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Originally published as JCO Early Release 10.1200/JCO.2008.20.8223 on February 17 2009 © 2009 American Society of Clinical Oncology.
Triple Cytotoxic Therapy for Advanced Ovarian Cancer: A Failed Application, Not a Failed StrategyBritish Columbia Cancer Agency, Vancouver, British Columbia, Canada Recommended standard therapies for the initial treatment of advanced ovarian cancer are carboplatin and paclitaxel, on the basis of equivalent efficacy but lesser toxicity compared with cisplatin and paclitaxel,1–4 carboplatin and docetaxel,5 or the initial use of a platin analog as a single agent with the subsequent use of a taxane.6,7 The good news is that such therapies have increased median overall survival to 3 years, compared with the 1-year survival achieved in the era before platinum. The bad news is that they are still not curative for the great majority. Long-term follow-up in the Gynecologic Oncology Group (GOG) 111 study and European Canadian Intergroup study (OV.10) demonstrated progression-free survival in only 18% of patients at 6 years.8 Efforts to improve these poor long-term outcomes have resulted in a variety of experimental strategies. One extensively tested approach has beent to add a third cytotoxic drug. Selection criteria for picking that third drug are mechanisms of resistance that are different from the platins or taxanes, and more importantly, evidence of some degree of non–cross-resistance in the clinical setting. Gemcitabine, topotecan, and liposomal doxorubicin have been used in this setting because of their known and reproducible single-agent activity in the cohort of platinum-resistant patients; epirubicin has been used because of the apparent superiority of anthracycline-containing platin-based regimens in meta-analyses. However, they have all been tested without apparent benefit in nine phase III studies.9–17 There was absolutely no statistically significant superiority or clinically useful benefit associated with the three drugs, compared with the control arms receiving carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg/m2 over 3 hours) every 3 weeks for six or more cycles (Table 1). In fact, when comparing hazard ratios for progression-free survival (PFS), the standard arms were often as superior as the three-drug arms. For example, the maximum degree of benefit achieved by adding a third drug in the large, well-conducted GOG 182 study10 was an increase in median PFS of 2 weeks (16 to 16.4 months) and a 2% absolute overall survival increase at 3 years (57% to 59%), with the triplets containing gemcitabine or liposomal doxorubicin. In contrast, in patients in the sequential doublet arms receiving topotecan or gemcitabine, there was a 3-week decrement in median PFS.
It is essential for us to understand why the triple-drug strategy has failed, not only in ovarian cancer but also, for example, in lung cancer. The negative consequences resulting from abandoning the strategy on the basis of flawed analysis will be significant, and these consequences are already becoming apparent. The assumption has already been made that it was a failed strategy, not a failed design or incorrect choice of drugs. The pharmaceutical industry has moved away from developing new cytotoxics and is now concentrating on targeted therapies instead, with new product pipelines consisting almost exclusively of targeted therapies. Similarly, the cooperative groups have moved wholeheartedly toward testing targeted therapies, such as vascular endothelial growth factor inhibition in conjunction with carboplatin and paclitaxel in women newly diagnosed with ovarian cancer, and away from testing additional cytotoxics in first-line combinations. It is unlikely that any single approach will result in the curing of women with ovarian cancer. It is much more likely that a cure will come about from a series of small improvements resulting from differing approaches, including newer, better cytotoxics. Thus, we must not throw out the baby with the bath water, if the strategy was valid but our choice of drugs was wrong. There are a variety of reasons why a survival benefit would not have been demonstrated in the experimental arm of a phase III study. First, there may have been technical problems with the study design, such as a small sample size that missed a clinically relevant (but statistically nonsignificant) difference, or imbalance in prognostic factors between arms, or a lack of mandated, equivalently scheduled follow-up procedures that resulted in a systematic bias affecting the date of relapse in one arm. Second, there may have been treatment dosing problems, resulting in the inability to deliver adequate doses due to toxicity in the experimental arm or undue toxicity with increased number of deaths in the experimental arm. Third, relapse therapies may have had an impact, which would have been relevant to overall survival, but not to PFS. Finally, there is the experimental arm itself; in the nine phase III studies,9–17 the three-drug arms