Paclitaxel plus carboplatin versus paclitaxel plus alternating carboplatin and cisplatin for initial treatment of advanced ovarian cancer: long-term efficacy results: a Hellenic Cooperative Oncology Group (HeCOG) study

G. Aravantinos1,*, G. Fountzilas2, P. Kosmidis3, M. A. Dimopoulos4, G. P. Stathopoulos5, N. Pavlidis6, D. Bafaloukos7, C. Papadimitriou4, S. Karpathios4, V. Georgoulias9, P. Papakostas8, H. P. Kalofonos10, E. Grimani1 and D. V. Skarlos5

1 ‘Agii Anargiri’ Cancer Hospital, Athens; 2 Aristotle University of Thessaloniki-School of Medicine, Thessaloniki; 3 Hygeia Hospital, Athens; 4 ‘Alexandra’ General Hospital, Athens; 5 ‘Henry Dunant’ Hospital, Athens; 6 University Hospital of Ioannina, Ioannina; 7 ‘Metropolitan’ Hospital, Piraeus; ; 8 ‘Ipokration’ General Hospital, Athens; 9 University Hospital of Herakleion-Crete, Herakleion; 10 University Hospital of Rio-Department of Medicine, Rio-Patras, Greece

Correspondence to: Dr G. Aravantinos, Hellenic Cooperative Oncology Group, Laskaridou 1 & Kifissias, 11524 Athens, Greece. Tel: +30210-6912-520; Fax: +30210-6912-713; Email: hecogaga{at}otenet.gn


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: We compared the combination plus Carboplatin plus paclitaxel, which is considered the treatment of choice for initial chemotherapy of advanced ovarian cancer (AOC) with a regimen combining alternating carboplatin and cisplatin plus paclitaxel. The two platinum derivatives have been previously combined as they are not totally cross-resistant and as they share no overlapping toxicities.

Patients and methods: Patients with AOC, after the initial cytoreductive surgery were randomized to either 6 courses of paclitaxel at 175 mg/m2 as 3h infusion plus Carboplatin at 7 AUC (Arm A) or Paclitaxel at the same dose plus Carboplatin again at 7 AUC for cycles 1,3,5, while for cycles 2,4,6 Cisplatin at 75 mg/m2 substituted for Carboplatin (Arm B).

Results: 247 patients are analyzed. Significant differences were not found, both in terms of PFS (38 vs 39 months, p=0.95) and overall survival (40.6 vs 38.6 months, p=0.79). There was not also difference in 5-year survival rate (35% vs 39%) or 5-year PFS rate (23% vs 28%). Age >60, PS 2, stage IV disease and presence of residual disease were adversely related to the overall survival.

Conclusion: Both regimens are well tolerated and effective. Alternating cisplatin with carboplatin does not improve the results compared with the standard combination.

Key words: alternating cisplatin with carboplatin, chemotherapy, initial treatment, ovarian cancer


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Based on the results of the Gynaecologic Oncology Group 111 study, the combination of paclitaxel plus cisplatin was proven superior to at that time treatment of choice cyclophosphamide plus cisplatin and became the new ‘gold standard’ treatment of advanced ovarian cancer (AOC) [1Go]. These results were confirmed by an intergroup study, which included patients with optimally debulked disease, while paclitaxel was given at 175 mg/m2 as a 3-h infusion [2Go]. At the same time three cooperative groups, one in the USA [3Go] and two European [4Go, 5Go], demonstrated that paclitaxel plus carboplatin could be combined at full doses, while the efficacy is similar to the paclitaxel/cisplatin regimen. The combination of paclitaxel plus carboplatin has progressively become the new treatment of choice and it is used as the control arm in the majority of the current phase III trials.

On the other hand, in the pre-taxane era, there was some clinical evidence suggesting that the two platinum compounds, cisplatin and carboplatin, apart from demonstrating different pharmacological properties and a different toxicity profile, may not be totally cross-resistant. Since the two drugs share no overlapping toxicities, combining them could enable us to increase the total platinum dose intensity and therefore, at least theoretically, to improve the disease outcome [6Go–8Go].

