Abstract

Background

The addition of anthracyclines to platinum-based chemotherapy may provide benefit in survival in ovarian cancer patients. We evaluated the effect on survival of adding epirubicin to standard carboplatin and paclitaxel.

Patients and methods

We carried out a prospectively randomized phase III study comparing carboplatin plus paclitaxel (TC; area under the curve 5 and 175 mg/m2) with the same combination and epirubicin (TEC; 75 mg/m2 i.v.). Between March 1999 and August 2001, 887 patients with epithelial ovarian, tubal or peritoneal cancer International Federation of Gynecology and Obstetrics stages IIB–IV were randomized to receive either TC (442 patients) or TEC (445 patients).

Results

Median time to progression was 16.4 months in the TEC arm and 16.0 months in the TC arm (hazard ratio 0.99; 95% confidence interval [CI]: 0.9–1.2). Median overall survival time was 42.4 months for the TEC arm and 40.2 for the TC arm (hazard ratio 0.96; 95% CI: 0.8–1.1). Grade 3/4 hematologic toxic effects and most grade 3/4 non-hematologic toxic effects were more frequent in the TEC arm. Accordingly, a quality-of-life analysis showed inferiority of TEC versus TC.

Conclusion

The addition of epirubicin to standard carboplatin and paclitaxel treatment did not improve survival in patients with advanced ovarian, tubal or peritoneal cancer.

introduction

The recommended regimen for advanced ovarian cancer and standard comparator in clinical trials is the combination of carboplatin with paclitaxel [1]. Despite the improvement in treatment of ovarian cancer with debulking surgery and platinum-based chemotherapy, the majority of patients with advanced stages still relapses and dies of their disease. The addition of a third drug in first-line therapy might therefore improve prognosis, and anthracyclines are among the candidates for this combination. Three successive meta-analyses have enlightened the importance of the addition of doxorubicin to various first-line regimens in ovarian cancer [2–4]. Epirubicin, a doxorubicin analog, has also shown effective in ovarian cancer patients [5, 6]. A synergistic effect between anthracyclines and paclitaxel is also suggested by studies in the treatment of patients with metastatic breast cancer [7–10]. However, in ovarian cancer, the previously published randomized phase III trial of the German Arbeitsgemeinschaft Gynaekologische Onkologie OVAR (AGO-OVAR) and the French Groupe d'Investigateurs Nationaux pour l'Étude des Cancers Ovariens et du sein (GINECO) group failed to show any improvement in progression-free or overall survival in patients with advanced ovarian cancer treated with the anthracycline-containing regimen (paclitaxel–carboplatin plus epirubicin [TEC]) [11].

The Nordic Society of Gynaecological Oncology, the EORTC Gynaecological Cancer Group and the Clinical Trials Group of the National Cancer Institute of Canada (NCIC CTG) conducted a prospectively randomized phase III study evaluating the effect of adding epirubicin to the standard treatment with carboplatin and paclitaxel in the first-line treatment of advanced ovarian/tubal/peritoneal cancer. Some results of this trial were previously presented at the 2004 Annual Meeting of the American Society of Clinical Oncology, the 15th International Meeting of the European Society of Gynaecological Oncology and the Geico Symposium 2005. We present the final results in this article.

patients and methods

The study was designed and carried out in accordance with good clinical practice, the declaration of Helsinki and national laws. Local ethics committee of each participating center approved the study. All patients provided written informed consent before study entry.

eligibility criteria, randomization and quality assurance

Patients with histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stages IIB to IV epithelial ovarian, fallopian tube or peritoneal cancer were eligible. Age at baseline had to be at least 18 years with a World Health Organization (WHO) performance status of 0–2. Adequate hematologic, renal and hepatic function, defined as follows, was required: absolute neutrophil count (ANC) ≥1.5 × 109/l, platelet count ≥100 × 109/l, glomerular filtration rate (GFR) ≥50 ml/min and bilirubin ≤2× upper normal limits. Exclusion criteria were: symptomatic brain metastases, a history of other primary malignancies except for carcinoma in situ of the cervix and basal cell carcinoma of the skin, previous radiation or chemotherapy, severe neuropathy (National Cancer Institute Common Toxicity Criteria grade >1) [12], a history of important cardiac disease such as ventricular arrhythmias, myocardial infarction within 1 year, severe or uncontrolled hypertension, congestive heart failure (New York Heart Association classification >2) or a left ventricular ejection fraction below 50%.

