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© 2003 American Society for Clinical Oncology
Maybe More Is BetterDivision of Oncology, University of Mississippi Medical Center, Jackson, MS IT HAS often been said that the medical oncologist’s mantra is, "More is better." Throughout the 1980s, investigators expended much effort to evaluate multiple ways of giving more to patients with ovarian carcinoma, including escalating doses of standard chemotherapy, stem-cell–supported high-dose chemotherapy, and intraperitoneal chemotherapy. Despite the fact that these efforts consisted primarily of uncontrolled trials, the virtue of ever higher doses was largely unchallenged.1,2 The 1990s saw a more rigorous evaluation of higher doses. Randomized trials indicated that dose escalation beyond a certain dose added little benefit and much toxicity.3–9 Intraperitoneal chemotherapy fell into disfavor as a result of a more detailed examination of reported results in the setting of second-line therapy.10 Finally, in the late 1990s, even uncontrolled data failed to support the potential role of stem-cell–supported high-dose chemotherapy.11 As the new century dawned, more was regarded as not necessarily better, and clinical research shifted to other directions. By the new millennium, aggressive surgical cytoreduction followed by six cycles of paclitaxel plus carboplatin represented the standard of care for advanced ovarian carcinoma.12–15 For patients with advanced disease (stage III and IV with either small-volume or large-volume disease), response rates approached 90%, clinical complete response rates reached 75%, and median survivals ranged from 26 months for patients with bulky residual disease to more than 60 months for patients with small-volume residual disease. Despite these remarkable figures, follow-up shows that, of the 75% of advanced-disease patients who achieve a clinical complete response, almost 75% will relapse and eventually die of their disease. Although efforts to improve further the complete response rate have continued, focus has also begun to turn to ways to consolidate or maintain complete response. Studies of maintenance or consolidation strategies during the last 20 years had failed to show any advantage. These efforts had consisted of continued chemotherapy, hormonal agents such as tamoxifen, radiotherapy, and, in some instances, secondary surgical cytoreduction. The selection of agents, for the most part, had been empirically based on the activity in first- or second-line settings. No agent showed any additional benefit. The study by Markman et al16 (Gynecologic Oncology Group and Southwest Oncology Group intergroup trial) differs from these prior trials in two significant respects. First, the specific question addressed is not whether a longer duration of chemotherapy yields a better result; rather, the question is whether patients with a demonstrated clinical complete response to initial chemotherapy benefit from more prolonged therapy with one of the initial agents, paclitaxel. This avoids the problem presented by a recent trial of extended duration of chemotherapy in lung cancer, in which random assignment to treatment before initiation of first-line therapy led to the median number of cycles of therapy in both arms being the same (four cycles) because failure to respond to initial therapy occurred at a high frequency.17 Second, there are reasons for believing that extension of the duration of paclitaxel, specifically, might be beneficial. These include anecdotal reports from early trials of responses that did not occur until the 10th, 11th, or 12th cycle of therapy and preclinical observations of an antiangiogenic effect of paclitaxel over a prolonged period of treatment.18 The study did not continue administration of carboplatin because there were no data to suggest potential benefit. One would think that a trial showing benefit for a maintenance or consolidation strategy in a disease with a high complete response rate but a high relapse rate would be greeted with great enthusiasm. This has not been the case. In fact, significant segments of the academic community have raised a series of concerns about the study. These can best be summarized as follows: the trial was closed prematurely; the regimen with the more prolonged duration of therapy was associated with excessive toxicity; the benefit is a longer progression-free survival, not overall survival, and the difference is less than the increased length of therapy; and there is no confirmatory trial. With regard to the first of these concerns, the alleged premature closure of the trial, it should be noted that the trial was not closed prematurely. The trial was closed by the Southwest Oncology Group Data Safety Monitoring Committee as the result of a prospectively