Using this information as a background, the Hellenic Cooperative Oncology Group (HeCOG) conducted a phase III randomized trial in order to assess and compare the antitumor efficacy and tolerability of paclitaxel with either carboplatin or with carboplatin alternating with cisplatin as first-line treatment of AOC. Our preliminary results (mainly toxicity and response data) have been published earlier [9Go], while more mature results have been reported on various occasions [10Go–12Go].


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
This was a prospective, multicenter, phase III study. Patients were enrolled in 10 oncology centers in Greece.

To be eligible for the study patients had to meet all the following inclusion criteria: (i) histologically confirmed epithelial ovarian carcinoma FIGO stage IIc, III or IV; (ii) no previous chemotherapy; (iii) no age restriction; (iv) laboratory values within normal levels; (v) performance status (ECOG) ≤2; (vi) no symptoms or signs of cardiac insufficiency or acute coronary disease; (vii) patients had to be enrolled within 6 weeks from laparotomy; (viii) informed consent.

Exclusion criteria included: (i) other malignant tumor, except for non-melanoma skin cancer or radically excised in situ carcinoma of the uterine cervix; (ii) history of atrial or ventricular arrhythmias and/or history of congestive heart failure; history of clinically and electrocardiographically documented myocardial infraction within the last 6 months or abnormal left ventricular ejection fraction (LVEF); (iii) active infection or other serious medical conditions, which would impair the ability of the patient to receive the treatment; (iv) administration of other therapeutic drugs or hormonal therapy during the study period; (v) patients with complete bowel obstruction and/or with brain metastases.

Treatment plan
Patients were stratified according to stage (IIc versus III versus IV) and the presence of residual disease. To define a patient with no residual disease, there should be a surgery report showing that no macroscopic disease was left behind (>1 cm). Baseline CT should be negative. Patients were then randomized to receive either paclitaxel with carboplatin (group A) or paclitaxel with carboplatin alternating with cisplatin (group B), as follows. Group A: paclitaxel 175 mg/m2 (3-h infusion) cycles 1–6; carboplatin 7 AUC (1-h infusion) cycles 1–6. Group B: paclitaxel 175 mg/m2 cycles 1–6; carboplatin 7 AUC cycles 1, 3 and 5; cisplatin 75 mg/m2 (2-h infusion) cycles 2, 4 and 6.

Treatment was given every 3 weeks up to a total of six courses. Paclitaxel was given prior to platinum compounds. Dexamethasone 20 mg i.m. or i.v. 12 h and 6 h prior to paclitaxel infusion was given as premedication. Cimetidine (150 mg i.v.) and dimethydene maleate (4 mg i.v.) or promethazine (50 mg i.m.) were given 30 min prior to paclitaxel infusion. As antiemetic treatment, ondasetron 16 mg i.v., was administered 15 min prior to chemotherapy, and on the next day ondasetron 8 mg every 12 h p.o. was given. The AUC (area under the plasma concentration versus time curve) was calculated according to the Calvert formula [13Go]. Creatinine cleareance was calculated from the creatinine, the age and patient's BSA by the method proposed by Jelliffe [14Go].

Complete blood count (CBC), liver and kidney function tests, electrolytes, chest X-ray, ECG, abdominal CT scan and CA-125 determination were performed prior to initiation of chemotherapy. CBC was measured on the 14th day of the first cycle and thereafter if indicated. CBC, liver and kidney function tests were repeated at each cycle.