Patients were stratified into one of three a priori strata according to timing of surgery, residual tumor size and FIGO stage. Stratum 1 contained patients with FIGO stages IIB–III disease and residual tumor size of <1 cm. Stratum 2 contained patients with FIGO stage IV disease or residual tumor size of >1 cm. Stratum 3 contained patients with delayed surgery after three courses of chemotherapy.

Randomization was carried out by computer using minimization techniques.

The responsible study office of each study group checked all the data collected on case report forms for consistency.

treatment plan and dose modifications

Patients were randomized to receive six to nine cycles of paclitaxel at a dose of 175 mg/m2 given as a 3-h infusion followed by carboplatin given as a 60-min infusion with area under the curve (AUC) 5. The carboplatin dose was calculated with the Calvert formula: carboplatin dose in milligrams = AUC × (GFR + 25). The GFR was estimated using CrEDTA, iohexol or creatinine clearance. In cases where none of those methods were feasible, the formulas of Chatelut [13] or Cockroft [14] were used. Patients in the TEC arm received epirubicin at a dose of 75 mg/m2 i.v. before paclitaxel. Courses were given on a 3-weekly schedule.

Dose reductions were allowed depending on predefined levels of hematologic or non-hematologic toxicity (Table 1). Any subsequent treatment cycle was delayed when the patient’s ANC was <1.5 × 109 cells/l or the platelet count was <100 × 109 cells/l. The use of supportive granulocyte colony-stimulating factor (G-CSF) treatment was not allowed in place of dose reduction but was left to the investigator’s opinion. If hematologic recovery was not achieved at day 35, the patient was withdrawn from study treatment, and further treatment was on the investigators discretion.

Table 1.

Dose modifications according to non-hematologic or hematologic toxic effects

Dose level −4 −3 −2 −1 
TEC      
 Epirubicin (mg/m260 60 60 75 
 Paclitaxel (mg/m2150 150 150 175 175 
 Carboplatin (AUC) 
TC      
 Paclitaxel (mg/m2  150 150 175 
 Carboplatin (AUC)   
Dose level −4 −3 −2 −1 
TEC      
 Epirubicin (mg/m260 60 60 75 
 Paclitaxel (mg/m2150 150 150 175 175 
 Carboplatin (AUC) 
TC      
 Paclitaxel (mg/m2  150 150 175 
 Carboplatin (AUC)   

TEC, paclitaxel–carboplatin plus epirubicin; TC, paclitaxel–carboplatin; AUC, area under the curve.

Premedication consisting of a single-dose dexamethasone of 20 mg i.v. and both a histamine receptor type 1 and type 2 blocking agent (e.g. clemastine 2 mg and cimetidine 300 mg) was administered 30 min before the paclitaxel infusion. Antiemetic prophylaxis consisted of 5-hydroxytryptamine-3 antagonists and corticosteroids. Patients with disease progression during therapy discontinued protocol treatment. Patients with residual tumor after six treatment cycles, but still responding to the treatment could receive three additional treatment cycles.

evaluations and follow-up

Adverse events and toxicity were graded during each cycle by the study investigator according to the National Institute Common Toxicity Scale version 3.0, National Cancer Institute Common Toxicity Criteria version 3.0 [12]. Toxic effects were recorded continuously and were evaluated using the worst score over all cycles for each patient. Hematologic parameters were measured before each treatment cycle. A complete blood cell count was carried out on day 14 ± 2 days of each cycle. In patients with residual tumor after surgery, imaging was carried out at baseline and after every three cycles of treatment using the same imaging technique. Computed tomography (CT) was the preferred method used by all institutions except one, who used ultrasound. Objective tumor response and progression were assessed according to WHO [15]. In case of clinical complete remission at the end of treatment, a second look laparotomy was allowed but not recommended. Follow-up visits were scheduled every 3–4 months until 24 months after the day of last treatment course, every 6 months, years 3–5 and yearly thereafter. The visits included gynecological examination, vaginal ultrasound and measurement of CA-125. In case of rising in CA-125 or symptoms, a CT scan was carried out.

