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Journal of Clinical Oncology, Vol 22, No 9 (May 1), 2004: pp. 1542-1545 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.02.150
The Ethics of Early Stopping Rules: Who Is Protecting Whom?Program in Gynecologic Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA Well-conducted clinical investigation, in concert with basic laboratory research, is the cornerstone for progress in medicine. Without it, we are forced to depend solely on experience and bias in the choice of proper treatment, which can sometimes be misleading. Our well-intended predecessors from the time of Hippocrates would envy our analytic approach to clinical investigation, releasing them from the limitations of leeches, bad humors, and evil spirits in the management of patients with life-threatening disease. Given the importance of the clinical trial process, our greatest challenge as clinical investigators is to ensure that trials yield interpretable results while preserving the safety of study participants. For phase III randomized trials, these issues are typically under the purview of an independent Data and Safety Monitoring Board (DSMB), composed of statisticians and clinical investigators not directly involved with the study. The DSMB is responsible for reviewing the data, performing interim analyses when the study reaches its specified number of events, and deciding whether or not to close the study on the basis of predetermined early stopping rules that relate to toxicity or outcome. If excess harm is observed, or if a statistically significant benefit is observed, the study is stopped early and the patient is informed of the results. If treatment is ongoing, the patient is typically offered the opportunity to receive the regimen that is perceived to be superior. Thus, the early stopping rule has the potential to minimize harm and to maximize benefit for those patients enrolled in a randomized trial. Despite the importance of early stopping rules, the results of two recent studies suggest that there are instances in which such rules might compromise proper interpretation of clinical trial results and thereby jeopardize the very patients that they are designed to protect. Southwestern Oncology Group (SWOG) study 9701 (Gynecologic Oncology Group 178) was a phase III randomized trial designed to determine whether a prolonged maintenance phase of single-agent paclitaxel could improve outcome in patients with advanced epithelial ovarian cancer in first clinical remission.1 In this intergroup study, patients were randomly assigned to receive an experimental arm of single-agent maintenance paclitaxel administered monthly for 12 months, or a control arm of the same drug and dose for 3 months. The primary objective of SWOG 9701 was to determine whether 12 cycles of paclitaxel resulted in superior progression-free survival (PFS) and overall survival (OS). Anticipated total accrual was 450 patients over 5 years, with the first interim analysis to be performed by the DSMB after 50% accrual was reached. The interim analysis was "conducted to guard against extreme findings, either excessive toxicity or a substantial improvement in efficacy".1 At the time of the first interim analysis, a median PFS advantage of 7 months was observed in favor of the 12-month paclitaxel arm (P = .0023, one-tailed test), resulting in early study termination. At the time of study closure, only 17 deaths had occurred, and there was no evidence of an OS benefit for the 12-month paclitaxel arm. In addition, 23% of patients receiving 12 months of paclitaxel developed grade 2 or 3 neuropathy, 7.5% of patients discontinued therapy as a result of neuropathy, and the lack of a formal quality of life (QOL) assessment prevented conclusions regarding quality-adjusted survival.1,2 Although the authors acknowledged the limitations of this study because of early termination, including the inability to assess the effects of this treatment on either OS or QOL, they concluded that prolongation of median PFS by 7 months justifies consideration of 12 months of maintenance paclitaxel in patients with advanced epithelial ovarian cancer in first clinical remission.1,3 In a separate study, the National Cancer Institute of Canada Clinical Trials Group designed a randomized trial comparing 5 years of treatment with the aromatase inhibitor letrozole compared with placebo in hormone receptor-positive, early stage postmenopausal breast cancer patients who had recently completed 5 years of tamoxifen adjuvant therapy.4 The study was powered to detect a difference of 2.5% in 4-year disease-free survival (DFS), with a planned enrollment of 4,800 women over a 4 year period and 2 years of follow-up. Interim analysis by the DSMB required a minimum of 171 events, and efficacy end points under consideration were DFS and OS. A total of 5,187 women were enrolled, with 207 events reported at the first interim analysis, after a median follow-up of 2.4 years. A statistically significant difference in the 4-year DFS rate was observed in favor of the letrozole group compared with placebo (93% v 87%, respectively; P < .001), with a hazard ratio for recurrence or contralateral breast cancer of 0.57. Based on these data, the DSMB recommended study termination and disclosure of the results to patients in the placebo arm, thereby permitting cross-over. However, there was no statistically significant difference in OS, and the letrozole group experienced a greater frequency of osteoporosis, fractures, hot flashes, and myalgias. In addition, no patient received letrozole for more than 3 years, precluding any meaningful assessment of long-term toxicity or optimal duration of therapy. Although a QOL analysis was performed as part of this study, the results were not available at the time of the initial study publication. The investigators concluded that, based on the difference in DFS, letrozole is a reasonable option for postmenopausal patients who have completed 5 years of adjuvant tamoxifen therapy. The purpose of a medical or surgical intervention is to enable patients to live longer (OS), to make them feel better (QOL), or both. There are essentially