mandated interim analysis and prospectively defined criteria that would prompt consideration of study closure. It might be argued that the prospective criteria set the bar too low or used the wrong end point (progression-free survival rather than overall survival). In this respect, some of the investigators now debating these points accepted the design of the trial while they were members of one or both of the cooperative groups performing the trial. The time to make such arguments was before the initiation of the study, not after the results failed to meet preconceived expectations. The second objection finds its basis in the known cumulative neurotoxicity associated with short-infusion paclitaxel and the amendment to the protocol adopted because of a perceived excessive drop-out rate in the 12-cycle arm. The amendment reduced the starting dose of paclitaxel to 135 mg/m2 rather than 175 mg/m2. This resulted from an observed 10 drop-outs in the 12-cycle arm as opposed to three drop-outs in the three-cycle arm; all drop-outs were related to grade 2 to 3 neurotoxicity. All of the patients included in the analysis reported by Markman et al,16 however, received the 175 mg/m2 starting dose. Several observations are relevant to these data. First, the study directed that paclitaxel be given at monthly intervals rather than every 3 weeks; hence, it is reasonable to expect the amount of neurotoxicity observed to be less than might be expected were the interval between cycles to be shortened to 3 weeks. Second, the overall drop-out rate presumably caused by neurotoxicity was only 6%; even in the 12-cycle arm the drop-out rate was less than 10%. Third, patients in the 12-cycle arm had 9 more months of opportunity to drop out; hence, one might have expected 12 drop-outs on the 12-cycle arm as opposed to three on the basis of the four-fold greater duration of therapy, even in the absence of neurotoxicity. Although it cannot be denied that those on the 12-cycle arm experienced more toxicity, the toxicity does not appear to have been an overwhelming problem. The third objection reflects the constant struggle between scientific objectives and medical ethics in clinical trials. The design of the study provided for an interim analysis after 225 patients had been enrolled. Extreme differences in progression-free survival were to be considered as evidence supporting early study termination. The decision to terminate the study was also to reflect other factors including toxicities, overall survival, and other complications. The Data Safety and Monitoring Committee of the Southwest Oncology Group is a group independent of the study chairs and participating investigators; their view of the differences observed dictated early closure of the study according to prospectively designed criteria. In addition, ethics dictated that study participants be notified of such results and given the opportunity to switch to the superior regimen. Although Markman et al16 do not provide data on how many patients on the three-cycle arm crossed over to 12 cycles or, if finished with therapy, requested nine more cycles, it is reasonable to assume that cross-over was frequent enough to cause potential problems with the interpretation of any additional survival information. At the time of this report, survival data reflected only 17 events; hence, these data cannot support a meaningful conclusion regarding the influence of 12 cycles of paclitaxel on overall survival. With additional follow-up contaminated by cross-over, meaningful survival data may never be available from this study. One must therefore decide whether prolongation of progression-free survival results is sufficient benefit to justify 12 additional cycles of paclitaxel. Some critics have noted that a 7-month–longer progression-free survival median is shorter than the 9 additional months of treatment required to achieve this difference. Consideration of progression-free survival simply as a discrete rather than a continuous variable, with the median as the only meaningful point, leads to a disingenuous argument at best. Nevertheless, assume for the moment that it is fair to examine only the median progression-free survival. It would then also be fair to examine how the median progression-free survival correlates with overall survival in studies of paclitaxel-containing regimens. In the Gynecologic Oncology Group study of cyclophosphamide plus cisplatin versus paclitaxel plus cisplatin, a 5-month improvement in the progression-free survival with paclitaxel plus cisplatin resulted in a 13-month improvement in the overall survival. Moreover, in the European-Canadian study of the same two regimens, a 4-month improvement in the progression-free survival produced a 10-month improvement in overall survival. Using this logic, the 