Quality of life (QoL) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) version 3.0. The questionnaires were handed out before randomization and again after three and six cycles, independent of treatment or disease status. In case of nine cycles, another assessment was carried out after completion of the ninth cycle. After cessation of treatment, QoL was assessed every six months during the first year. QoL responses were evaluated according to the EORTC guidelines [16].

statistical analyses

The primary outcome measure was progression free survival. A total of 542 progressions were required to detect a hazard ratio of 0.786 or less with a power of 80% and 5% significance (two sided).

Secondary end points were overall survival, toxicity and QoL.

Progression free survival was defined as the time from randomization to disease progression or death of any cause. Patients still alive without progression were censored at the date of their last follow-up visit. Overall survival was defined as the time from randomization to death of any cause. Overall response was defined as the number of patients who had a partial or complete response divided by the number of patients with measurable disease at baseline. Time-to-event data were analyzed using the Kaplan–Meier method. The log-rank test was used to compare survival. Two-sided tests were used for significance testing. The Cox proportional hazards model was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Efficacy analyses were carried out on all randomly assigned patients (intention-to-treat basis). Patients receiving at least one treatment cycle were qualified for safety analysis. Differences in toxicity between treatment arms were evaluated with the Mann–Whitney rank sum test. Patients with overall health score recorded on at least three different time points were considered qualified for the analysis of QoL. For each patient, the measurement at baseline was compared with, respectively, mean and max score of the rest of the time points. Measurements were compared using a paired t-test within treatments. Additionally, the change from baseline to max or mean of the remaining measurements was compared between treatment arms using an unpaired t-test. The STATA statistical package, version 10.0, was used for the analysis.

results

patients and follow-up

Between March 1999 and August 2001, 887 patients with epithelial ovarian, tubal or peritoneal cancer FIGO stages IIB–IV were enrolled. Of the 887 patients, 329 patients for stratum 1, 485 patients for stratum 2 and 73 fulfilled the criteria for stratum 3. At randomization, 445 patients were assigned to TEC and 441 to paclitaxel–carboplatin (TC). The treatment arms were well balanced for baseline characteristics (Table 2).

Table 2.

Baseline patient characteristics

Characteristic TEC arm
 
TC arm
 
Total
 
 n n n 
No. of patients 445 50.17 442 49.83 887 100 
Age (years)       
 Range 28–79 25–80 25–80 
 Median 57 58 57 
FIGO stage       
 IIb 19 4.3 23 5.2 42 4.7 
 IIc 34 7.6 31 7.0 65 7.3 
 IIIa 17 3.8 27 6.1 44 5.0 
 IIIb 39 8.8 48 10.9 87 9.8 
 IIIc 259 58.2 250 56.6 509 57.4 
 IV 77 17.3 63 14.3 140 15.8 
Residual tumor (cm)       
 <1 177 39.8 185 41.9 362 40.8 
 ≥1 268 60.2 257 58.1 525 59.2 
Strata       
 1 159 35.7 170 38.5 329 37.1 
 2 243 54.6 242 54.8 485 54.7 
 3 43 9.7 30 6.8 73 8.2 
Histology       
 Serous 303 68.1 289 65.4 592 66.7 
 Mucinous 17 3.8 16 3.6 33 3.7 
 Clear cell 18 4.0 19 4.3 37 4.2 
 Endometroid 53 11.9 53 12.0 106 12.0 
 Undifferentiated 1.8 14 3.1 22 2.5 
 Unclassified 1.6 11 2.5 18 2.0 
 Other 31 7.0 36 8.1 67 7.6 
 Unknown 1.8 0.9 12 1.4 
Grade       
 Well diff. 48 10.8 44 10.0 92 10.4 
 Mod. diff. 105 23.6 114 25.8 219 24.7 
 Poor diff. 248 55.7 244 55.2 492 55.5 
 Not specified 44 10.0 40 9.0 84 9.5 
Performance status       
 0 237 53.3 237 53.6 474 53.4 
 1 178 40.0 184 41.6 362 40.8 
 2 30 6.7 21 4.8 51 5.8 
Characteristic TEC arm
 
