Correspondence to: William P. McGuire, M.D., The Gynecologic Oncology Center, Mercy Medical Center, Baltimore, MD 21202 (e-mail: wmcguire52{at} aol.com).
The article by Piccart et al. (1) in this issue of the Journal confirms the importance of paclitaxel in the initial treatment of advanced ovarian cancer in a more heterogeneous group of patients (i.e., patients with stage IIB, IIC, III, or IV disease; 35% low-volume disease) than in the previously reported Gynecologic Oncology Group (GOG) trial (patients with stage IIIC or IV disease; 0% low-volume disease) (2). Perhaps, of more importance, it teaches us some important lessons about the politics of clinical trials. As Piccart et al. pointed out, this trial was designed, initiated, and completed in a short time period (<2 years) and accrued more than 650 patients from 18 countries, and the data were collected in four coordinating centers. Appropriately, the trial was necessary to confirm the results of the GOG report, which suggested a new standard of care for treating advanced ovarian cancer, in which paclitaxel replaced cyclophosphamide. The results of this trial confirm the GOG results in terms of all outcome parameters and suggest that late application of salvage paclitaxel therapy (at the time of clinical progression) does not confer a survival advantage and that dose and schedule of paclitaxel are relatively unimportant to these outcome parameters. Furthermore, the study clearly demonstrates that the higher dose and shorter infusion duration of paclitaxel lead to more neurotoxicity, creating an inferior therapeutic index compared with that from the lower dose and longer infusion regimen used in the GOG study. Both factors probably increase the neurotoxicity of the cisplatinpaclitaxel doublet. Connelly et al. (3) initially showed that even six cycles of cisplatin at a dose of 75 mg/m2 with paclitaxel doses of 135175 mg/m2 resulted in a 20% incidence of grade 3 or 4 neurotoxicity. Short-infusion paclitaxel with cisplatin is no longer optimal for therapy.
Although one might expect the progression-free survival and the overall survival to be somewhat better in both arms of this study than in the GOG trial because of the inclusion of a population with low-volume disease, it does not necessarily follow that the similar outcomes were due to the crossover of patients in the control arm to the paclitaxel arm at disease progression. The end results in the paclitaxel arm were similar to those in the GOG study as well. A more likely explanation is that some patients in the GOG trial had cryptic optimal disease but were not aggressively debulked. There were early data during the conduct of that trial of the efficacy of paclitaxel, and the competing GOG protocol for optimal disease did not contain paclitaxel in either arm.
As the decade of the 1990s ended, two additional studies exploring the role of paclitaxel in primary therapy for ovarian cancer have been initiated. The Medical Research Council in the U.K. (4) evaluated paclitaxel and non-paclitaxel-based therapies in more than 2000 patients, and the GOG (5) evaluated the cisplatinpaclitaxel combination versus sequential monotherapies of each agent in more than 600 patients. Furthermore, several studies addressing the preferable platinum analogue and the proper dose and infusion duration of paclitaxel (68) have been completed with the use of more than 1600 patients. These studies probably support a carboplatin and paclitaxel doublet as a "new" standard of care, but investigators worldwide are still exploring the proper dose of carboplatin, the proper infusion duration of paclitaxel, and whether substitution of docetaxel for paclitaxel can improve the therapeutic index. Thus, even though more than 5400 patients with advanced ovarian cancer have been accrued to randomized trials in the last decade to "fine-tune" the regimen with the best therapeutic index, what is best is still unclear. Furthermore, none will be good enough, since the study with the longest follow-up (2) shows only a 9% survival advantage at 5 years for the paclitaxel arm (27% for paclitaxelcisplatin versus 18% for cyclophosphamidecisplatin).
In the early 1990s, the only valid drug to add to or to substitute in the primary treatment of ovarian cancer was paclitaxel, since no other agents with well-documented single-agent activity in platinum-resistant disease existed. As we enter a new millennium, there is a plethora of agents with activity that deserve consideration. Candidates include topotecan and pegylated liposomal doxorubicin, both approved by the U.S. Food and Drug Administration (FDA) for use in platinum-resistant disease, as well as gemcitabine and oral etoposide, which are not FDA approved for use in ovarian cancer but have clear activity in platinum-resistant disease on the basis of more than two phase II trials in each drug (9). Moreover, the anthracyclines doxorubicin and epirubicin are once again candidates, since a meta-analysis (10) has shown a survival advantage with the doxorubicin-based three-drug regimen compared with the two-drug regimen.
This multinational study demonstrates the clear ability to accession large numbers of patients quickly and does, as stated by Piccart et al. (1), represent "a turning point in the history of the conduct of ovarian cancer trials." With the many new agents available for evaluation as sequential monotherapies or doublets or triplets, what is the best way to manage the myriad possibilities that now exist for clinical trials? Do we really need multiple studies that address identical or similar questions? Or should we use the lesson learned from this trial that single, large, multinational, rapidly accruing studies are possible and perhaps preferable to multiple national studies? Verification of a new standard of care has always required and should continue to demand confirmation, as was done appropriately in the current study. But what if five clinical trial groups each compare a different experimental arm with the current standard that is still not completely elucidated and two or more of these studies show superiority? Will we then require a comparison of each followed by confirmation of which of these "new standards" we should accept? This seems inefficient and an unnecessary utilization of patient resources. The time has come to learn from the efficient design and accrual of this trial and to initiate a multinational trial that simultaneously asks multiple questions with a plan for confirming whether one or more of the new regimens deserve to be the new standard of care. This approach will use fewer patients and will obtain more generalizable results than multiple small studies. We all seek the same goal of further improving the therapeutic envelope for advanced ovarian cancer, and working in concert seems an obvious way to proceed.
REFERENCES
1
Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, et al. Randomized intergroup trial of cisplatinpaclitaxel versus cisplatincyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000;92:699708.
2
McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:16.
3 Connelly E, Markman M, Kennedy A, Webster K, Kulp B, Peterson G, et al. Paclitaxel delivered as a 3-hr infusion with cisplatin in patients with gynecologic cancers: unexpected incidence of neurotoxicity. Gynecol Oncol 1996;62:1668.[Medline]
4 Harper P. A randomised comparison of paclitaxel (T) and carboplatin (J) versus a control arm of single agent carboplatin (J) or CAP (cyclophosphamide, doxorubicin and cisplatin): 2075 patients randomised into the 3rd International Collaborative Ovarian Neoplasm Study (ICON3) [abstract]. Proc ASCO 1999;18: abstract 1375.
5
Muggia FM, Braly PS, Brady MF, Sutton G, Nieman TH, Lentz SL, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2000;18:10615.
6 Ozols RF, Bundy BN, Fowler J, Clarke-Pearson D, Mannel R, Hartenbach EM, et al. Randomized phase III study of cisplatin(CIS)/paclitaxel (PAC) versus carboplatin (CARBO)/PAC in optimal stage III epithelial ovarian cancer (OC): a Gynecologic Oncology Group trial (GOG 158) [abstract]. Proc ASCO 1999;18:abstract 1373.
7 du Bois A, Lueck HJ, Meier W, Moebus V, Costa SD, Bauknecht T, et al. Cisplatin/paclitaxel vs carboplatin/paclitaxel in ovarian cancer: update of an Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) study group trial [abstract]. Proc ASCO 1999;18: abstract 1374.
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10 Cyclophosphamide plus cisplatin versus cyclophosphamide, doxorubicin, and cisplatin chemotherapy of ovarian carcinoma: a meta-analysis. The Ovarian Cancer Meta-Analysis Project. J Clin Oncol 1991;9:166874.[Abstract]
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