ANTICANCER RESEARCH 28: (2008)

Transcription

1 Biweekly Pegylated Liposomal Doxorubicin as Second-line Treatment in Patients with Relapsed Ovarian Cancer after Failure of Platinum and Paclitaxel: Results from a Multi-center Phase II Study of the NOGGO. GUELTEN OSKAY-OEZCELIK 1, DOMINIQUE KOENSGEN 1, HANS-JOACHIM HINDENBURG 3, PETER KLARE 3, BARBARA SCHMALFELDT 4, WERNER LICHTENEGGER 1, RADOSLAV CHEKEROV 1, SALAH-EDDIN AL-BATRAN 5, ULF NEUMANN 2 and JALID SEHOULI 1 ; The Ovarian Cancer Study Group of the North-Eastern German Society of Gynecological Oncology (NOGGO) 1 Departments of Gynecology and Obstetrics, and 2 Medical Surgery, Charité University Hospital Berlin; 3 Private Practice, Berlin; 4 Department of Gynecology and Obstetrics, University Hospital Munich; 5 Department of Medical Oncology, Hospital Nordwest Frankfurt, Germany Abstract. Background: Pegylated liposomal doxorubicin (PLD) is one of the most effective cytotoxic agents in recurrent ovarian cancer. Palmar-plantar erythrodysesthesia (PPE) is a typical and commonly noted adverse event and often represents the dose-limiting toxicity. The purpose of this multicenter study was to determine the efficacy of this regimen as second-line therapy for patients with recurrent ovarian cancer. Patients and Methods: Patients with recurrent epithelial ovarian cancer after surgery and initial treatment with carboplatin and paclitaxel were enrolled. Eligible patients were required to have an ECOG performance status of 2, and sufficient organ function. PLD was administered at a dose of 20 mg/m 2 every two weeks. Results: Twenty patients were recruited into this trial. Overall, 155 cycles of chemotherapy with a median of six courses (range 4-24) were administered. The median patient age was 64 years (range, years). The hematological and non-hematological toxicity profile was favorable. No grade IV toxicity was observed. PPE grade III toxicity was noted in only one patient. Median overall survival was 19.2 months (range Correspondence to: Dr. Med. Guelten Oskay-Oezcelik and Prof. Dr. Med. Jalid Sehouli, Charité University Hospital Berlin, Germany. Department of Gynecology and Obstetrics Augustenburger Platz 1, Berlin, Germany. Tel: , Fax: , sehouli@aol.com Key Words: Ovarian cancer, second-line therapy, pegylated liposomal doxorubicin, biweekly schedule, toxic skin reactions, palmar-plantar erythrodysesthesia. 1.8 to 39 months; 95% confidence interval (CI) months) Progression-free survival was 3.3 months (range 1.38 to 36.4 months; 95% CI months). Conclusion: Biweekly PLD is an effective second-line treatment for patients with relapsed ovarian cancer. Toxicity incidence with this treatment schedule does not appear to be associated with the number of previous chemotherapies. Our data supports the need for a randomized study comparing biweekly with conventional monthly administration of 40 mg/m 2 or 50 mg/m 2 PLD to determine the best therapeutic index for PLD. Despite radical surgery and high response rates to first-line chemotherapy with paclitaxel and carboplatin, most patients with advanced ovarian cancer will experience tumor recurrence and will die due to progression of disease (1, 2). Therefore, effective treatment options with acceptable toxicity profiles are badly needed for symptom control in these incurable patients. Several studies have demonstrated that anthracyclines are effective in recurrent ovarian cancer. To improve the toxicity profile of anthracyclines, a special formulation of doxorubicin was developed. Pegylated liposomal doxorubicin (PLD) is a stealth formulation of doxorubicin in which a polyethylene glycol layer surrounds a doxorubicin-containing liposome (3).These modifications significantly alter the pharmacokinetics of the drug, resulting in increased bioavailability of this agent. In comparison with conventional doxorubicin, PLD causes less frequent hematological and cardiac side effects but more frequent skin toxicities and stomatitis (4, 6) /2008 $

