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Phase III Trial of Gemcitabine Compared With Pegylated Liposomal Doxorubicin in Progressive or Recurrent Ovarian Cancer

Gabriella Ferrandina, Manuela Ludovisi, Domenica Lorusso, Sandro Pignata, Enrico Breda, Antonella Savarese, Pietro Del Medico, Laura Scaltriti, Dionyssios Katsaros, Domenico Priolo, Giovanni Scambia

From the Department of Oncology, Catholic University, Campobasso; Gynecologic Oncology Unit, Catholic University of Rome; Medical Oncology, Ospedale S. Giovanni Calibita Fatebenefratelli; Medical Oncology, Regina Elena Institute, Rome; Medical Oncology, National Cancer Institute, Naples; Medical Oncology, Ospedali Riuniti, Reggio Calabria; Department of Medical Oncology, "Ramazzini" Hospital, Carpi; Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, University of Turin, Turin; and Medical Oncology, S. Vincenzo Hospital, Taormina, Italy

Corresponding author: Gabriella Ferrandina, MD, Department of Oncology, Catholic University, Campobasso, Contrada Tappino, L.Go A. Gemelli, 1, Campobasso, Italy; e-mail: gabriella.ferrandina{at}libero.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose We aimed at investigating the efficacy, tolerability, and quality of life (QOL) of gemcitabine (GEM) compared with pegylated liposomal doxorubicin (PLD) in the salvage treatment of recurrent ovarian cancer.

Patients and Methods A phase III randomized multicenter trial was planned to compare GEM (1,000 mg/m² on days 1, 8, and 15 every 28 days) with PLD (40 mg/m² every 28 days) in ovarian cancer patients who experienced treatment failure with only one platinum/paclitaxel regimen and who experienced recurrence or progression within 12 months after completion of primary treatment.

Results One hundred fifty-three patients were randomly assigned to PLD (n = 76) or GEM (n = 77). Treatment arms were well balanced for clinicopathologic characteristics. Grade 3 or 4 neutropenia was more frequent in GEM-treated patients versus PLD-treated patients (P = .007). Grade 3 or 4 palmar-plantar erythrodysesthesia was documented in a higher proportion of PLD patients (6%) versus GEM patients (0%; P = .061). The overall response rate was 16% in the PLD arm compared with 29% in the GEM arm (P = .056). No statistically significant difference in time to progression (TTP) curves according to treatment allocation was documented (P = .411). However, a trend for more favorable overall survival was documented in the PLD arm compared with the GEM arm, although the P value was of borderline statistical significance (P = .048). Statistically significantly higher global QOL scores were found in PLD-treated patients at the first and second postbaseline QOL assessments.

