1 Medical Oncology Service, Hospital Universitario Ramón y Cajal, Madrid; 2 Hospital Virgen del Rocío, Sevilla; 3 Hospital Sant Joan, Reus; 4 Hospital Reina Sofía, Córdoba; 5 Hospital de Terrasa, Barcelona; 6 Hospital Clínico San Carlos, Madrid; 7 Hospital Sant Creu i Sant Pau, Barcelona; 8 Hospital Trias i Puyol de Badalona, Barcelona; 9 Hospital Virgen de la Luz, Cuenca; 10 Hospital Miguel Servet, Zaragoza; 11 Institut Catalá de Oncología, Barcelona; 12 Hospital General de Alicante, Alicante; 13 Hospital Son Dureta, Palma de Mallorca; 14 Hospital General Universitario, Valencia; 15 Hospital Clínico de Valencia, Valencia, Spain
* Correspondence to: Dr A. J. González Martín, Medical Oncology Service, Hospital Universitario Ramón y Cajal, Ctra. Colmenar Viejo Km. 9,100, Madrid, Spain. Tel: +34-91-336-8263; Fax: +34-91-336-8263; Email: agonzalezm{at}seom.org
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients and methods:: Patients with recurrent ovarian carcinoma, 6 months after treatment with a platinum-based regimen and with no more than two previous chemotherapy lines, were randomized to receive carboplatin area under the curve (AUC) 5 (arm A) or paclitaxel 175 mg/m2 + carboplatin AUC 5 (arm B). The primary end point was objective response, following a pick up the winner design. Secondary end points included time to progression (TTP), overall survival, tolerability and quality of life (QoL).
Results:: Eighty-one patients were randomized and included in the intention-to-treat analysis. The response rate in arm B was 75.6% [26.8% complete response (CR) + 48.8% partial response (PR)] [95% confidence interval (CI) 59.7% to 87.6%] and 50% in arm A (20% CR + 30% PR) (95% CI 33.8% to 66.2%). No significant differences were observed in grade 34 hematological toxicity. Conversely, mucositis, myalgia/arthralgia and peripheral neurophaty were more frequent in arm B. Median TTP was 49.1 weeks in arm B (95% CI 36.961.3) and 33.7 weeks in arm A (95% CI 25.841.5). No significant differences were found in the QoL analysis.
Conclusions:: Paclitaxelcarboplatin combination is a tolerable regimen with a higher response rate than carboplatin monotherapy in platinum-sensitive recurrent ovarian carcinoma.
Key words: combination chemotherapy, platinum sensitive, randomized clinical trial, recurrent ovarian carcinoma
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients who initially respond to platinum-based chemotherapy and maintain a relapse-free interval >6 months have a probability of response to a new platinum-based treatment of at least 30%, and are considered to have platinum-sensitive disease. As Markman et al. [3] demonstrated, those with a longer platinum-free interval, i.e. >24 months, reach a significantly higher response rate than patients with an interval <24 months (77% versus 28%; P <0.001). For those patients with a platinum-sensitive relapse, carboplatin has been the preferred option by the majority of oncologists because of its easy administration, favorable toxicity profile (no alopecia, limited nausea, manageable hematological toxicity) and recognized antitumor activity [4
, 5
]. All these aspects contribute to an improved quality of life (QoL) of these patients. Moreover, when our trial was designed, no single agent or combination had as yet demonstrated a clear superiority over carboplatin alone, in any randomized trial.
The combination of carboplatin and paclitaxel is nowadays considered as the standard front-line therapy for advanced ovarian cancer. This regimen has also been studied as second-line therapy for platinum-sensitive relapsed patients. Two phase II trials and three retrospective studies have shown a significant response rate of 70% to 100% and a progression-free survival of 913 months [610
]. Moreover, this combination was shown to be active in patients who had previously been treated with paclitaxel and platinum as first-line therapy. In addition, in a recently reported large phase III trial, the ICON/AGO investigators demonstrated the superiority of paclitaxel and platinum-based combination over a conventional platinum-based chemotherapy in platinum-sensitive patients [11
].