2 Various randomized phase III trials of PLD demonstrated activity in both platinum-sensitive and -resistant pretreated ovarian cancer patients (4, 7). A large randomized phase III study compared PLD with topotecan in 481 patients with relapsed ovarian cancer after failure of a platinum-based chemotherapy. Progression-free survival and overall survival for the total population did not differ, but a subgroup analysis showed a statistically significant long-term survival benefit for platinum-sensitive patients who were treated with PLD (4). Topotecan induced more hematological toxicity and PLD significantly induced more skin toxicity (4). This typical skin toxicity associated with PLD, called palmar plantar erythrodysesthesia (PPE), is characterized by erythema, swelling, desquamation with or without blisters and ulcerations. PPE compromises quality of life and is one of the main reasons for treatment delay and the withdrawal of PLD therapy. Various retrospective studies have indicated that reducing the PLD dose lowers the incidence and severity of PPE (6, 8). Previous investigations conducted by us showed that a biweekly schedule, splitting the dosage into 20 mg/m 2 every two weeks, is associated with a low incidence of PPE and is well tolerated in heavily pre-treated patients with relapsed ovarian cancer (9). The study presented in this paper was conducted to evaluate the efficacy of this schedule as a second-line treatment. Patients and Methods Study design. This was an open label, multi-institutional study performed according to Good Clinical Practice and the World Medical Assembly s Declaration of Helsinki (10). An independent third party (Alcedis GmbH, Germany) monitored data control. Each collaborating center elicited prior approval of the study protocol from their local Ethics Committee. Evaluation of toxicity was defined as the primary objective of this study. The secondary objective was to establish the progression free and overall survival expectations. Treatment plan. Pegylated liposomal doxorubicin, 20 mg/m 2 diluted in a 250 ml water solution containing 5% dextrose, was administered as a 1-h intravenous infusion on day one, once every 14 days. Premedication consisting of a 5-HT3-antagonist was given 15 minutes prior to PLD. The use of granulocyte colonystimulating factor (G-CSF) for primary prophylaxis was not allowed. Patients were scheduled to receive up to 8 cycles of biweekly PLD at a dose of 20 mg/m 2. Prolongation of treatment was possible at the investigator s discretion. Study treatment was to be discontinued in patients experiencing intolerable toxicity or progression of disease at any time during the trial. Eligibility criteria. Subjects in a second-line situation with relapsed ovarian, peritoneal or fallopian cancer after primary surgery and first-line treatment with platinum and paclitaxel were eligible. The following quantitative criteria were used: i) An ECOG performance status of less than 3. ii) Adequate bone marrow function (defined as hemoglobin 9 g/dl; neutrophil count 1,500/ µl and platelets 100,000/µl). iii) Adequate renal function (serum creatinine at 1.25 times the upper limit of normal or a glomerular filtration rate greater than 60 ml/min). iv) Adequate liver function (aspertate-amino transferase (AST); alanine-amino transferase (ALT) at three times the upper limit of normal). v) Bilirubin concentrations 1.25 times the upper limit of normal Furthermore, the left ventricular ejection fraction (LVEF) was evaluated in all patients within 14 days prior to the first cycle. Patients with an LVEF 50% and a history of severe cardiac disease were excluded. Before study entry, written informed consent, a complete history and a physical examination were required for every patient. Ultrasound evaluation of LVEF and a baseline documentation of disease by radiological assessment (using one or more of the following techniques: CT scan, MRI scan, chest X-ray, abdominal ultrasound) were performed in all patients within 4 weeks before administration of the first dose. Toxicity evaluation. Toxicity analyses were performed in all patients who received at least one infusion of the study drug. Toxicity was evaluated on the basis of the Common Toxicity Criteria (11). Full physical examination, ECG tracing and a full blood count including hemoglobin, hematocrit, RBC, WBC, neutrophils, platelets and blood chemistry (serum creatinine, alkaline phosphatase, serumglutamat-oxalacetat-transaminase (SGOT), serum- glutamat-pyruvattransaminase (SGPT), bilirubin) were carried out prior to every chemotherapy cycle. In order for treatment to proceed, the neutrophil count and platelet count had to exceed 1500/µl and 100,000/µl, respectively. Weekly blood samples (hemoglobin, hematocrit, WBC, RBC, platelets) were