Conclusion GEM does not provide an advantage compared with PLD in terms of TTP in ovarian cancer patients who experience recurrence within 12 months after primary treatment but should be considered in the spectrum of drugs to be possibly used in the salvage setting.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Despite the advances in surgical efforts and the achievement of high response rates with platinum/paclitaxel front-line treatment,^1-3 ovarian cancer remains the most lethal gynecologic malignancy, with a 5-year survival rate of 25% to 30% in advanced-stage disease.^4,5 The major determinants of clinical outcome are the extent of residual tumor at primary surgery and sensitivity to platinum-based chemotherapy.⁶ Indeed, in platinum-resistant ovarian cancer patients, salvage chemotherapy with nonplatinum agents mostly results in short-lived response rates of approximately 10% to 25% and poor survival.^7,8 In this context, special attention has to be paid to the issue of quality of life (QOL) preservation because prolongation of survival and palliation of symptoms remain the most realistic objectives. With the limits inherent in the comparison of response rates across nonrandomized phase II studies, none of the drugs currently proposed for the management of platinum-resistant ovarian cancer patients has shown superiority over the others; moreover, few randomized clinical trials have addressed this issue.^9-12 Besides the studies conducted in the time frame preceding the confirmation of paclitaxel inclusion in front-line treatment,^9,10 two randomized clinical trials have investigated nonplatinum, non–cross-resistant agents as salvage chemotherapy in platinum-resistant ovarian cancer recurrence. In particular, in the study by Gordon et al,¹¹ which was recently updated with long-term follow-up analysis,¹³ pegylated liposomal doxorubicin (PLD) and topotecan have been reported to exhibit, in this clinical setting, equivalent activity in terms of time to progression (TTP) and overall survival (OS) but a substantially different toxicity profile; in particular, grade 3 and 4 hematologic toxicity and alopecia were more frequently documented in topotecan-treated patients, whereas palmar-plantar erythrodysesthesia (PPE), stomatitis, and mucositis were more common with PLD and, in some patients, severe enough to require treatment discontinuation. On the basis of the promising results from phase II studies investigating gemcitabine (GEM) as a single agent or in combination in the salvage^14-16 treatment of ovarian cancer, a phase III trial has been conducted and recently published¹² comparing the efficacy and safety of GEM versus PLD in platinum-resistant ovarian cancer patients. In this trial, PLD was used according to the schedule approved by the US Food and Drug Administration (50 mg/m² every 4 weeks), which is characterized by rates of PPE of up to 23%^11-13 and, generally, by a higher rate of mucositis/stomatitis compared with the dosage of 40 mg/m² every 4 weeks.^17-20

On behalf of the Multicenter Italian Trials in Ovarian Cancer Group, a phase III randomized multicenter trial was planned with the aim to investigate the efficacy, tolerability, and QOL outcomes of GEM (standard schedule) compared with PLD (40 mg/m² every 28 days) in ovarian cancer patients who experienced treatment failure with only one platinum/paclitaxel regimen and recurrence/progression within 12 months after completion of primary treatment.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Study Design
This is a phase III, randomized, multicenter, comparative study of PLD versus GEM in women with epithelial ovarian carcinoma recurring within 12 months after completion of a primary platinum/paclitaxel-containing regimen. The primary end point of the study was the assessment of TTP in GEM-treated patients versus PLD-treated patients, whereas secondary end points were the assessment of OS, response rate, safety/toxicity, and QOL.

From January 2003 to January 2007, 153 patients were enrolled. All participating centers were required to obtain protocol approval by their appropriate institutional ethical committee. Registration, random assignment by central telephone service, and data management procedures were performed at the Gynecologic Oncology Unit, Catholic University of Rome (Rome, Italy). Outcome evaluators were blinded, whereas participants and physicians administering the treatment were not. Before random assignment in a 1:1 fashion, patients were stratified according to the enrolling institutions, platinum-free interval (PFI; < 6 v 7 to 12 months), and initial stage of disease. For both drugs, treatment was planned to begin immediately after random assignment. The inclusion of patients with a PFI within 7 to 12 months was justified by the demonstration that these patients, although classically considered as platinum sensitive, really do not entirely share the favorable clinical outcome of patients experiencing recurrence after 12 months from completion of primary therapy.^21,22

Eligibility Criteria
Women 18 years of age with measurable or assessable ovarian cancer according to Response Evaluation Criteria in Solid Tumors²³ who had experienced recurrence or treatment failure with one first-line, platinum/paclitaxel-containing chemotherapy were eligible. Additional criteria included adequate bone marrow function (platelets 100,000/µL, hemoglobin 9 g/dL, and absolute neutrophil count [ANC] 1,500 cells/µL), renal function (serum creatinine 1.5 mg/dL), liver function (AST 1.5x the upper limit of normal, alkaline phosphatase 1.5x the upper limit of normal, and bilirubin upper limit of normal), and cardiac function (left ventricular ejection fraction 50% or the institutional normal); Eastern Cooperative Oncology Group performance status of 0 to 2; and no prior malignancies (with the exception of curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma-in-situ of the cervix). Patients were excluded if they were pregnant or breast-feeding, were expected to live 3 months, had a history of cardiac disease that met the New York State Heart Association classification of class II or greater, or had an uncontrolled systemic infection. Patients were also excluded if they had received an investigational agent within 30 days of the first dose of study drug, had received prior PLD or GEM, or had received chemotherapy within 30 days of the first dose of study drug. Additionally, no concurrent investigational or antineoplastic agents were permitted during the study.