To assess whether the combination of paclitaxelcarboplatin is more active than carboplatin alone in platinum-sensitive relapsed ovarian carcinoma, we performed a randomized phase II trial, the results of which are the basis of this report.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The protocol was approved by the Agencia Española del Medicamento (Spanish Drug Agency), as well as by the local ethics committee of each participating institution.
Pretreatment evaluation
Baseline examinations included a complete history and physical examination with documentation of all measurable disease. Further analyses included: a complete blood count, blood chemistry analyses including liver and renal function test, ovarian tumor marker CA-125, electrolytes, urinalysis, chest X-ray, electrocardiogram and a CT scan to document measurable disease.
Treatment
Patients were randomized to either single-agent carboplatin area under the curve (AUC) 5 (arm A) or paclitaxel 175 mg/m2 over 3 h + carboplatin AUC 5 (arm B). Both treatments were administered every 3 weeks for a minimum of six cycles unless there was progression, unacceptable toxicity or patient refusal. After six courses the patients could continue therapy for three further cycles if, in the opinion of the attending physician, further clinical benefit could be expected.
The carboplatin dose was determined by the AUC method of Calvert [dose in mg = AUC x (GFR + 25]. The AUC chosen was 5 in both arms. The glomerular filtration rate (GFR) was calculated by the CockcroftGault formula. Carboplatin was diluted in 250 ml of 5% dextrose and infused over a period of 3060 min.
Patients assigned to arm B received paclitaxel 175 mg/m2 infused over 3 h before carboplatin administration. All patients were treated with standard premedication of dexamethasone, dyphenhydramine and ranitidine 30 min before the administration of paclitaxel.
Treatment was repeated on a 21-day schedule if blood counts recovered (neutrophils 1500/mm3 and platelets
100 000/mm3) and non-hematological toxicity recovered to grade
1. A delay of more than 42 days in any one course of treatment administration was sufficient to have the patient transferred out of the study.
Dose modifications
Patients with neutropenic fever, grade 4 neutropenia lasting >7 days or grade 4 thrombocytopenia could continue treatment with a dose reduction of carboplatin to AUC 4 in arm A and to carboplatin AUC 4 + paclitaxel 150 mg/m2 in arm B.
Paclitaxel was reduced to 135 mg/m2 in case of grade 2 peripheral neurotoxicity, or grade 3 mucositis.
When dose reduction was required, no subsequent dose escalation was allowed.
Patients with cardiac arrhythmia or grade 3 hypersensitivity reaction were withdrawn from the study.
Evaluation of response, toxicity and time-related parameters
All patients who received at least the first dose were evaluated for toxicity and response. All toxicities encountered during the study were evaluated according to the National Cancer Institute Common Toxicity Criteria.
Evaluation during the study included: (i) before each course of therapy: a history and physical examination, a complete blood count, differential count, platelet count, blood chemistry survey with renal and liver function tests, and evaluation of measurable disease by physical examination; (ii) CA-125 was measured following every two courses; and (iii) appropriate imaging studies were performed to assess measurable disease every three cycles. WHO response criteria were employed for evaluation of measurable disease.
In those patients without measurable disease, response was determined according to CA-125 Rustin's criteria [12].
Overall survival was measured from the date of randomization to the date of death. Time to progression was defined as the time from date of randomization to date of documentation of tumor progression.
QoL was assessed by the validated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30). The QLQ-C30 should be filled out before study entry, every two cycles, and 6 and 12 months after the last treatment.
Criteria for withdrawal from the study
Patients were removed from the study for any one of the following reasons: (i) evidence of disease progression after a minimum of one cycle of therapy; (ii) development of unacceptable toxicity; or (iii) patient refusal or inability to comply with protocol requirements.
Statistical analyses
This is a randomized phase II trial in which patients meeting all the inclusion criteria were randomized by a central data center. Eligible patients were blocked by platinum-free interval (612 months versus >12 months) and the number of previous chemotherapy lines (one versus two).