Dose modifications
Chemotherapy was to be given on schedule providing that ANC was ≥1.5x109/l and platelet count ≥100x109/l. A week delay was allowed for ANC recovery, otherwise patients had to be treated with granulocyte colony stimulating factor (G-CSF) (lenograstim 0.263 mg). A maximum of 2 weeks delay was allowed for platelet recovery, otherwise patients went off protocol. If platelet recovery occurred within 1 week, the next treatment was repeated every 4 weeks. If 2 weeks were required for platelet recovery, the next courses were repeated again every 4 weeks but a 25% reduction of the carboplatin dose was performed. For grade 3 and 4 thrombocytopenia during treatment a reduction of 25% and 50%, respectively, was performed. If the patient demonstrated febrile neutropenia, G-CSF was to be administered prophylactically for the following courses.

For each 20 ml/min reduction of the creatinine clearance, a 25% dose reduction of the dose of cisplatin was performed. For WHO grade >2 mucositis, 25% dose reduction of all drugs was performed. For WHO grade >2 neurotoxicity, treatment had to be stopped. Paclitaxel had to be stopped in case of severe hypersensitivity reactions or severe cardiac toxicity (symptomatic ventricular arrythmias, more than first degree AV block).

Response evaluation
Response was assessed every three cycles, unless clear evidence of progression was seen. Patients with either disease progression before the third cycle or discontinuing treatment due to toxicity or personal reasons (refusal) were considered treatment failures.

Statistical analysis
The main end point for sample size determination was survival rate. In order to detect a ±15% difference at a 3-year time point, 240 patients were needed, so as to have 80% power at the 5% significance level. Taking into consideration a 3% withdrawal rate, the number of patients was increased to 247. An interim analysis, based on the O'Brien Fleming boundary values, was carried out when 50% (68 deaths) of the end points had been reached and the decision was to continue the study.

World Health Organization (WHO) criteria for toxicity and response were applied [15Go]. Overall survival time (OS) was defined as the time from treatment initiation to the date of last contact or to the date of death by any cause. Surviving patients were censored at the date of last contact. Progression-free survival (PFS) was calculated from the initiation of treatment to the date progression of the disease was firstly documented (patients who discontinued their treatment for any reason or who died from disease-related causes were considered at that time, as treatment failures).

Fisher's exact test [16Go] was used to compare patients' characteristics, response and toxicity. Exact binomial confidence intervals (CI) were used to determine the 95% upper and lower confidence limits of response rate [17Go]. The Kaplan–Meier method [18Go] was used to calculate PFS and survival curves, while the log rank test was used to compare time to event distributions.

The Cox proportional hazards models were used to assess the strength of association of OS and PFS with various clinical and histological variables [19Go]. A backward selection procedure, with removal criterion P >0.10, identified the subclass of significant prognostic factors among the following: age (≤60 versus >60); PS (0 versus 1 versus 2); presence of residual disease (no versus yes); stage (IIc versus III versus IV); and treatment group (CB–T versus CB–T–C). All statistical tests were two-sided and performed at significance level of 0.05. The analysis was conducted on an intention to treat basis.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Between January 1995 and May 1999, 247 eligible patients entered the study, 121 in group A and 126 in group B (Figure 1), in five major oncology centers. Another five centers joined the study later. Patient characteristics were well balanced between the two groups (Table 1). Almost 78% of patients presented with residual disease after the initial operation. Seventy-three percent of the patients had stage III, while 18% had stage IV disease. Almost 46% of patients had performance status (PS) 0 (ECOG scale).



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Figure 1. Progress through the various stages of the trial.

 

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Table 1. Selective patient and tumor characteristics

 
Toxicity and compliance with treatment
Treatment was generally well tolerated and there were no differences between the two arms in terms of severe (grade 3–4) toxicity with the exception of nausea and vomiting (1.6% versus 8.4%, P=0.02) (Table 2). The incidence of severe leukopenia and neutropenia was somewhat higher in group B (12.6% versus 19.3% and 26.7% versus 36.1%, respectively) although not statistically significant (P >0.05 in both cases). Severe thrombocytopenia was low for both arms (10.2% versus 13.5%). Febrile neutropenia developed in five patients (4%) in group A and six (5%) in group B. Although peripheral neurotoxicity was frequent (48.8% versus 66.4%), it was severe only for 2.4% versus 5.9% of patients. Severe arthralgia/myalgia was observed in 5.7% of patients while alopecia was almost universal.