TC arm
 
Total
 
 n n n 
No. of patients 445 50.17 442 49.83 887 100 
Age (years)       
 Range 28–79 25–80 25–80 
 Median 57 58 57 
FIGO stage       
 IIb 19 4.3 23 5.2 42 4.7 
 IIc 34 7.6 31 7.0 65 7.3 
 IIIa 17 3.8 27 6.1 44 5.0 
 IIIb 39 8.8 48 10.9 87 9.8 
 IIIc 259 58.2 250 56.6 509 57.4 
 IV 77 17.3 63 14.3 140 15.8 
Residual tumor (cm)       
 <1 177 39.8 185 41.9 362 40.8 
 ≥1 268 60.2 257 58.1 525 59.2 
Strata       
 1 159 35.7 170 38.5 329 37.1 
 2 243 54.6 242 54.8 485 54.7 
 3 43 9.7 30 6.8 73 8.2 
Histology       
 Serous 303 68.1 289 65.4 592 66.7 
 Mucinous 17 3.8 16 3.6 33 3.7 
 Clear cell 18 4.0 19 4.3 37 4.2 
 Endometroid 53 11.9 53 12.0 106 12.0 
 Undifferentiated 1.8 14 3.1 22 2.5 
 Unclassified 1.6 11 2.5 18 2.0 
 Other 31 7.0 36 8.1 67 7.6 
 Unknown 1.8 0.9 12 1.4 
Grade       
 Well diff. 48 10.8 44 10.0 92 10.4 
 Mod. diff. 105 23.6 114 25.8 219 24.7 
 Poor diff. 248 55.7 244 55.2 492 55.5 
 Not specified 44 10.0 40 9.0 84 9.5 
Performance status       
 0 237 53.3 237 53.6 474 53.4 
 1 178 40.0 184 41.6 362 40.8 
 2 30 6.7 21 4.8 51 5.8 

TEC, paclitaxel–carboplatin plus epirubicin; TC, paclitaxel–carboplatin.

The median follow-up was 61.0 months for patients still alive.

treatment compliance and toxicity

A total of 5419 treatment cycles were administered, 2672 in the TEC arm and 2749 in the TC arm. A total of 881 patients (99.3%) received at least one treatment cycle. Most patients received at least six treatment cycles: 82.9% in the TEC arm and 86.4% in the TC arm. In total, 181 (20%) patients received >6 treatment cycles, 82 (18.4%) in the TEC arm and 99 (22.3%) in the TC arm.

Treatment delays of at least 7 days occurred in 7 of 445 patients (1.6%) in the TEC and in 5 of 442 (1.1%) in the TC arm. In the TEC arm, the overall dose intensity (i.e. received/planned) was 63%. Epirubicin was reduced to 60 mg/m2 in 76 patients (17%). Further dose modifications with a reduction to a Paclitaxel dose of 150 mg/m2 was necessary in 58 patients (13%) and to carboplatin AUC = 4 in 31 patients (7%). In the TC arm, the overall dose intensity (i.e. received/planned) was 85% of that planned. Paclitaxel was reduced to 150 mg/m2 in 44 patients (10%) and to carboplatin AUC = 4 in 22 patients (5%).

Grade 3/4 hematologic toxic effects were more frequent in the TEC arm than in the TC arm, but apart from hemoglobin, differences did not reach statistical significance (Table 3). Febrile neutropenia occurred much more often in the TEC arm (18.2%) than in the TC arm (3.6%). Patients treated with TEC received more often G-CSF than patients in the TC arm.

Table 3.