The primary end point of our study was objective response [complete (CR) plus partial response (PR)]. Secondary end points were toxicity, QoL, time to progression (TTP) and overall survival (OS). The response rate was calculated on all randomized patients following the intention-to-treat principle. A corresponding 95% confidence interval (95% CI) for the response rate was estimated. Survival rates and TTP were described using the KaplanMeier method.
This study was a pick up the winner design based on the randomized phase II clinical trials approach proposed by Simon et al. [13], which gives a 90% chance of selecting the better treatment if the difference is at least 15% and the smaller response rate is assumed to be 30%. Although no formal statistical comparison between the two arms was planned, Fisher's exact test was performed on the response rate and toxicity levels, while the log-rank test was applied to the survival curves. These tests were for exploratory purposes only, and all expressed P values are two-sided.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Toxicity
There were 78 patients who received at least one cycle of treatment and were evaluable for the analysis of safety of treatment. Severe neutropenia (grade 34) was more common in the paclitaxelcarboplatin arm at 18.4% of patients, compared with 10% in the carboplatin arm (P=0.24). Conversely, grade 34 thrombocytopenia and anemia were more frequent in the carboplatin arm; 12.5% versus 2.6% and 15% versus 5.3%, respectively. However, these differences were not statistically significant. Four patients were transferred out of the study owing to delay in hematological recovery, two in arm A (prolonged thrombocytopenia and prolonged neutropenia) and two in arm B (prolonged neutropenia and prolonged thrombocytopenia). One patient in arm A and two patients in arm B had one febrile neutropenia episode each. No toxic deaths were observed.
Significant (grade 24) non-hematological toxicity was more commonly associated with the paclitaxelcarboplatin combination. Only one patient had a grade 4 event, consisting of anaphylaxis related to the carboplatin infusion, but this was resolved immediately with standard medication. The more relevant toxicities observed in arm B were: grade 23 mucositis in 18.4% of patients, grade 23 myalgia/arthralgia in 36.8% of patients and peripheral neurosensory toxicity in 23.7% of patients. All these toxicities were statistically significantly more frequent in arm B than in arm A. All patients with peripheral neuropathy had grade 2 toxicity, and no grade 34 was observed.
Other toxicities of note were nausea and vomiting, asthenia and anorexia. All were of mild to moderate intensity, and similar in both treatment arms.
There were 10 patients (12.8%) in whom there was some form of grade 24 carboplatin-related hypersensitivity reaction (four in arm A and six in arm B), and which was the reason for withdrawal from the study in seven patients (two in arm A and five in arm B). Tables 2 and 3 summarize the toxicity data.
|
|
|
|
|
No significant differences were observed during therapy in any of the five function scales of the QLQ-C30 questionnaire; physical (PF), role (RF), emotional (EF), cognitive (CF) and social (SF). There were no differences in the two symptom scales of fatigue (FA) and pain (PA), nor on the six single-item scales of dyspnea (DY), sleep disturbance (SL), appetite loss (AP), constipation (CO), diarrhea (DI) and financial impact of the disease/treatment (FI). The overall health status/QoL status was not statistically different between the two treatment arms. Only nausea and vomiting (NV) was higher in the carboplatin monotherapy arm (P=0.033). A trend towards a better overall QoL was observed in both arms between cycles 2 and 6.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The results of the present study show that the combination of paclitaxel (175 mg/m2) combined with carboplatin (at AUC 5) achieves a significantly higher response rate compared with carboplatin alone in patients with ovarian carcinoma recurring >6 months after a platinum-based treatment regimen. The response rate observed in the combination arm of our study is similar to those observed in phase II trials with paclitaxelcarboplatin combination in platinum-sensitive patients [610
]. Conversely, the response rate obtained with carboplatin alone is comparable to data derived from studies recently reported involving retrospective analyses in patients with platinum-sensitive relapse following paclitaxelplatinum first-line therapy [5
].