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Table 2. Incidence (%) of various toxicities

 
Despite the low febrile neutropenia rate, five toxic deaths were noted, four in group A. All but one occurred during febrile neutropenia. The other was caused by pneumonia. All these patients had poor performance status (PS=2).

A total of 1397 cycles of chemotherapy (5.65 cycles per patient) were delivered. Almost 90% of the cycles were given at full dose (>90% of the dose defined in the protocol). It appears that we were able to deliver more than 90% of the planned dose intensity (DI) for paclitaxel in both arms (relative DI 0.90 versus 0.94), while the DI for cisplatin was 0.91. According to calculations based on the dose of carboplatin at first cycle expressed according to body surface area with no corrections for changes of the creatinine clearance for the following cycles, it appears that roughly 92% of the planned dose of carboplatin was actually delivered for group A, compared with 96% for group B.

Response, survival and progression-free survival
Sixty-three percent of patients (157 patients, 78 versus 79) were assessable for evaluation of response to chemotherapy. ORR was 68% (95% CI 56.4% to 78%) in group A and 67% (95% CI 55.6% to 77.3%) in group B (P=1.0) (Table 3).


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Table 3. Best response to treatment (for patients with measurable or evaluable disease)

 
After a median follow-up of 61 months (range 0.2–90), 191 patients (77.3%) had progressed (95 in group A and 96 in group B) and 153 (62%) had died (76 in group A and 77 in group B) (Table 4). The estimated 5-year OS rates in group A and group B were 35% (95% CI 26% to 44%) versus 39% (95% CI 30% to 48%). No significant difference was found between the two groups in terms of median OS (40.6 versus 38.6 months, respectively, P=0.79) (Figure 2). The median PFS was 38 months (range 0.2–90.2) in group A and 39 (range 0.4–83.5) in group B (P=0.95). The estimated 5-year PFS rates were 29% (95% CI 21% to 37%) versus 28% (95% CI 20% to 36%) (Figure 3).


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Table 4. Survival and progression-free survival (PFS)

 


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Figure 2. Effect of treatment on overall survival group A (CB–T) (_____), group B (CB–T–C) (–––-).

 


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Figure 3. Effect of treatment on progression free survival group A (CB–T) (_____), group B (CB–T–C) (–––-).

 
Results of the Cox regression multivariate analysis for OS (Table 5) revealed that several prognostic factors including age (>60 versus ≤60: HR = 1.6, 95% CI 1.1–2.3, P=0.01), worse performance status (1 versus 0: HR = 1.3, 95% CI 0.85–1.85, P=0.24; 2 versus 0: HR = 2.5, 95% CI 1.5–4.0, P <0.001) and worse stage (III versus IIc: HR=3.1, 95% CI 1.24–7.72, P=0.02; IV versus IIc: HR = 5.2, 95% CI 1.94–13.79, P=0.001) were related to significantly poorer survival.


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Table 5. The impact of selected variables on overall survival and PFS