Hematologic toxic effects and G-CSF use by treatment arm and toxicity grade

Toxicity NCI–CTC grade (%)
 
 
 TC arm
 
TEC arm
 
 
 n n P* 
Hemoglobin 439 16.6 61.5 20.5 0.5 0.9 441 3.9 37.6 51.0 6.4 1.1 <0.0001 
Leucocytes 439 41.9 46.0 11.0 1.1 441 39.2 49.0 9.3 1.8 0.7 0.5026 
Granulocytes 437 38.4 41.0 17.9 2.8 437 35.0 43.9 15.6 4.6 0.9 0.3251 
Platelets 439 96.4 3.2 0.5 441 96.8 2.3 0.5 0.5 0.7136 
Febrile neutropenia 437 96.3 3.7 439 81.8 18.2 <0.0001 
G-CSF 237 87.8 — — 12.2 — 251 72.9 — — 27.1 — <0.001** 
Toxicity NCI–CTC grade (%)
 
 
 TC arm
 
TEC arm
 
 
 n n P* 
Hemoglobin 439 16.6 61.5 20.5 0.5 0.9 441 3.9 37.6 51.0 6.4 1.1 <0.0001 
Leucocytes 439 41.9 46.0 11.0 1.1 441 39.2 49.0 9.3 1.8 0.7 0.5026 
Granulocytes 437 38.4 41.0 17.9 2.8 437 35.0 43.9 15.6 4.6 0.9 0.3251 
Platelets 439 96.4 3.2 0.5 441 96.8 2.3 0.5 0.5 0.7136 
Febrile neutropenia 437 96.3 3.7 439 81.8 18.2 <0.0001 
G-CSF 237 87.8 — — 12.2 — 251 72.9 — — 27.1 — <0.001** 

Use of G-CSF was coded as toxicity of grade 3, a grade of toxicity was applied otherwise.

*Except for G-CSF support, P value according to Mann–Whitney rank sum test; **P value according to Fischer exact test.

NCI–CTC, National Cancer Institute–Common Toxicity Scale; TC, paclitaxel–carboplatin; TEC, paclitaxel–carboplatin plus epirubicin; G-CSF, granulocyte colony-stimulating factor.

Table 4 shows all non-hematologic toxic effects according to treatment arm. Most of the grade 3/4 non-hematologic toxic effects were more frequent in the TEC arm. Among those were nausea, vomiting and mucositis. However, grade 3/4 allergic reactions and grade 3 arthralgia and myalgia were more often in the TC arm. Reduction of left ventricular function of at least 20% compared with baseline was seen in three patients (0.7%) in the TEC arm and none in the TC arm. This difference was not statistically significant.

Table 4.

Non-hematologic toxic effects by treatment arm and toxicity grade

Toxicity NCI–CTC grade (%)
 
P* 
 TC arm
 
TEC arm
 
 
 n n  
Allergy 436 71.3 17.0 6.4 3.7 1.6 441 83.7 10.0 3.0 3.0 0.5 <0.0001 
Arthralgia 435 39.8 30.6 22.5 7.1 440 45.0 32.5 18.4 4.1 0.0225 
Myalgia 435 33.6 34.9 25.1 6.4 440 42.7 35.5 18.0 3.9 0.0005 
Nausea 436 33.0 44.7 18.1 3.9 0.2 440 20.0 40.5 28.4 10.9 0.2 <0.0001 
Vomiting 436 65.6 20.4 10.1 3.4 0.5 439 43.1 26.7 20.0 9.3 1.4 <0.0001 
Mucositis 435 73.3 20.2 5.8 0.7 439 50.8 29.2 15.7 3.9 0.5 <0.0001 
Neuropathy motoric 434 73.7 16.8 7.8 1.4 0.2 439 71.3 19.8 4.8 3.9 0.2 0.4533 
Neurohearing 435 90.1 6.9 2.5 0.5 439 90.7 5.9 2.7 0.7 0.8092 
Neuropathy sensory 436 26.8 49.8 20.0 3.2 0.2 439 27.6 49.4 20.3 2.7 0.7813 
Toxicity NCI–CTC grade (%)
 