Treatment Plan
Patients in the control arm received PLD (Caelyx; Schering-Plough, New York, NY) 40 mg/m² via a 1-hour infusion every 28 days. Premedication with methylprednisolone (20 mg intravenous) 30 minutes before drug infusion was always performed. In the experimental arm, GEM (Gemzar; Eli Lilly, Indianapolis, IN) was administered at 1,000 mg/m² as a 30-minute infusion on days 1, 8, and 15 of a 28-day cycle.

Treatment with either drug was to be temporarily suspended or discontinued under any of the following conditions: disease progression, serious or intolerable adverse events precluding further treatment, inability to tolerate study drug despite dose modification, or patient's decision to withdraw participation.

Dose Adjustment
The study drug dose was reduced by 20% if, at nadir, platelets were less than 50,000/µL, hemoglobin was less than 7 g/dL, or ANC was less than 500 cells/µL for more than 5 days; in case of persistent febrile neutropenia; or in case of hepatic, renal, or cutaneous toxicity grade 2. In case of platelets less than 100,000/µL, hemoglobin less than 9 g/dL, or ANC less than 1,500 cells/µL on day 28, treatment was postponed by 1 week; treatment was discontinued if there was a delay of more than 2 weeks. The treatment was also discontinued in case of nonhematologic toxicity grade 3 (excluding alopecia and nausea/vomiting). For GEM, in case of ANC less than 1,500 cells/µL and/or platelets less than 100,000 cells/µL or hemoglobin less than 9 g/dL on days 8 or 15, the next dose of GEM would not be administered. For PLD, treatment was discontinued in case of left ventricular ejection fraction less than 45% or a 20% decrease from the baseline. Prophylactic cytokine administration was not allowed; however, growth factor support (granulocyte colony-stimulating factor) was allowed in subsequent cycles for any patient with grade 4 neutropenia lasting more than 5 days or febrile neutropenia. In case of hemoglobin less than 9 g/dL, erythropoietin or RBC transfusion was allowed at the physician's discretion.

Assessment of Response and Safety
Within 30 days before the first dose of study drug, patients were evaluated by medical history, physical examination, CBC, serum chemistries, CA-125 analysis, and thorax/abdomen computed tomography scan to define and measure the extent of disease. Assessment of response according to the Response Evaluation Criteria in Solid Tumors²³ was performed every two cycles. Data on CA-125 levels were also used to provide data on response, according to Rustin's²⁴ criteria.

Safety analyses were performed on all patients who received at least one partial infusion of the study drug. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria.²⁵

QOL Assessment
Within 2 weeks before enrollment and before each cycle, QOL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30.²⁶ Changes in this QOL measure from baseline scores were compared using the Wilcoxon signed rank sum test; all analyses were performed using SOLO Statistical Software (BMDP Statistical Software Inc, Los Angeles, CA).

Statistical Analysis
The required sample size was calculated assuming that a median TTP of 12 weeks from study drug administration would be observed in the PLD arm (control arm). Overall, 147 patients were needed to detect an improvement with GEM (experimental arm) in median TTP to 19 weeks, corresponding to a hazard ratio (HR) of progression of 0.63, based on a two-sided log-rank test at the error = .05 and a power of 80%. No interim analysis was planned. Efficacy analysis was performed on all randomly assigned patients based on the intent-to-treat principle. Response rates were compared using an unadjusted normal approximation for the difference of two binomial proportions, and 95% CIs were evaluated. TTP was estimated from the first day of study drug dosing to the date of disease progression or the date last seen, whereas OS was defined as the time interval from the first day of drug administration to death from disease or the date last seen. Medians and life-tables were computed using the product-limit estimate of the Kaplan-Meier method²⁷ and analyzed using the log-rank test.²⁸ Cox proportional hazards model²⁹ was used to assess the effect of treatment after adjusting for other variables.