Although, the present study was not designed and powered to detect differences in survival, the exploratory analysis of TTP and OS showed a significant superiority of the paclitaxelcarboplatin combination over the single-agent carboplatin in both survival end points.
The results of this trial are consistent with those recently published by the ICON/AGO investigators [11]. The ICON-4/AGO-OVAR 2.2 trial is the largest trial communicated to date in platinum-sensitive, relapsed ovarian carcinoma. The trial involves a total of 802 patients randomized to a platinum regimen without paclitaxel or the combination of paclitaxel with a platinum-derived salt. The majority of patients received carboplatin alone in the control arm (71%). With a median follow-up of 42 months, the combination arm achieved a significantly higher progression-free survival (9 versus 12 months) and OS (24 versus 29 months).
In addition, the recently reported result of the adequately powered AGO-2.5 trial showing a significant better response rate and progression-free survival of carboplatin and gemcitabine combination over carboplatin alone, adds to the evidence of the superiority of platinum-based combination chemotherapy over platinum-based monotherapy [14].
If we compare the patient characteristics of both studies (ICON-4 and GEICO-0199), the populations are very similar. For example, the majority received only one prior line of chemotherapy (90% in ICON-4 and 84.6% in GEICO-0199). However, there are some notable differences, such as more patients with a platinum-free interval >12 months in the ICON study compared with the GEICO (75% versus 57.7%, respectively).
One point of contention in the ICON/AGO study is that only 40% of patients had received paclitaxel previously, which could explain the superiority of the paclitaxel arm following the relapse [15]. In our study, 87.2% of patients had received paclitaxel previously and in 83.3% this treatment was part of the last one prior to the present trial. The results suggest that the combination of paclitaxel and carboplatin is still active in patients with relapse several months after the initial paclitaxelplatinum combination was administered as first-line therapy.
Another issue worth noting is the influence on survival of treatment following disease progression with the carboplatin regimen. The results from the GOG-132 trial suggested that sequential administration of cisplatin and paclitaxel could achieve the same outcome as the combination therapy used as first-line treatment [16]. In our study, only five patients treated with carboplatin alone had received paclitaxel as further therapy following disease progression. As such, we cannot rule out the possibility that sequential administration of paclitaxel following carboplatin therapy could have reduced the differences observed with respect to survival. However, the re-introduction of paclitaxel in relapse is not as widely accepted as the re-introduction of a platinum in those patients with a platinum-free interval over 6 months. Actually, more than 50% of patients in both arms received further active drugs (such as pegylated liposomal doxorubicin or topotecan) at progression. Moreover, this study was not designed to determine whether carboplatin and paclitaxel should be given concurrently or sequentially at platinum-sensitive relapse, since the principal objective of our trial was to assess whether the combination of paclitaxelcarboplatin was more active than carboplatin alone in platinum-sensitive relapsed ovarian carcinoma.
The analysis of safety shows that both treatments are well tolerated. However, non-hematological toxicity was higher in the paclitaxelcarboplatin arm, with clinically significant (grade 23) mucositis (18.4% of patients), alopecia (86.8%) myalgia/arthralgia (36.8%) and peripheral neurosensory toxicity (23.7%) as the most relevant adverse events. It should be noted that the rate of grade 24 peripheral neurotoxicity is similar to the 20% reported by the ICON/AGO investigators, but with our patient population having a higher prior exposure to paclitaxel than those in the ICON/AGO trial. In addition, no grade 34 peripheral neuropathy was observed. Despite these differences in toxicity, the QoL analysis during therapy did not show significant differences between the two treatment arms, except for more nausea and vomiting in the monotherapy arm. Clearly no deteriorating toxicity influenced QoL in patients allocated to the combination therapy. On the other hand, our QoL assessment method may not have been sensitive enough to discriminate relevant differences among arms, and this could explain why a better response rate and TTP did not translate into better QoL.