no other universally agreed upon reasons for recommending treatment. And yet neither of these large, expensive studies, requiring hundreds or thousands of patients, was allowed to address benefit as defined in these terms. Each study clearly implied that the observation of prolonging PFS (or DFS) is important, based on the assumption that prolongation of PFS might be associated with either improvement in QOL or OS. However, it is widely recognized that prolongation of PFS does not necessarily translate into a QOL benefit, since many regimens that yield improvement in PFS may do so at the expense of greater toxicity. For example, the use of paclitaxel in SWOG 9701 was associated with increased neuropathy and prolonged alopecia, which may negatively impact QOL. Similarly, letrozole-related side effects in the National Cancer Institute of Canada Clinical Trials Group trial were observed with even short durations of treatment (such as osteoporosis), and the full toxicity profile of this drug when administered for 5 years may never be assessed because of early study closure. Perhaps more importantly, PFS as a surrogate for OS may be unreliable, as demonstrated by several randomized trials performed in the oncology patient population.5-8 For example, Eastern Cooperative Oncology Group study 1193 demonstrated a statistically significant improvement in median PFS and response rate for combination doxorubicin and paclitaxel compared with single-agent therapy for patients with metastatic breast cancer, but without improvement in either OS or QOL.6 Likewise, Gynecologic Oncology Group study 132 demonstrated a statistically significant improvement in median PFS and response rate for combination paclitaxel and cisplatin compared with single-agent paclitaxel for patients with suboptimally-debulked epithelial ovarian cancer, without improvement in OS.7 Studies of high-dose compared with lower-dose chemotherapy may demonstrate this trend as well, as recently reported by Omura et al8 in patients with recurrent ovarian cancer treated with paclitaxel at two different dose levels. This dissociation of PFS from OS can be partly understood by considering those situations where a salvage treatment can be administered at recurrence, thereby resulting in tumor control and prolongation of survival. Such a strategy might expose patients to less toxicity by limiting treatment to only those who relapse, resulting in improved QOL for the remaining patients who do not require treatment. Thus, it is conceivable that the survival of patients randomly assigned to the 3-month paclitaxel arm of SWOG 9701 might indeed be equivalent to that of the 12-month maintenance arm (but with less toxicity), since patients may still enjoy prolongation of survival through the use of second-line paclitaxel administered at the time of relapse. Prolongation of PFS means that disease progression is delayed in the experimental treatment arm and does not necessarily indicate that a greater fraction of patients have been cured of disease. In this regard, the hazard ratio for recurrence in SWOG 9701 increased dramatically once maintenance paclitaxel was discontinued, suggesting that the effect of treatment was simply to suppress, rather than eradicate, residual disease.1,2 This issue may be especially pertinent for prolonged maintenance strategies that are used after the completion of first-line therapy, since in that situation continued treatment is directed at chemoresistant disease that is less amenable to eradication with conventional approaches. Taken together, these considerations suggest that a direct correlation may not always exist between PFS (or DFS) and other important measures of clinical outcome. Some investigators have interpreted the SWOG 9701 and letrozole studies as positive, based on the assumption that an OS or QOL advantage would have been shown if the studies were allowed to mature as originally intended. However, if these trials had matured to completion and demonstrated no improvement in either OS or QOL, the same investigators would have almost certainly concluded that these studies were negative. In that event, despite the observed PFS advantage, we would not now be recommending these approaches to our patients. Thus, the recommendation for maintenance paclitaxel or post-tamoxifen letrozole is intrinsically tied to our ignorance of the future, not in our certainty of the present, and it is based on the hope that these therapies might have led to a survival advantage if the studies had been allowed to mature. We should not base our recommendations on hope, when we could have the facts. A typical way to rationalize the results of such studies is to acknowledge their deficiencies, but at the same time suggest that the treatment options be discussed with patients nonetheless. The implication is that patients will know the right answer, despite the fact that their physicians do not know how the new treatment will affect important measures of clinical outcome. In this regard, it is legitimate to consider whether the results of the letrozole or maintenance paclitaxel trials might unfairly tantalize patients with the prospect of prolonged PFS, in the absence of a known survival benefit, and with the possibility of treatment-related toxicity. What patient would easily refuse the prospect of prolonged progression-free or disease-free survival under these circumstances, and how many would be able to understand the uncertain and oftentimes tenuous relationship between PFS, OS, and QOL, when data regarding these important outcomes do not exist as a result of early study closure? In view of these considerations, it might be asked why perfectly reasonable and well-intended clinical investigators could view an improvement in PFS or DFS as a legitimate early stopping criterion, and direct a DSMB to consider these end points in their decision-making for early closure of clinical trials. First and foremost, it is likely that this is related to the perceived ethics of depriving study participants of the possibility of a survival advantage, as gleaned from the imperfect surrogate of PFS. Although at first glance, this appears to be an understandable attitude, perhaps we should be more concerned with the possibility of exposing patients (present and future) to potential harm and burdening the medical system with added expense, without fully defining the long-term risks and benefits of a treatment intervention. It is also reasonable to consider the possibility that more subtle factors may influence the decision to use improvement in PFS as an early stopping criterion in randomized clinical trials, as embodied by the following questions: 1) Are we actually protecting the patient with an early stopping rule based on PFS, or are we really protecting ourselves against a public perception that we are not protecting the patient? In other words, are we worried that if we do not stop a study on the basis of a PFS end point, we might be perceived as being unethical? 