Multivariate analyses including age, CA-125 levels, performance status, and PFI duration were done for both TTP and OS. For TTP, high CA-125 levels (> 500 U/mL; ² = 6.0; HR = 1.5; 95% CI, 1.0 to 1.9; P = .013) at recurrence and a shorter duration of PFI (< 6 months; ² = 10.7; HR = 1.9; 95% CI, 1.5 to 2.4; P = .001) at study entry maintained their independent negative prognostic value.

For OS, high CA-125 levels at recurrence (² = 5.0; HR = 1.3; 95% CI, 1.0 to 1.4; P = .025), a shorter duration of PFI (² = 9.9; HR = 1.6; 95% CI, 1.4 to 2.4; P = .001), and a performance status of more than 0 (² = 10.1; HR = 1.9; 95% CI, 1.1 to 2.1; P = .001) were independently associated with poor prognosis. The treatment difference was no longer significant for either TTP (² = 2.5; HR = 0.9; 95% CI, 0.8 to 1.0; P = .102) or OS (² = 1.9; HR = 0.9; 95% CI, 0.7 to 1.2; P = .158).

	RESULTS

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Patient Characteristics
As of January 2007, 153 patients were assessed for study eligibility, and all were enrolled (Fig 1). Seventy-six patients were randomly assigned to the PLD arm, and 77 patients were allocated to GEM treatment. Four patients in the PLD arm and six patients in the GEM arm refused treatment, thus leaving 72 and 71 patients assessable for safety analysis in the PLD and GEM arms, respectively. The treatment arms were well balanced for clinicopathologic characteristics (Table 1). Overall, a total of 600 courses are assessable for toxicity (312 in PLD arm and 288 in GEM arm; Table 2); the median cumulative dose for each treatment group was close to that specified in the protocol, indicating good compliance in following the dosing guidelines. There was no difference in the frequency of patients requiring dose reduction in the PLD arm versus the GEM arm, whereas patients administered GEM more frequently required dose delay compared with patients on the PLD arm. A higher percentage of GEM-treated patients had to discontinue treatment compared with PLD-treated patients, although statistical significance was not reached (P = .114).

View larger version (30K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Study design. PLD, pegylated liposomal doxorubicin; GEM, gemcitabine.

One hundred thirty-seven patients had elevated CA-125 levels at baseline evaluation; based on Rustin's criteria²⁴, complete and partial response were documented in 17 patients (12%) and 13 patients (9%), respectively. Stabilization and progression of disease were found in 54 patients (39%) and 32 patients (23%), respectively. In 21 patients, no data on CA-125 levels during treatment were available.

As of June 2007, 134 patients (88%) experienced progression of disease, and 95 patients (62%) died of disease. After a median follow-up time of 39 weeks (range, 3 to 215 weeks), no statistically significant difference in TTP curves according to treatment allocation was documented (Fig 2A); in particular, median TTP was 16 weeks in PLD-treated patients compared with 20 weeks in GEM-treated patients (P = .411). However, a trend toward a more favorable OS was documented in the PLD arm compared with the GEM arm, although the trend was of borderline statistical significance (P = .048); the median OS time was 56 weeks in PLD-treated patients compared with 51 weeks in GEM-treated patients. There was no difference in TTP curves according to treatment allocation in the two groups. Regarding OS, there was no difference in the clinical outcome between GEM- and PLD-treated patients in the subgroup with a PFI of less than 6 months, whereas a better survival favoring the PLD arm versus the GEM arm was documented in the subgroup of patients with a PFI of 7 to 12 months (P = .013). Given the primary objective of the study, the data relative to postprogression treatment were not prospectively collected and were, therefore, available in only 36 patients (23%).

