The Editor,
Current Oncology
April 15, 2010
Taxane and platinum combination chemotherapy forms the cornerstone for the management of epithelial ovarian cancer. Recently, altering the schedule of every-3-weeks paclitaxel to weekly paclitaxel has shown benefits in platinum-resistant epithelial ovarian cancer, and it is one of the treatment options for this subgroup of patients 1.
The recent data from the Japanese Gynecologic Oncology Group on first-line weekly paclitaxel in ovarian cancer is a new horizon of success in the management of epithelial ovarian cancer 2. That phase iii open-label trial compared dose-dense weekly paclitaxel with every-3-weeks paclitaxel in combination with carboplatin in advanced ovarian cancer. Of the 637 enrolled patients, 631 were eligible for treatment and were included in the intention-to- treat population (dose-dense regimen: n = 312; conventional regimen: n = 319). Table I describes the results.
TABLE I.
Results of the trial by Katsumata et al. 2
| Parameter | Paclitaxel trial arm |
|
|---|---|---|
| Dose-dense weekly, with every-3-weeks carboplatin | Every-3-weeks, in combination with carboplatin | |
| Response rate (%) | 56 | 53 |
| Median pfs (months)a | 28.0 (95% ci: 22.3 to 35.4) | 17.2 (95% ci: 0.58 to 0.88) |
| Overall survivalb | 72.1 | 65 |
| Patients discontinuing treatment (n) | 165 | 117 |
| Neutropenia (%) | 92 | 88 |
| Grade iii or iv anemia (%) | 69 | 44 |
Hazard ratio 0.71 and p = 0.0015 in favour of dose-dense regimen.
Hazard ratio 0.75 and p = 0.03 in favour of dose-dense regimen.
pfs = progression-free survival; ci = confidence interval.
Women assigned to dose-dense paclitaxel and carboplatin had a 29% lower risk of disease progression and a 25% lower risk of death than did patients assigned to the conventional regimen. This is the first study to show benefits for dose density over dose intensity in the first-line setting in epithelial ovarian cancer. The main concerns arising from the trial are its significant dropout rate because of hematologic toxicity, which exceeds that of the Eastern Cooperative Oncology Group 1199 trial of weekly paclitaxel in breast cancer 3.
A study published by Rose et al. 4 showed benefits with weekly paclitaxel 60 mg/m2, also pointed out by Bookman et al. 5 For future clinical trials, 60 mg/m2 can therefore be used as an optimal dosing schedule.
What are the implications of the Japanese trial in clinical practice?
First, after decade of research, this trial is the first to have shown survival benefit with a taxane– platinum regimen using a conventional intravenous route of delivery. The trials of triplet regimens have failed to show benefit over doublet regimens.
After the results about the role of intraperitoneal cisplatin-based chemotherapy in optimally cytoreduced epithelial ovarian cancer were published in 2006 by Armstrong et al. 6, the National Cancer Institute issued a clinical announcement that all patients should be given the option of intraperitoneal chemotherapy. The problems of intraperitoneal chemotherapy are catheter-related complications, fatigue, pain, and hematologic, gastrointestinal, metabolic, and neurologic toxicity. The median progression-free survival was 23.8 months in the intraperitoneal group as compared with 18.3 months in the intravenous group.
As pointed out by Rao et al. 7, the intraperitoneal chemotherapy trials have these weaknesses: None of the trials tested purely the benefits of intraperitoneal chemotherapy, and in all the trials, the control arm was not the standard paclitaxel–carboplatin combination. The standard reference regimen for subsequent trials with an intraperitoneal chemotherapy arm has been day 1 intravenous paclitaxel and day 8 intraperitoneal paclitaxel 6. Therefore, whether the intraperitoneal route was the reason for benefit or whether the dose-dense paclitaxel was beneficial is poorly understood.
A cross-comparison of the Katsumata et al. and Armstrong et al. trials shows that progression-free survival in the weekly paclitaxel trial is as good as that with intraperitoneal chemotherapy, with fewer toxicities. Hogberg 8 recently undertook careful observation of these trials and concluded that weekly paclitaxel appears more promising than intraperitoneal chemotherapy because the weekly paclitaxel trial is a trial of “real world” circumstances, with a more representative epithelial ovarian cancer population than the optimally cytoreduced population of the intraperitoneal chemotherapy trials.
The role of weekly paclitaxel in epithelial ovarian cancer is therefore evolving, but it must be kept in mind that multiple visits are required and that, surprisingly, more neurotoxicity is seen in breast cancer trials than in epithelial ovarian cancer trials.
Footnotes
CONFLICT OF INTEREST DISCLOSURES
The authors declare that no financial conflict of interest exists.
REFERENCES
- 1.Markman M, Blessing J, Rubin SC. Phase ii trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study. Gynecol Oncol. 2006;101:436–40. doi: 10.1016/j.ygyno.2005.10.036. [DOI] [PubMed] [Google Scholar]
- 2.Katsumata N, Yasuda M, Takahashi F, et al. on behalf of the Japanese Gynecologic Oncology Group. 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;374:1331–8. doi: 10.1016/S0140-6736(09)61157-0. [DOI] [PubMed] [Google Scholar]
- 3.Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008;358:1663–71. doi: 10.1056/NEJMoa0707056. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.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. doi: 10.1016/j.ygyno.2004.03.046. [DOI] [PubMed] [Google Scholar]
- 5.Bookman MA. Dose-dense chemotherapy in advanced ovarian cancer. Lancet. 2009;374:1303–5. doi: 10.1016/S0140-6736(09)61305-2. [DOI] [PubMed] [Google Scholar]
- 6.Armstrong DK, Bundy B, Wenzel L, et al. on behalf of the Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34–43. doi: 10.1056/NEJMoa052985. [DOI] [PubMed] [Google Scholar]
- 7.Rao G, Crispens M, Rothenberg ML. Intraperitoneal chemotherapy for ovarian cancer: overview and perspective. J Clin Oncol. 2007;25:2867–72. doi: 10.1200/JCO.2007.10.8167. [DOI] [PubMed] [Google Scholar]
- 8.Hogberg T. Current drugs still have potential in advanced ovarian cancer. Nat Rev Clin Oncol. 2010;7:191–3. doi: 10.1038/nrclinonc.2010.37. [DOI] [PubMed] [Google Scholar]