg/mq), administered each 21 days. All other patients experienced progression of disease (71.5%), and 2 of them died after the first cycle (11%) because of a dramatic worsening of general clinical conditions. Time to progression was 9 weeks. Time to death was 24 weeks.



Two patients (11%) completed the planned 6 cycles, whereas in the remaining 16 patients, chemotherapy was interrupted before the completion of study treatment for progression of disease or worsening of general condition (88%). A total of 44 courses were administered, and a median of 2 courses (range, 1-6) per patient were given. Three patients received dose reductions for grade 4 neutropenia.

Grade 3/4 anemia was reported in 2 patients (11%); both patients required red blood cell (RBC) transfusion. Grade 3 and 4 neutropenia was observed in 16.5% and 44% of patients, respectively. No grade 3/4 thrombocytopenia occurred (Table 4). The major nonhematologic toxicities (grade 3-4) were fatigue (22%), nausea (5.5%), and vomiting (5.5%). Organ toxicity was not recorded. One patient experienced hypersensitivity reaction. Complete hair loss was reported in 16 patients (89%). No patient experienced palmar-plantar erythrodysesthesia, stomatitis, and heart dysfunction (Table 5).





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Advanced and recurrent endometrial cancer remains a treatment dilemma. The results of GOG-122 and of NSGO 9501-EORTC 55991 trial underline the role of chemotherapy as adjuvant treatment in advanced-stage and high-risk early-stage endometrial cancer. The first-line chemotherapy treatment often consists of a combination of platinum and taxane,25 with or without anthracycline,4 thus limiting the number of chemotherapeutics agents to be used in case of progression or relapse. Endocrine therapy may represent a treatment possibility in recurrent endometrial cancer, but the activity of agents such as megestrol acetate and tamoxifen is limited to low-grade cancers. Several active cytotoxic agents have been identified for second-line regimens (Table 1), but these results usually refer to patients pretreated with anthracyclines and taxane-naive and, for earlier studies, even platinum-naive. Therefore, the applicability of these results to the present recurrent endometrial cancer population who has already received platinum, taxanes, and/or anthracyclines as part of first-line treatment is unclear. Moreover, for patients who experience endometrial cancer recurrence and for patients with endometrial carcinoma that is beyond the scope of definitive surgery, the prognosis remains poor, so the identification of novel active agent with an acceptable toxicity profile, in the attempt to minimize adverse effects and maximize patients' quality of life, represents a priority of the clinical research. Moreover, many of the recurrent endometrial cancer patients experience a number of concurrent diseases, often from the cardiovascular system as well as diabetes, and these aspects should be taken into account for the choice of treatment weighing drug efficacy against tolerability and toxicity.

In advanced or recurrent endometrial carcinoma, 10 agents have been tested in the second-line setting, with response rate ranging between 0% and 27%. Pegylated liposomal doxorubicin had been tested in the treatment of advanced and recurrent endometrial cancer in monotherapy, with response rate ranging from 9.5% to 21%,5,16 and in combination with carboplatin, with response rate ranging from 44% to 58.5%.17,18 The drug was well tolerated with an exactable toxicity profile mainly characterized by moderate hand-foot syndrome (grade 3/4).

This phase 2 study failed to show clinical activity of Myocet 60 mg/m2 every 28 days in advanced or recurrent endometrial cancer. Despite the evidence of the activity of the drug in advanced breast cancer, no promising activity has been observed in this setting.

In our study, Myocet was administered to 18 advanced and/or recurrent endometrial cancer patients after the failure of 1 platinum-based chemotherapy regimen; no objective responses were observed, and only 5 patients (27.5%) experienced stabilization of disease for a limited 5-month period.

Angioli et al26 described their experience with Myocet in recurrent metastatic gynecologic malignancies with reported quite similar results. Among 11 heavily pretreated endometrial cancer cases, 18% response rate (2/11 patients) and 27% of stabilization of disease using a slightly higher dose of Myocet were reported. Because of hematologic toxicity, the dose was reduced to 60 mg/m2 in 50% of patients. So the author concluded that this was the most appropriate dose in this setting of heavily pretreated patients.

The experimental drug revealed a very acceptable toxicity profile: The hematologic and nonhematologic events were not associated with delays or discontinuations in chemotherapy administration, and the majority of the cycles was given on time. Neutropenia and anemia were common, but no neutropenia-associated complications were reported. No significant thrombocytopenia was registered. No cardiac toxicity was reported, and gastrointestinal toxicity was limited. The absence of stomatitis and hand-foot syndrome is of utmost importance, given the fact that these events often represent the dose-limiting toxicity of pegylated liposomal doxorubicin. On the other hand, we registered a high incidence of hair loss (89%), compared with pegylated liposomal doxorubicin, according to what was reported previously for Myocet.27

In conclusion, Myocet presents no activity and only few stabilizations of disease of limited duration in this recurrent endometrial carcinoma population previously treated with platinum-taxane chemotherapy. However, it is worth noting that cisplatin, which forms the backbone of the adjuvant and first-line treatment of advanced and metastatic endometrial cancer, had a 4% response rate when tested in the second-line setting,8 and other promising agents such as ixabepilone and topotecan were associated with a 12% response rate. Therefore, second-line treatment options for women with endometrial cancer remain limited, and Myocet's modest activity in combination with its acceptable toxicity profile may warrant additional clinical exploration especially in combination with platinum derivates.

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Chemotherapy; Myocet; Recurrent endometrial cancer

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