P* 
 TC arm
 
TEC arm
 
 
 n n  
Allergy 436 71.3 17.0 6.4 3.7 1.6 441 83.7 10.0 3.0 3.0 0.5 <0.0001 
Arthralgia 435 39.8 30.6 22.5 7.1 440 45.0 32.5 18.4 4.1 0.0225 
Myalgia 435 33.6 34.9 25.1 6.4 440 42.7 35.5 18.0 3.9 0.0005 
Nausea 436 33.0 44.7 18.1 3.9 0.2 440 20.0 40.5 28.4 10.9 0.2 <0.0001 
Vomiting 436 65.6 20.4 10.1 3.4 0.5 439 43.1 26.7 20.0 9.3 1.4 <0.0001 
Mucositis 435 73.3 20.2 5.8 0.7 439 50.8 29.2 15.7 3.9 0.5 <0.0001 
Neuropathy motoric 434 73.7 16.8 7.8 1.4 0.2 439 71.3 19.8 4.8 3.9 0.2 0.4533 
Neurohearing 435 90.1 6.9 2.5 0.5 439 90.7 5.9 2.7 0.7 0.8092 
Neuropathy sensory 436 26.8 49.8 20.0 3.2 0.2 439 27.6 49.4 20.3 2.7 0.7813 

*P Value according to Mann–Whitney rank sum test. Given the number of tests carried out, only P values below 0.005 should be considered significant.

tumor response and survival

Only 391 had measurable disease at study entry. Of those, response to treatment could be assessed in 184 patients in the TEC arm and 195 in the TC arm. Complete response was achieved in 121 patients (65.7%) in the TEC arm and in 107 patients (54.9%) in the TC arm. A partial response was obtained in 37 (20.1%) and 49 (25.1%) patients, respectively. The overall response rate was 85.8% and 80.0%, respectively, with no statistically significant difference between treatment arms.

A total of 731 (82.4%) had progressive disease during follow-up. Median progression free survival time was 16.4 months (95% CI: 15.1–17.8) in the TEC arm and 16.0 months (95% CI: 14.3–17.1) in the TC arm, corresponding to an HR of 0.99 (95% CI: 0.9–1.2) (Figure 1). In the group of patients with residual tumor of <1 cm (stratum 1), median progression-free survival time was 24.4 months (95% CI: 20.3–28.8). For patients with residual tumor of >1 cm (stratum 2) and delayed surgery after three courses of chemotherapy (stratum 3) median progression-free survival time was 13.8 months (95% CI: 12.8–14.6) and 13.8 months (95% CI: 11.8–15.7), respectively. There was no significant difference in progression-free survival between the treatment arms according to these strata supplemental Figure S1 (available at Annals of Oncology online).

Figure 1.

Kaplan–Meier estimates of progression-free survival according to treatment.

Figure 1.

Kaplan–Meier estimates of progression-free survival according to treatment.

By the end of the observation period, 581 (65.5%) patients had died. Median overall survival time was 42.4 (95% CI: 35.2–48.5) months for the TEC arm and 40.2 (95% CI: 34.7–43.8) for the TC arm corresponding to an HR of 0.96 (95% CI: 0.8–1.1) (Figure 2). The overall survival curves according to treatment and stratum are shown in supplemental Figure S2 (available at Annals of Oncology online). In the group of patients with residual tumor of <1 cm (stratum 1) median overall survival time was 57.5 months (95% CI: 49.0–77.8). However, patients with delayed surgery after three courses of chemotherapy (stratum 3) had a median overall survival time of 33.2 months (95% CI: 29.2–36.7). Patients with residual tumor of >1 cm (stratum 2) also had a median overall survival time of 33.2 months (95% CI: 29.2–36.7).

Figure 2.

Kaplan–Meier estimates of overall survival according to treatment.

Figure 2.

Kaplan–Meier estimates of overall survival according to treatment.

quality of life

QoL was measured for a total of 887 patients on 1–13 time points per patient with a mean of 3.28 (95% CI: 3.2–3.4) time points. We analyzed overall health score comparing baseline to both mean and maximal score for the remaining visits. In the TEC arm, 284 patients qualified for the analysis compared with 282 patients in the TC arm. Patients in the TEC arm had a slightly better global health score at baseline of 4.65 (95% CI: 4.5–4.8) compared with 4.49 (95% CI: 4.3–4.7) in the TC arm. In both arms, there was a substantial change in QoL from baseline to the mean as well as max of the remaining time points (all P < 0.0001). In both groups, an improvement during chemotherapy was observed, but the patients in the TC arm experienced a significantly greater change from baseline to both the mean (P = 0.0112) and to max of the remaining time points (P = 0.0374).

discussion

This trial confirmed the lack of benefit of adding the anthracycline epirubicin to a platinum-based therapy in advanced ovarian, tubal or peritoneal cancer. There was no difference in progression-free or overall survival between the two treatment arms TEC and TC. However, the TEC regime was associated with higher toxicity and lower QoL.

