Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open label, randomised controlled trial
February 2010
Commentary by Professor Paul Harnett and Dr Alexander Menzies
The article:
Katsumata N., Yasuda M., Takahashi F., et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open label, randomised controlled trial. Lancet 2009; 374(9698):1331-8.
The reviewers:
Professor Paul Harnett is Director of Cancer Services & Dr Alexander Menzies is a Medical Oncology Advanced Trainee at Westmead Hospital.
Abbreviations
Confidence Interval (CI), Granulocyte Colony-Stimulating Factor (GCSF), Hazard Ratio (HR), Intention to Treat (ITT), Randomised Controlled Trial (RCT)
Summary
Study Design
Paclitaxel and carboplatin administered every 3 weeks is standard treatment for advanced ovarian cancer. This phase 3, open-label, randomised controlled trial (RCT), compared a conventional regimen of paclitaxel and carboplatin with a dose-dense weekly regimen in women with stage II to IV epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer. Patients were randomly assigned to receive six cycles of either paclitaxel (180 mg/m²; 3-h intravenous infusion) plus carboplatin (area under the curve [AUC] 6 mg/mL per min), given on day 1 of a 21-day cycle, or dose-dense paclitaxel (80 mg/m²; 1-h intravenous infusion) given on days 1, 8, and 15 plus carboplatin given on day 1 of a 21-day cycle. The primary endpoint was progression-free survival. Analysis was by intention to treat (ITT).
Findings
Of the 637 enrolled patients, 631 were eligible for treatment; conventional, n=319; dose-dense regimen, n=312. Median progression-free survival was 28mths in the dose-dense group compared with 17.2mths in the conventional treatment group (HR 0.71, 95% CI 0.58-0.88, p=0.0015). Overall survival at 3yrs was higher in the dose-dense treatment group than in the conventional treatment group, 72.1% vs. 65.1% respectively (HR 0·75, 95% CI 0·57–0·98; p=0·03). Analysis by baseline characteristics indicated progression-free survival was longer in the dose-dense than the conventional treatment group across all subgroups of patients, apart from those with clear-cell or mucinous tumours. More patients discontinued treatment early in the dose-dense group than in the conventional treatment group (165 vs. 117 respectively); more patients withdrew due to toxicity in the dose-dense treatment group (113 vs. 69). Treatment-related adverse events were analysed in patients who received at least one cycle of chemotherapy. The most common adverse event was neutropenia (92% vs. 88% p=0.15, for dose-dense and conventional regimens, respectively). The frequency of grade 3 and 4 anaemia was higher in the dose-dense treatment group than in the conventional treatment group 69% vs. 44% p=<0.0001. The frequencies of other toxic effects were similar between groups.
Conclusion
A dose-dense regimen of paclitaxel once a week plus carboplatin every 3 weeks is associated with longer progression-free and overall survival than a conventional regimen of paclitaxel and carboplatin given every 3 weeks in women with advanced epithelial ovarian cancer. Dose-dense chemotherapy represents a new treatment option in women with advanced epithelial ovarian cancer.
Commentary
What does this article add to existing clinical evidence in this area?
Until now, many studies have attempted to improve on conventional first-line carboplatin-paclitaxel chemotherapy for advanced epithelial ovarian cancer. Most recently, the Gynaecologic Cancer InterGroup (GCIC) published a large Phase III trial involving over 4000 patients and including five arms of treatment to determine whether additional agents given along with, or sequential to, standard treatment would improve outcome.1 Disappointingly no benefit in progression-free or survival difference was found, with the cost of significant toxicity. A large trial is currently underway assessing the benefit of adding bevacizumab to conventional treatment.2
This randomised phase III study involved a novel approach to compare conventional treatment with a dose-dense protocol in the Japanese population on the basis of preclinical and small phase II studies suggesting that duration of exposure to paclitaxel is an important determinant of cytotoxicity.3,4,5 Furthermore, large clinical studies in breast cancer have shown clear benefit of weekly dosing of paclitaxel in the both the adjuvant and metastatic setting, and it was hypothesised that this would be seen with ovarian cancer also.6,7
At a time when the majority of research in medical oncology is directed toward new agents, this study demonstrated that we may be able to improve the care of patients with ovarian cancer with medications already available, and those clinicians are familiar with.
How adequate was the methodology used in addressing the aim of this study?
The study was well designed to detect a difference in progression-free survival between the two protocols as patient characteristics in both arms were evenly matched and most patients received 6 cycles of therapy (the accepted standard) across both groups. Whilst including patients with an earlier stage of disease (II) and lower rate of surgical debulking than seen in previous trials, the median progression free survival in the conventional arm of the study matched those seen with similar studies.1,8 As a result, any outcome seen in the experimental arm would likely reflect a real difference.