may truly not have been better than the standard control arms. Because the studies were for the most part large, well designed, and well described, and used different strategies for adding the third drug (especially planned sequential and consolidation strategies), one can confidently rule out design flaws, underdosing, and differential toxicity as the reason for the equivalent results. Therefore, an ineffective third drug is left as the only explanation. The issue of salvage therapy after relapse is not applicable. For this to be of concern, the initial PFS would have had to have been shorter in the standard arms, with subsequent compensatory benefit from the delayed use of the third drug leading to equivalent overall survival. However, in all these studies, the PFS was the same in the experimental and control arms. Design flaws are the easiest to rule out. The great majority of the studies were large enough to detect a clinically meaningful, absolute improvement in survival of 3 months. As discussed, citing the GOG 182 study10 as an example, any differences in PFS fell in the range of a few weeks. Few would regard this as clinically meaningful. In addition, the modest improvements in PFS recorded were seen in the control arm as often as they were in the experimental arm. The studies were well balanced regarding the known prognostic factors of age, performance status, stage, histology, and amount of cancer remaining after debulking, and were large enough that any unsuspected or unknown prognostic factors would have occurred by random chance equally as often in both arms. Delivery of the third drug in an adequate dosage was problematic in both the triplet and the sequential doublet strategies. The planned protocol doses were all lower than the approved single-agent doses, and the actual doses delivered were even lower. The carboplatin and paclitaxel dose delivered (both planned and actual) was the same in the experimental arms as it was in the controls. So the inability to deliver an effective dose of the third drug is a valid potential explanation for the lack of effect. However, luckily, both sequential and consolidation strategies were also evaluated. In this design, topotecan and epirubicin were delivered—after completion of the full dose of carboplatin and paclitaxel—in doses compatible with their recommended single-agent dosing. There was still no additional PFS benefit, which suggests underdosing was not the reason. Finally, death as a result of toxicity was not more common in the experimental arms, leaving only an ineffective third drug as the likely explanation. Put simply, the third drugs that have been tested have had insufficient additional activity for any survival improvement to occur, compared with platin-taxane backbones. This conclusion—like the excessive optimism in designing the studies—is obvious with the benefit of hindsight. The response rates in the platin-resistant cohort of the phase II studies18–26 that were available when the triple-drug studies were being designed were 12% to 18% for topotecan, 9% to 19% for gemcitabine, and 18% to 24% for liposomal doxorubicin. These figures would potentially have been higher if stable disease had also been regarded as an indicator of activity, albeit of a lesser extent. Such levels of activity are significant, and were expected to improve outcomes in triple-drug regimens. However, the activity of these drugs was tested in the wrong cohort of patients who had relapsed. Platin resistance—defined as progression during treatment, stable disease, or relapse within 6 months—does not equate to guaranteed inactivity of platin on relapse. Re-treatment with the platinum analog, oxaliplatin, in so-called platin-resistant patients still resulted in response rates of 4% to 6%.27,28 Interestingly, the response rates achieved with topotecan and paclitaxel in these same oxaliplatin randomized studies were 6% and 16%, suggesting some additional low level of activity. If one assumes that topotecan or paclitaxel were also killing cells that would otherwise have been killed by the platin analog, which is a reasonable assumption given the superiority of cisplatin over paclitaxel in chemotherapy-naive women, then their true non–cross-resistant activity would only be in the 2% to 12% range.6 Evidence of activity of the new drug is needed in patients with cancer that progressed while they were receiving a platin analog (ie, true platin-refractory patients), rather than in platin-resistant patients. This is the essential prerequisite for choosing a drug to use with platinum in first-line therapy. In addition, ideally, the new drug should be tested in patients with cancer that progressed during first-line therapy—a bad scenario—and not in patients with cancer that progressed during latter rounds of treatment, because such a cohort of women would be a selected group of survivors with less virulent disease that is more amenable to treatment.29 It is not possible to extract data from the original studies on the true platin-refractory patients only, but