Despite the implementation of carboplatin and paclitaxel as the current standard of care in first-line treatment of ovarian cancer, rates of recurrence and death remains high. Generally, trials evaluating three-drug combinations in patients with advanced ovarian cancer have produced disappointing results. Three-drug regimens were mostly associated with higher toxicity without any benefit for survival. Our trial confirms the results of the AGO-OVAR/GINECO study [11] despite the slightly higher epirubicin dose of 75 mg/m2 in our study. They reported a nonsignificant reduction of 10% in overall survival (OS) in the TEC arm, while we observed a 2.2-month improvement for the TEC arm.

Sequential studies of epirubicin and paclitaxel have suggested that epirubicin clearance is reduced when paclitaxel precedes the administration of epirubicin. A sequence-dependant effect on myelotoxicity has been observed [17]. However, clinical consequences with regard to efficacy are less clear. Therefore, the classical way of administration (i.e. anthracyclines followed by paclitaxel) was used in the present trial.

The incorporation of liposomal doxorubicin, another anthracycline, in the standard regime in the five-arm trial GOG182-ICON5 did not improve survival either [18]. The other arms in that multi-international trial also evaluated combinations with gemcitabine and topotecan but failed to show superiority of any of those treatment regimes. This is in concordance with two European studies which evaluated the benefit of adding those agents to carboplatin–paclitaxel [19, 20]. Current clinical trials focus on the targeted treatment options and the addition of antiangiogenic agents has received growing attention. Two intergroup studies, International Collaborative Ovarian Neoplasm study 7 (ICON-7) and Gynecologic Oncology Group 218 (GOG 218), have evaluated the addition of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) antibody, to standard chemotherapy in primary treatment and reported improvements of PFS [21, 22]. Final results on overall survival from those studies will gather more evidence as to whether the addition of antiangiogenic agents in first-line therapy will provide any benefit for patients with primary advanced ovarian cancer.

In our study, we report PFS and OS in three strata according to tumor burden at baseline. Patients in stratum 1 with FIGO stages IIB–III disease and residual tumor size of <1 cm had a significantly better PFS and OS in both treatment arms than patients with surgery after neoadjuvant chemotherapy or residual tumor of >1cm (Figure S2). There was no difference in PFS and OS between patients with delayed surgery and suboptimally debulked patients with residual tumor of >1 cm. This confirms the key role of maximally cytoreductive surgery at baseline in patients with advanced disease.

We are now confident that the addition of a third cytotoxic agent will not add benefit to standard treatment with carboplatin–paclitaxel. Hope may lie in the inclusion of targeted agents addressing fundamental mechanisms of disease progression. Besides VEGF, promising results from a phase II study on progression-free survival have been published on poly (ADP-ribose) polymerase inhibition [23].

The greatest success to date has been achieved with the use of agents that target the VEGF pathway. Questions remain, however, about the requirement for documented single-agent activity and their use in concurrent or maintenance therapy. We have to acknowledge that ovarian cancer is a heterogeneous group of tumors with distinctly different etiologies, clinical behavior and treatment responsiveness. We may have to select patients carefully in order to achieve the greatest impact of targeted treatment options. Future intergroup studies are crucial in order to systematically evaluate targeted agents in selected patient populations.

funding

Pharmacia-Upjohn (educational grant).

disclosure

The authors have declared no conflict of interest.