The main concerns in the design of the study involved the lack of blinding for clinicians and patients, which may have led to bias. Furthermore, despite the aim of the study to assess dose density and response, treatment intensity was not matched between the groups, with the conventional arm receiving 180mg/m2 of paclitaxel and the dose-dense arm 240mg/m2 over a three week period. The authors cited earlier small studies showing that dose intensity of paclitaxel does not affect outcome, however, any difference seen between the groups in this study cannot be presumed to be entirely due to the dose density of paclitaxel.9
What are the implications of this study for clinical practice in Australia?
This study provides a new insight into the management of advanced ovarian cancer, and is encouraging in that it involves medications which are readily available and familiar to clinicians. The improvement in progression-free survival of 11 months over standard treatment is impressive but appears to come at a significant cost of both toxicity and expense in this study.
This study was performed in the Japanese population, including a large proportion of patients with earlier stage disease, and those receiving less surgical debulking than seen in other populations. Furthermore, toxicity (particularly haematological) seen in the conventional group was significantly higher than that seen in previous studies using similar protocols in other populations.1,8 A reason for this could be differences in drug metabolism between the Japanese and other populations, and this would need to be assessed prior to recommending a change in routine clinical practice.
The majority of patients in both arms of the study had numerous dose delays and dose reductions during the course of treatment, with a high use of Granulocyte Colony-Stimulating Factor (GCSF) (60%), and therefore, cost. Whilst this alone would not make this treatment approach unfeasible, it would be vital to demonstrate a significant difference in larger studies across broader populations to prove economic viability.
Overall, while this study provides a new management strategy for ovarian cancer, confirmatory studies are required ideally in wider populations. In individual cases this treatment approach may be reasonably adopted, but one must be aware of the risk of significant toxicity and subsequent dose interruption and delay. In time, the potential improvements in progression-free and overall survival suggested by this study should lead to further interest and confirmatory studies on dose-dense paclitaxel protocols with less toxicity and cost, to demonstrate both clinical utility and economic viability.
References
- Bookman MA, Brady MF, McGuire WP, et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the Gynaecologic Cancer InterGroup. J Clin Oncol 2009; 27: 1419-25.
- ICON7. Overview. Feb 16, 2009. http://www.ctu.mrc.ac.uk/icon7/overview.asp (accessed July 27, 2009).
- Lopes NM, Adams EG, Pitts TW, Bhuyan BK. Cell kill kinetics and cell cycle effects of taxol on human and hamster ovarian cell lines. Cancer Chemother Pharmacol 1993; 32: 235-42.
- Rose PG, Smrekar M, Fusco N. A phase II trial of weekly paclitaxel and every 3 weeks of carboplatin in potentially platinum-sensitive ovarian and peritoneal carcinoma. Gynecol Oncol 2005; 96: 296–300.
- Sehouli J, Stengel D, Mustea A, et al. Weekly paclitaxel and carboplatin (PC-W) for patients with primary advanced ovarian cancer: results of a multicenter phase-II study of the NOGGO. Cancer Chemother Pharmacol 2008; 61: 243–50.
- Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Eng J Med 2008; 358: 1663-71.
- Seidman AD, Berry D, Cirrincione C, et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 2008; 26: 1642–49.
- Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003 Sep 1;21:3194-3200. Epub 2003 Jul 14.
- Bolis G, Scarfone G, Polverino G, et al. Paclitaxel 175 or 225 mg permeters squared with carboplatin in advanced ovarian cancer: a randomized trial. J Clin Oncol 2004; 22: 686–90.
Editor: Dr Anne Nelson, Evidence Review and Research Leader, National Breast and Ovarian Cancer Centre.
Clinical Update - Ovarian Cancer Editorial Committee: Prof Michael Friedlander – Medical Oncologist, Prof Neville Hacker – Gynaecological Oncologist, Ms Kim Hobbs – Social Worker, Dr Gillian Mitchell – Medical Oncologist, Dr Deborah Neesham – Gynaecological Oncologist, Ms Georgie Richter – Gynaecological Nurse.
Disclaimer
Clinical Update - Ovarian Cancer is produced by the National Breast and Ovarian Cancer Centre (NBOCC) and is intended to provide health professionals with timely expert commentary on new research in ovarian cancer. Commentaries included in Clinical Update - Ovarian Cancer do not replace recommendations included in NBOCC clinical practice guidelines.
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