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier estimate of (A) time to progression (TTP) and (B) overall survival (OS) curves. P values were calculated using the log-rank test. PLD, pegylated liposomal doxorubicin; GEM, gemcitabine.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Box-whiskers plots of the global quality of life (QoL) scores for patients treated with pegylated liposomal doxorubicin (PLD; n = 60 at baseline) and gemcitabine (GEM; n = 61 at baseline). Scores range from 0 to 100 (100 = best score). The bottom and top edges of the box represent the 25th and 75th percentiles, respectively; whereas the horizontal line corresponds to the median value. The vertical lines show the range of values. (*) P < .05.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

Although we documented a trend for a more favorable OS in the PLD arm versus the GEM arm in the overall series and in the subgroup of patients with a PFI duration of 7 to 12 months, the relatively low number of patients, the borderline statistical significance, and the scarcity of data on postprogression chemotherapy regimens do not allow any firm conclusion to be drawn.

In conclusion, we showed that GEM does not provide an advantage compared with PLD in terms of TTP of ovarian cancer patients experiencing recurrence within 12 months from primary treatment, but GEM has to be considered in the spectrum of drugs to be possibly used in the salvage setting. Overall, PLD proved to be more manageable compared with GEM because, with this schedule, negligible hematologic toxicity and, more importantly, low rates of mucositis and skin toxicity were documented. This leads to a hypothesis that the already recognized more favorable therapeutic index of PLD³³ could be further improved with an advantage in terms of cost savings.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Sandro Pignata, Giovanni Scambia

Provision of study materials or patients: Gabriella Ferrandina, Domenica Lorusso, Sandro Pignata, Enrico Breda, Antonella Savarese, Pietro Del Medico, Laura Scaltriti, Dionyssios Katsaros, Domenico Priolo, Giovanni Scambia

Collection and assembly of data: Gabriella Ferrandina, Manuela Ludovisi, Domenica Lorusso

Data analysis and interpretation: Gabriella Ferrandina

Manuscript writing: Gabriella Ferrandina, Sandro Pignata, Giovanni Scambia

Final approval of manuscript: Gabriella Ferrandina, Manuela Ludovisi, Domenica Lorusso, Sandro Pignata, Enrico Breda

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The following are members of the Multicenter Italian Trials in Ovarian Cancer Group: Mario Nardi: Medical Oncology, Ospedali Riuniti, Reggio Calabria; Giovanni Di Vagno, Francesco Petruzzelli: Department of Obstetrics and Gynecology, Casa Sollievo della Sofferenza, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Foggia; Mauro Colangelo: Medical Oncology, SS. Annunziata Hospital, Sulmona; Luca Moscetti: Department of Medical Oncology, Belcolle Hospital, Azienda Sanitaria Nazionale Viterbo; Lanzetta Gaetano: Department of Radiotherapy and Oncology, Istituto Neurotraumatologico Italiano, Grottaferrata, Rome; Mauro Antimi: Division of Medical Oncology, S. Eugenio Hospital, Rome; Gianfranco Filippelli: Medical Oncology Unit, Presidio Ospedaliero di Paola, Paola; Nicola Gebbia, Maria Rosaria Valerio: Medical Oncology, University of Palermo, Palermo; Desiderio Gueli Alletti: Gynecologic Oncology Unit, Cervello Hospital, Palermo; Marisa Di Seri: Medical Oncology, University of Rome "La Sapienza," Rome; Paolo Scollo: Gynecology Unit, Cannizzaro Hospital, Catania; Alberto Ballestrero: Department of Internal Medicine, University of Genoa, Genoa; Roberto Bordonaro: Department of Oncology, S. Luigi Currò Hospital, Catania; Rodolfo Mattioli; S Croce Hospital, Fano, Ancona; and Teresa Gamucci: Division of Medical Oncology, Umberto I Hospital, Frosinone, Italy.

	NOTES

 
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted July 26, 2007; accepted November 7, 2007.

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