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appendix

the manuscript is published in the name of the following collaborators: Nordic Society of Gynaecological Oncology (NSGO) group

The Norwegian Radium Hospital, Oslo, Norway (Kristensen GB, Kern J, Scheistroen M, Sert B); Trondheim University Hospital, Norway (Hagen B); Tromsø University Hospital, Norway (Himmelmann A); Karolinska University Hospital, Stockholm, Sweden (Åvall-Lundquist E); Lund University Hospital, Sweden (Ridderheim M); Århus University Hospital, Denmark (Havsteen H); Odense University Hospital, Denmark (Bertelsen K, Mirza M); Sønderborg Hospital, Denmark (Lindegaard Madsen E); Vejle Hospital, Denmark (Jakobsen A); Esbjerg Hospital, Denmark (Sandberg E); Herning Hospital, Denmark (Keldsen N); Clinical Hospital, Split, Croatia (Vrdoljak E); Ljubljana University Hospital, Slovenia (Cerar O); Ilica Hospital, Zagreb, Croatia (Mrsic-Krmpotic Z); Merkur University Hospital, Zagreb, Croatia (Kukura V).

the European Organisation for Research and Treatment of Cancer (EORTC) Gynaecological Cancer Group

University Hospital Leuven, Belgium (Vergote I); General Hospital Middelheim, Antwerpen, Belgium (Makar AP, Vandebroek A, Joosens E); University Hospital Antwerpen, Belgium (Vermorken J, van den Brande J); University Hospital Bordet-Erasme, Brussels, Belgium (Piccart M); Cazk Maria’s Voorz, Belgium (Van Eygen K); H.-Hartziekenhuis Roeselare, Belgium (Van Aelst F, Demol Y); Hospital Universitario 12 de Octubre, Madrid, Spain (Mendiola C); Hospital Clinico Universitario Valencia, Spain (Cervantes A); Hospital Universitario San Carlos, Madrid, Spain (Casado Herraez A); Instituto Valenciano De Oncologica, Spain (Poveda A); The Centre François Baclesse, Caen, France (Joly F, Heron JF); University Hospital Leiden, Netherlands (Nooji M); Hospitais da Universidade de Coimbra, Portugal (De Oliveira CF); I.P.O. Francisco Gentil Centro de Lisboa, Portugal (Kristeller TV); Clatterbridge Hospital, Wirral, Great Britain (Green JA); Queen Elizabeth Hospital, Gateshead, Great Britain (De Barros Lopes A); University of Brescia, Italy (Pecorelli S); Osp Umberto, Torino, Italia (Zola P).

Clinical Trials Group of the National Cancer Institute of Canada (NCIC-CTG)

The Baker Cancer Centre, Calgary (Stuart G, Nation J); BCCA, Vancouver (Swenerton K, Miller D, Ehlen T); BCCA, Frazer Valley (Lee U); BCCA, Southern Interior (Ellard S); BCCA Vancouver Island, Victoria (MacNeil M); Juravinski Cancer Centre, Hamilton (Hirte H, Moens F, Mazurka J, Elit L); Ottawa Hospital, Ottawa (Fungkee F, Faught W); Hotel-Dieu de Quebec, Quebec (Plante M, Roy M); Nova Scotia Cancer Centre, Halifax (Grimshaw R); Hospital Notre-Dame, Hearst (Charpentier D, Provencher D, Gauthier J); Princess Margaret Hospital, Toronto (Oza A); London Cancer Centre, London (Carey M); Cancer Care, Manitoba (Lotocki R); Centre hospitalaire universitaire de Sherbrooke, Sherbrooke (Bessette P); Saskatoon Cancer Center, Saskatoon (Le T); Hotel Dieu Hospital, Niagara Health System, St. Catharines, Ontario (Findlay B); Dr. H. Bliss Murphy Cancer Centre, St. John’s, Newfoundland (Popadiuk C); Thunder Bay Regional Health Science Centre, Thunder Bay (Vergidis D); Windsor Regional Cancer Centre, Windsor (Yoshida S); Cancer Centre of Southeastern Ontario, Kingston General Hospital, Kingston (Jeffery J, Gregg R); Cross Cancer Institute, Edmonton (Schepansky A); Regional Cancer Program, Hospital Regional de Sudbury, Sudbury (Germond C); SMDC Cancer Center, Duluth, Minnesota, USA (Krook JE).