taken one week after chemotherapy to check for hematological toxicity. Special attention was given to all skin toxicities. All patients were thoroughly apprised of the need to avoid all skin irritation from tight clothing, pressure, friction or physical activity. Efficacy. Progression-free survival was defined as the time from the date of enrolment to the date of disease progression or death from any cause. Only patients who received at least one course of chemotherapy were evaluated for response. With respect to clinical response, the same radiological imaging technique (CT scan, MRI scan, chest x-ray, abdominal ultrasound) chosen for baseline documentation was performed every eight weeks. Response was determined according to the criteria of the International Union Against Cancer ( CA-125 was not used as a response marker. Statistical analysis. All analyses were conducted in an exploratory fashion. Data is presented in the form of raw numbers, rates, or medians and ranges, according to the underlying distribution. Exact binomial 95% confidence intervals (CI) were computed for risk estimates, where appropriate. Survival was modeled by the nonparametric Kaplan-Meier method. STATA 8.0 statistical software (STATA Corp., TX, USA) was employed for all analyses. Results Twenty patients with relapsed ovarian cancer were enrolled at six institutions in Germany. Table I shows the demographic data and characteristics of the patients. The median age of the patients was 64 years (range, years) 1330

3 Oskay-Oezcelik et al: PLD as Second-line Treatment in Relapsed OC with a median performance status of 1 (range, 0-2). The majority (n=13/65%) of the patients were classified as platinum-sensitive (progression-free interval of >6 months). Ten out of these 13 patients experienced tumor relapse within an interval of 6 to12 months. The other three patients relapsed after 12 months following the first-line chemotherapy. Seven patients (35%) were defined as platinum-resistant. A total of 155 cycles of chemotherapy with a median of six courses (range 4-24) were administered, whereby 8 patients received at least 8 cycles. Toxicity. All patients were assessed for toxicity. Generally, PLD administered in a bi-weekly schedule was well tolerated and only mild to moderate non-hematological side effects were noted. Alopecia and neurotoxicity were commonly observed, but these were mostly associated with previous taxane-based chemotherapy. The two toxicities were not cumulative. PPE occurred in eight patients (40%), but only one patient (5%) developed grade III PPE. No grade IV PPE was observed. An overview of the nonhematological toxicities is given in Table II. Biweekly PLD was associated with a highly acceptable and easily manageable hematological toxicity profile (see Table III). Significant non-hematological toxicity was infrequent. Only one patient developed grade 3 anemia and only one patient experienced grade 3 neutropenia, which was not complicated by fever or infection. There were no episodes of neutropenic fever, sepsis, or chemotherapy-related fatalities. In no case was the use of G-CSF applied. Only 3 patients received darbepoietin. Six patients received blood transfusions. There were no episodes of neutropenic fever, sepsis, infection or chemotherapy-related fatalities. In no case was the use of G-CSF applied. Only 3 patients received darbepoietin. Six patients received blood transfusions. Efficacy. Median follow-up was 13.3 months with a range of months. At the time of this analysis, nine patients (six of these classified as platinum-sensitive) were alive. Median time-to-progression was 3.3 months (range 1.38 to 36.4 months; 95% CI ) and median overall survival 19.2 months (range 1.8 to 39 months; 95% CI ) (Figure 1). In the platinum sensitive population (n=13) the median progression-free survival was 4.1 months (range ; 95% CI ) and the median overall survival 19.1 (range ; 95% CI ). Of these patients, one patient achieved PR, one SD and 11 developed progressive disease. In the platinum resistant population (n=7) the median progression-free survival was 2.3 months (range ; 95% CI ) and the median overall survival was 14.2 months (range ; 95% CI ). Table I. Patients characteristics. Discussion n % Median age, years (range) 64 (41-77) Median number of cycles (range) 6 (4-24) Body mass index (BMI) ( ) ECOG performance status FIGO