In summary, despite the limitations of a randomized phase II study, our results add to the evidence from ICON-4/AGO OVAR 2.2 trials indicating a benefit of paclitaxelcarboplatin over carboplatin monotherapy. Therefore, patients with ovarian carcinoma relapsing after 6 months of first line paclitaxelplatinum should be treated again with the same combination if no significant residual neuropathy is present. This is particularly appropriate for those patients with relapses occurring >12 months after therapy. Whether carboplatin followed by paclitaxel would obtain the same outcome in this situation is an hypothesis that should be confirmed in a randomized clinical trial.
![]() |
Acknowledgements |
---|
Received for publication October 12, 2004. Revision received December 8, 2004. Accepted for publication December 9, 2004.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Ozols RF. Treatment of recurrent ovarian cancer: increasing options"recurrent" results. J Clin Oncol 1997; 6: 21772180.
3. Markman M, Rothman R, Hakes T et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 1991; 9: 389393.[Abstract]
4. Markman M. Single Agent Carboplatin is the Treatment of Choice in Recurrent Potentially Platinum-Sensitive Epithelial Ovarian Cancer. ASCO Educational Book Alexandria, VA: ASCO 2002.
5. Dizon DS, Dupont J, Anderson S et al. Treatment of recurrent ovarian cancer: a retrospective analysis of women treated with single-agent carboplatin originally treated with carboplatin and paclitaxel. The Memorial Sloan-Kettering Cancer Center experience. Gynecol Oncol 2003; 91: 584590.[CrossRef][ISI][Medline]
6. Guastalla JP, Pujade-Lauraine E, Weber H et al. Efficacy and safety of the paclitaxel and carboplatin combination in patients with previously treated advanced ovarian carcinoma. A multicenter GINECO phase II study. Ann Oncol 1998; 9: 3743.[Abstract]
7. Havrilesky LJ, Alvarez AA, Sayer RA et al. Weekly low-dose carboplatin and paclitaxel in the treatment of recurrent ovarian and peritoneal cancer. Gynecol Oncol 2003; 88: 5157.[CrossRef][ISI][Medline]
8. Rose P, Fusco N, Fluellen L et al. Second-line therapy with paclitaxel and carboplatin for recurrent disease following first-line therapy with paclitaxel and platinum in ovarian or peritoneal carcinoma. J Clin Oncol 1998; 16: 14941497.[Abstract]
9. Gronlund B, Hogdall C, Hansen HH et al. Results of reinduction therapy with paclitaxel and carboplatin in recurrent epithelial ovarian cancer. Gynecol Oncol 2001; 83: 128134.[CrossRef][ISI][Medline]
10. Dizon D, Hensley M, Poynor E et al. Retrospective analysis of carboplatin and paclitaxel as initial second-line therapy for recurrent epithelial ovarian carcinoma: application toward a dynamic disease state model of ovarian cancer. J Clin Oncol 2002; 20: 12381247.
11. ICON and AGO Collaborators. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003; 361: 20992106.[CrossRef][ISI][Medline]
12. Rustin GJS, Nelstrop AE, Bentzen SM et al. Use of tumour markers in monitoring the course of ovarian cancer. Ann Oncol 1999; 10 (Suppl 1): S21S27.
13. Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep 1985; 9: 13751381.
14. Pfisterer J, Plante M, Vergote I et al. Gemcitabine/carboplatin vs carboplatin in platinum sensitive recurrent ovarian cancer. Results of a Gynecologic Cancer Intergroup randomized phase III trial of the AGO OVAR, the NCIC CTG and the EORTC GCG. Proc Am Soc Clin Oncol 2004; 23: 449 (Abstr 5005).
15. Kaye SB. Chemotherapy for recurrent ovarian cancer. Lancet 2003; 361: 20942095.[CrossRef][ISI][Medline]
16. Muggia FM, Braly PS, Brady MF et al. Phase III randomized study of cisplatin vs paclitaxel vs cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer. A GOG study. J Clin Oncol 2000; 18: 106115.