7-month improvement in progression-free survival observed in the study of Markman et al should therefore be associated with at least a 16-month improvement in overall survival—a result that would suggest clear superiority for the 12 additional cycles of paclitaxel. The truth is that this study does not now and probably never will define whether an improvement in overall survival results from 12 cycles of paclitaxel. The highly significant difference in progression-free survival, however, does provide sufficient evidence of benefit to warrant consideration of maintenance therapy in the patient with a clinical complete response to initial therapy. The fourth objection almost always follows any significant positive observation that does not fit with conventional wisdom. Simply put, this objection is, "There is no confirmatory trial." This objection is correct and is the sole reason why the report by Markman et al16 should not result in a change in the standard of care. In the absence of such a confirmatory trial, however, the data do mandate that the physician discuss this option with each patient in an honest and open way. Such discussion should not dismiss maintenance therapy as having no survival advantage. The honest answer is that we do not know whether an advantage in overall survival results, but that we do know that a clear advantage in progression-free survival occurs. When a second trial confirms these results and (it is hoped) provides information on survival, a change in the standard of care may be appropriate. Where does research now head? Among the objections to the study of Markman et al,16 only the lack of a confirmatory trial appears to be valid. The first priority should therefore be a confirmatory trial, preferably by a group other than the two participating cooperative groups involved in the Markman et al trial. If such a study confirms the value of maintenance therapy with paclitaxel, one might then logically ask whether 12 cycles are enough. The Markman et al data indicate a higher hazard for progression after therapy was stopped on both arms. A future trial might thus focus on whether even more treatment is feasible and beneficial. Other agents might also be tested, but these should be agents with characteristics that indicate that prolonged therapy might be both effective and tolerable. These considerations all lead to the important question for now: Should the study by Markman et al16 influence current practice, and, if so, how? Given the high clinical complete response rate and high relapse rate in ovarian carcinoma, maintenance therapy with 12 additional cycles of paclitaxel should at least be discussed with every patient who achieves a clinical complete response. The discussion should honestly present the information without the personal bias of the physician. Patients electing maintenance therapy should be treated with an initial dose of 175 mg/m2 because this is the only starting dose on which data are available. All of this probably was not on the mind of those who argued in the 1980s that "more is better." Nevertheless, the trial of Markman et al does resurrect the value of more. After all, maybe more is better if it includes more time as well as more total dose. REFERENCES
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5. Conte P, Bruzzone M, Carnino F, et al: High-dose versus low-dose cisplatin in combination with cyclophosphamide and epidoxorubicin in suboptimal ovarian cancer: A randomized study of the Gruppo Oncologico Nord-Ovest. J Clin Oncol 14:351–356, 1996 6. Gore M, Mainwaring P, Macfarlane V, et al: A randomized study of high versus standard dose carboplatin in patients with advanced epithelial ovarian cancer. Proc Am Soc Clin Oncol 15:284, 1996 (abstr 769) 7. Swenerton K, Eisenhauer E, ten Bokkel Huinink W, et al: Taxol in relapsed ovarian cancer: High vs low dose and short vs long infusion—European-Canadian study coordinated by the NCI Canada Clinical Trials Group. Proc Am Soc Clin Oncol 12:256, 1993 (abstr 810) 8. Rowinsky E, Mackey M, Goodman S: Meta-analysis of paclitaxel dose-response and dose-intensity in recurrent or refractory ovarian cancer. Proc Am Soc Clin Oncol 15:284, 1996 (abstr 770) 9. Omura G, Brady M, Delmore J, et al: A randomized trial of paclitaxel at 2 dose levels and filgrastim at 2 doses in platinum pretreated epithelial ovarian cancer: A Gynecologic Oncology Group, SWOG, NCCTG and ECOG study. Proc Am Soc Clin Oncol 15:280, 1996 (abstr 755) 10. Markman M, Reichman B, Hakes T, et al: Responses to second-line cisplatin-based intraperitoneal therapy in ovarian cancer: Influence of a prior response to intravenous cisplatin. J Clin Oncol 9:1801–1805, 1991[Abstract]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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