stage at primary diagnosis I a 1 5 III 2 10 III c IV 1 5 unknown 1 5 Grading I 0 0 II 8 40 III unknown 2 10 Prior platinum + taxane Progression free interval 6 months months >12 months 3 25 PLD has demonstrated efficacy in relapsed ovarian cancer. PLD was given in various phase III studies at a dosage of 50 mg/m 2, but a 55% incidence of grade III or IV PPE limited its use as a palliative treatment (9, 12, 13, 14). A number of agents, including dimethyl sulfoxide (DMSO) and steroids, were tested for their efficacy in preventing PPE, but none of these showed reproducible efficacy in prospective trials (8, 14, 15). Dose reduction, treatment delay and early discontinuation of treatment are common clinical implications when severe PLD-induced PPE occurs. Various studies indicate that toxicity depends on treatment schedules and suggest a strong correlation between the absolute dose of PLD and the risk of development of severe PPE (grade III and IV) (9, 13, 15, 17). Rose et al. performed a retrospective analysis in patients with recurrent ovarian cancers who were treated with different doses of PLD. Fewer treatment delays and a lower incidence of PPE were observed in the cohort of patients who were treated at an initial dose of 40 mg/m 2 monthly instead of the approved dose of 50 mg/m 2 (8). This analysis 1331

4 Table II. Non-hematological toxicities. Number of patients / number of cycles CTC grade I II III IV Alopecia 7 (35%) / 7 (5%) 0 / 0 0 / 0 0 / 0 PPE 4 (20%) / 4 (3%) 3 (15%) / 3 (2%) 1 (5%) / 1 (0.6%) 0 / 0 Stomatitis 6 (3%) / 6 (4%) 1 (5%) / 1 (0.6%) 0 / 0 0 / 0 Nausea 4 (20%) / 4 (3%) 4 (20%) / 4 (3%) 2 (10%) / 2 (1%) 0 / 0 Emesis 2 (10%) / 2 (1%) 3 (15%) / 3 (2%) 0 / 0 1 (5%) / 1 (0.6%) Cardiotoxicity 0 / 0 0 / 0 0 / 0 0 / 0 Table III. Hematological toxicities. Number of patients / number of cycles CTC-Grade I II III IV Anemia 8 (40%) / 63 (41%) 2 (10%) / 9 (6%) 1 (5%) / 1 (0.6%) 0 / 0 Leukopenia 4 (20%) / 27 (17%) 2 (10%) / 9 (6%) 1 (5%) / 3 (2%) 0 / 0 Neutropenia 4 (20%) / 10 (7%) 0 / 7 (5%) 0 / 2 (2%) 0 / 0 Thrombocytopenia 1 (5%) / 8 (5%) 0 / 0 0 / 0 0 / 0 Use of GCSF 0 (0%) Use of erythropoietin 3 (15%) Blood transfusion 6 (30%) disclosed no significant differences in response between the two dose levels. Other non-randomized studies have also concluded that an average weekly dose of 10 mg/m 2 is a reasonable treatment option for patients with relapsed ovarian cancer (8, 9, 14), but there are no prospective randomized studies comparing 40 mg/m 2 with 50 mg/m 2 of PLD every 28 days in relapsed ovarian cancer. Various working groups are modifying the treatment schedule of PLD to improve the therapeutic index. Larusso et al. (6) recently published a phase II study in heavily pretreated patients with relapsed ovarian cancer who received PLD at a dose of 35 mg/m 2 every three weeks. Palmar plantar erythrodysesthesia occurred in only 8 patients (21.6%) and reached grade 3 in only one (2.8%). Previously, we have demonstrated that PLD given at a dose of 20 mg/m 2 every two weeks is feasible in heavily pretreated patients with relapsed ovarian cancer (9). In that cohort, only 3 out of 64 patients developed severe PPE. Only a minority of the patients were in a second-line setting. Therefore, we performed the present trial applying the biweekly schedule as the second-line of treatment. The present trial confirmed the favorable toxicity profile, with only one patient developing severe PPE. In comparison to our previous study we did not see any significant differences in the hematological or non-hematological toxicity profile (9). Hence it can be speculated that the toxicity of biweekly PLD in relapsed ovarian cancer is not correlated with the number of previous chemotherapies. Despite the limitation due to the small number of patients here, the biweekly schedule seems as effective as a four-week regimen dosed at 50 mg/m 2 (6, 9). The median survival was 13.3 months (range: 1 to 36 months). Overall survival in large phase III second-line studies with PLD at a dose of 50 mg/m 2 every four weeks ranged from 9 to 13 months (4, 5, 6). In conclusion, PLD administered biweekly shows a favorable toxicity profile and is associated with a low incidence of PPE in both platinum-sensitive and -resistant ovarian cancer patients. Conventional treatment regimens of 50 or 40 mg/m 2 administered monthly need to be compared with this biweekly 20 mg/m 2 regimen to identify the best schedule of PLD in relapsed ovarian cancer. As our study did not employ internal controls, our findings must be regarded as hypothesis generating. Only a randomized study can determine for certain whether a biweekly schedule of 20 mg/m 2 is equally effective. In a warranted study of this kind, overall survival should be defined as the primary objective. Quality of life and cost effectiveness should be additionally analyzed to determine 1332