2) Are we fearful that if we do not use PFS as an early stopping criterion, and rather wait for OS data to mature, that our competitors will report a "positive" study first? 3) Are we fearful that an industry sponsor will not support a trial unless we agree to use the more rapidly assessable end point of PFS as an early stopping criterion? It is not claimed here that any of these biases are at work in the two trials discussed above, but rather that the decision to use PFS as an early stopping rule is complex, and might sometimes be influenced by factors not directly relevant to patient protection. For oncology trials investigating a chronic treatment intervention, the following recommendations are proposed as a framework for further discussion, as we attempt to refine the important role of early stopping rules in the conduct of phase III clinical trials: Recommendation 1. Early stopping rules for oncology trials evaluating a chronic treatment intervention should be based on two major criteria: A) development of prohibitive toxicity, and B) improvement in either OS or QOL. Improvement in PFS or DFS should not generally be used as an early stopping criterion, unless there are convincing data in the same setting to show that prolongation of PFS is a reliable surrogate for improved OS or QOL. As previously discussed, although an OS advantage is almost always associated with a PFS advantage, the reverse is not always the case. However, it may be reasonable to consider an improvement in PFS as an early stopping criterion for those instances in which standard treatment is so unsatisfactory that any effect could be interpreted as being clinically meaningful, and no effective salvage therapy at relapse is known to exist. Recommendation 2. The consent form should explicitly state the criteria to be used for early study closure, thereby permitting the patient to make an informed decision regarding study participation. If a patient is uncomfortable with the criteria chosen for early stopping, then he or she is not obliged to participate. Recommendation 3. The consent form should explicitly state that participants and clinical investigators alike will be informed of those results of interim analyses that have direct bearing on early stopping, especially as they relate to a change of therapy. Specifically, this means that the DSMB would be obliged to report the data if any of the two major criteria listed above were satisfied. If they are not satisfied, and thus there is no need for early stopping, it is acceptable for the DSMB to simply report that "none of the predetermined early stopping criteria have been met." If these criteria are adopted, clinical investigators should be strongly discouraged from reporting the results of PFS (or DFS) in those instances where the study is ongoing and where the early stopping rules have not been met. This particularly applies to abstract presentations at meetings. This approach will minimize the likelihood that study participants and their physicians will be tempted to switch therapies based upon potentially dangerous and misleading assumptions. Recommendation 4. The DSMB should invite participation from members of the lay public, such as patient representatives from advocacy groups. We should not underestimate the ability of well-informed patient advocates to understand these concepts and to be our allies in clinical research. The DSMB has the important task of implementing predefined early stopping rules, but it is not the purview of the DSMB to ensure that these early stopping rules are well-suited to the goals of the study. That is the responsibility of clinical investigators and statisticians involved in trial design—to protect patients against undue toxicity, to offer patients superior treatment once benefit is proven, and to ensure that the study will yield interpretable data for future generations of patients. Early stopping rules that do not capture each of these important elements may serve to undermine the clinical trial effort. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. Acknowledgment I thank Dr Maurie Markman for his helpful comments during the preparation of this manuscript. REFERENCES
1. Markman M, Liu PY, Wilczynski S, et al: Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 21:2460-2465, 2003
2. Ozols RF: Maintenance therapy in advanced ovarian cancer: Progression-free survival and clinical benefit. J Clin Oncol 21:2451-2453, 2003
3. Thigpen T: Maybe more is better. J Clin Oncol 21:2454-2456, 2003
4. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003 5. Muss HB, Case LD, Richards F 2nd, et al: Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. The Piedmont Oncology Association. N Engl J Med 325:1342-1348, 1991[Abstract]
6. Sledge GW, Neuberg D, Bernardo P, et al: Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: An intergroup trial (E1193). J Clin Oncol 21:588-592, 2003
7. Muggia FM, Braly PS, Brady MF, 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 18:106-115, 2000
8. Omura GA, Brady MF, Look KY, et al: Phase III trial of paclitaxel at two dose levels, the higher dose accompanied by filgrastim at two dose levels in platinum-pretreated epithelial ovarian cancer: An intergroup study. J Clin Oncol 21:2843-2848, 2003
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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