 
Regarding PFS, the hazard of disease progression at any time was significantly higher for older patients (>60 versus ≤60: HR=1.5, 95% CI 1.1–2.1, P=0.01) with worse performance status (1 versus 0: HR=1.1, 95% CI 0.75–1.53, P=0.7; 2 versus 0: HR=2.1, 95% CI 1.34–3.33, P=0.001), worse stage (III versus IIc: HR=2.6, 95% CI 1.25–5.52, P=0.01; IV versus IIc: HR=4.0, 95% CI 1.74–9.1, P=0.001) and presence of residual disease (yes versus no: HR=1.6, 95% CI 1.04–2.49, P=0.03).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In the pre-taxane era, two European groups studied the concept of intensification of platinum dose by combining the two platinum compounds, cisplatin and carboplatin [7Go, 8Go]. The results of these phase I/II and II trials were considered encouraging. In particular Piccart et al. [8Go] suggested that, since the two drugs demonstrate different toxicities, i.e. severe neurotoxic effects for cisplatin and profound myelosupression for carboplatin, combination of the two appears the most feasible way of maximizing platinum doses. Moreover, at that time there was some evidence that the two platinum derivatives are not completely cross-resistant [6Go]. To our knowledge, combination of the two drugs has not been compared in a phase III study. Based on this rationale we conducted this comparative phase III study. Since paclitaxel has become part of the first-line treatment of ovarian cancer, it was used in both arms. We chose to combine cisplatin with carboplatin not concurrently, but in an alternating way. As the control arm we chose the regimen of carboplatin/paclitaxel [3Go–5Go], which at that time was popular [20Go] and currently considered the ‘gold standard’.

Our results demonstrate that both study chemotherapeutic regimens can be administered safely in almost full doses with acceptable toxicity. In particular the carboplatin–cisplatin–paclitaxel (CB–C–T) combination appears feasible in this cohort of patients. There were some minor differences in terms of toxicity between the two arms. The CB–C–T combination appears to be more toxic in terms of peripheral neurotoxicity and severe leukopenia/neutropenia, but only in severe nausea/vomiting did the difference reach statistical significance in favour of the control arm. In contrast, there were less toxic deaths in the CB–C–T arm. Furthermore there were no differences in treatment characteristics, in terms of dose intensity. Regarding the efficacy, after a long follow-up period there were no significant differences between the two arms in terms of response to chemotherapy, PFS and OS. Of course this conclusion should be seen in conjunction with the limitations of the statistical hypothesis used. Possibly larger study size could detect a minor difference between the two arms. Nevertheless, it seems that the CB–C–T regimen is a feasible alternative for first-line chemotherapy of AOC, for example in patients with treatment delays due to myelosupression caused by the standard C–B regimen with co-existence of neurotoxicity. The CB–C–T regimen has been noted as a treatment option by others [21Go].

Both regimens produced a rather encouraging long-term outcome. Median survival for the study population as a whole is around 40 months. More than the one-third of patients (35% versus 39%) are alive at 5 years. Furthermore more than one out of four patients at 5 years is disease-free and this means that the cure rate seems encouraging. These figures are comparable with the results reported by many major groups with a taxane-containing combination [1Go–5Go]. On this particular point some reservations have been raised by the ICON-3 collaborators who achieved similar results to taxane-containing combinations with either single agent carboplatin or combination of cisplatin, doxorubicin and cyclophosphamide (CAP) [22Go]. Of note, in a previous study of our group in which we compared single agent carboplatin with a combination of carboplatin with epirubicin and cyclophosphamide, the median survival was 29.5 months [23Go]. In that study the patient population was practically similar to this one. Therefore, although this is not a direct comparison, it appears that the addition of paclitaxel in the first-line chemotherapeutic regimens for ovarian cancer resulted in a better long-term outcome.

In conclusion, our results show that paclitaxel with either carboplatin or carboplatin alternating with cisplatin, seem to be very active combinations for the treatment of AOC. The toxicity of both regimens is acceptable, although there is a trend for higher toxicity in the alternating group, while both can be given almost at full doses on schedule. Alternating cisplatin with carboplatin does not appear to improve the results compared with the standard carboplatin/paclitaxel combination.


    Acknowledgements
 
The authors wish to thank Professor U. Dafni and Mrs E. Grimani for statistical analysis, Mrs D. Katsala for secretarial assistance and data monitoring, Mrs M. Moschoni for the coordination of the protocol and Mr D. Kaziolas for computer programming.

Received for publication June 25, 2004. Revision received December 28, 2004. Accepted for publication February 23, 2005.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. McGuire WP, Hoskins WJ, Brady MR et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and IV ovarian cancer. N Engl J Med 1996; 334: 1–6.[Abstract/Free Full Text]

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