5 Oskay-Oezcelik et al: PLD as Second-line Treatment in Relapsed OC Figure 1. Progression-free survival and overall survival (n=20). the best therapeutic index for PLD as single-agent treatment for relapsed ovarian cancer. Acknowledgements Our thanks go to the study coordinators, nurses and patients who participated in this trial. Without their commitment and collaboration, this work would not have been possible. References 1 Ozols RF, Schwartz PE and Eifel PJ: Ovarian cancer, fallopian tube carcinoma, and peritoneal carcinoma. In: DeVita VT, Hellmann S and Rosenberg RA (ed.). Cancer: Principles and Practice of Oncology, sixth edn. Lippincott Williams and Willkins: , Ozols RF: Update on the management of ovarian cancer. Cancer J 8: 22-30, Lotem M, Hubert A, Lyass O, Goldenhersh MA, Ingber A, Peretz T and Gabizon A: Skin toxic effects of polyethylene glycol-coated liposomal doxorubicin. Arch Dermatol 136: , Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME and Lacave AJ: Recurrent epithelial ovarian carcinoma: a randomised phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19: , Lyass O, Uziely B, Ben-Yosef R, Tzemach D, Heshing NI, Lotem M, Brufman G and Gabizon A: Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer 89: , Lorusso D, Naldini A, Testa A, D Agostino G, Scambia G and Ferrandina G: Phase II study of pegylated liposomal doxorubicin in heavily pre-treated epithelial ovarian cancer patients. May a new treatment schedule improve toxicity profile? Oncology 67: , Thigpen JT, Aghajanian CA, Alberts DS, Campos SM, Gordon AN, Markman M, McMeekin DS, Monk BJ and Rose PG: Role of pegylated liposomal doxorubicin in ovarian cancer. Gynecol Oncol 96: 8-10, Rose PG: Pegylated liposomal doxorubicin: optimising the dosing schedule in ovarian cancer. Oncologist 10(3): , Sehouli J, Oskay-Özcelik G, Kühne J, Stengel D, Hindenburg H-J, Klare P, Heinrich G, Schmalfeldt B, Mertens H, Camara O and Lichtenegger W: Biwekly pegylated liposomal doxorubicin in patients with relapsed ovarian cancer: results of a multicenter phase-ii-trial. Ann Oncol 17: , World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. Nurs Ethics 9(1): , National Cancer Institute: Cancer Therapy Evaluation Program: Common Terminology Criteria for Adverse Events v3.0 (CTCAE) Campos SM, Penson RT, Mays AR, Berkowitz RS, Fuller AF, Goodman A, Matulonis UA, Muzikansky A and Seiden MV: The clinical utility of liposomal doxorubicin in recurrent ovarian cancer. Gynecol Oncol 81: , Nagore E, Insa A and Sanmartin O: Antineoplastic therapyinduced palmar plantar erythrodysesthesia ( hand-foot ) syndrome. Incidence, recognition and management. Am J Clin Dermatol 1: ,

6 14 Rose PG, Maxson J, Fusco N, Mossburger K and Rodriguez M: Liposomal doxorubicin in ovarian, peritoneal, and tubal carcinoma: a retrospective comparative study of single-agent dosages. Gynecol Oncol 82: , Al-Batran SE, Bischoff J, von Minckwitz G, Atmaca A, Kleeberg U, Meuthen I, Morack G, Lerbs W, Hecker D, Sehouli J, Knuth A and Jager E: The clinical benefit of pegylated liposomal doxorubicin in patients with metastatic breast cancer previously treated with conventional anthracyclines: a multicentre phase II trial. Br J Cancer 94: , Al-Batran SE, Meerpohl HG, von Minckwitz G, Atmaca A, Kleeberg U, Harbeck N, Lerbs W, Hecker D, Sehouli J, Knuth A and Jager E: Reduced incidence of severe palmar-plantar erythrodysesthesia and mucositis in a prospective multicenter phase II trial with pegylated liposomal doxorubicin at 40 mg/m every 4 weeks in previously treated patients with metastatic breast cancer. Oncology 70(2): , Markman M, Kennedy A, Webster K, Peterson G, Kulp B and Belinson J: Phase II trial of liposomal doxorubicin (40 mg/m 2 ) in platinum/paclitaxel refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. Gynecol Oncol 78: , Received November 19, 2007 Revised January 8, 2008 Accepted January 18,