as the topotecan studies18–21 illustrate, the overall response rate for the truly refractory patients combined with those with stable disease was only 9%. Activity in the truly refractory patients must have been overestimated. Platin refractoriness is important, but taxane refractoriness is as well. Gore et al30 in their study of topotecan compared with paclitaxel in patients with relapsed ovarian cancer recorded the response achieved when crossing over to the other drug. Of those patients who progressed on taxol, only 8% then responded to topotecan; conversely, only 4% responded to paclitaxel after progression on topotecan. Essentially, the drugs kill the same cells and are not non–cross-resistant to any significant degree. The aim of adding a third non–cross-resistant drug to platin and taxane is still a laudable approach. The studies conducted so far have failed not because of a failed strategy but rather because of the incorrect choice of drug. Before a new drug is included in any similar future trials, activity of the new drug must be tested in the correct subset of patients—those who are truly platin refractory. Only activity in this cohort should act as a green light for inclusion in first-line regimens. On the basis of these arguments, and the findings in the GOG 132 study6 and the International Collaborative Ovarian Neoplasm study (ICON3)7 of equivalent effectiveness with the initial use of single-agent platin compared with platin-taxane doublets and the low level of activity of taxanes in platin-refractory patients—and being deliberatively provocative—should we not instead add the new cytotoxic (selected for its activity in platin-refractory patients) to carboplatin and compare this doublet with carboplatin alone or carboplatin and taxane?28 The issue of whether the combination of platin and paclitaxel is superior to initial single-agent platin is still unresolved. First-line comparative studies have demonstrated equivalent effectiveness.6,7 However, other studies, such as the sensitive relapse trials, have demonstrated a benefit with doublet combinations.31,32 Similarly, an abstract at the 44th Annual Meeting of the American Society of Clinical Oncology reported the superiority of first-line dose-dense paclitaxel plus carboplatin over conventional carboplatin and paclitaxel in women newly diagnosed with cancer.33 AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Paul J. Hoskins, GlaxoSmithKline (U) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
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Hoskins P, Eisenhauer E, Beare M, et al: Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: A National Cancer Institute of Canada Clinical Trials Group Study. J Clin Oncol 16:2233–2237, 1998.[Abstract] 21. Bookman MA, Malstrom H, Bolis G, et al: Topotecan for the treatment of advanced epithelial ovarian cancer: An open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol 16:3345–3352, 1998.[Abstract] 22. Lund B, Hansen O, Theilade K, et al: Phase II study of gemcitabine (2', 2'-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 86:1530–1533, 1994. 23. Friedlander M, Millward MJ, Bell D, et al: A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer. Ann Oncol 9:1343–1345, 1998. 24. Shapiro JD, Millward MJ, Rischin D, et al: Activity of gemcitabine in patients with advanced ovarian cancer: Responses seen following platinum and paclitaxel. Gynecol Oncol 63:89–93, 1996.[CrossRef][Medline] 25. Muggia F, Hainsworth JD, Jeffers S, et al: Phase II study of liposomal doxorubicin in refractory ovarian cancer: Antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 15:987–993, 1997. 26. Gordon AN, Rose GPG, Hainsworth J, et al: Phase II study of liposomal doxorubicin in platinum and paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol 18:3093–3100, 2000. 27. Vermorken J, Gore M, Perren T, et al: Multicenter randomized phase II study of oxaliplatin (OXA) or topotecan (TOPO) in platinum-pretreated epithelial ovarian cancer (EOC) patients (pts). Proc Am Soc Clin Oncol 20:212a; 2001 abstr 847. 28. Piccart MJ, Green JA, Lacave AJ, et al: Oxaliplatin or paclitaxel in patients with platinum-pretreated advanced ovarian cancer: A randomized phase II study of the European Organization for Research and Treatment of Cancer Gynecology Group. J Clin Oncol 18:1193–1202, 2000. 29. Hoskins PJ, Le N: Identifying patients unlikely to benefit from further chemotherapy: A descriptive study of outcome at each relapse in ovarian cancer. Gynecol Oncol 97:862–869, 2005.[CrossRef][Medline] 30. Gore M, ten Bokkel Huinink W, Carmichael J, et al: Clinical evidence for topotecan-paclitaxel non–cross-resistance in ovarian cancer. J Clin Oncol 19:1893–1900, 2001. 31. Pfisterer J, Plante M, Vergote I, et al: Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: An intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 24:4699–4707, 2006. 32. 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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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