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© 2002 American Society for Clinical Oncology
Is There a "Best" Choice of Second-Line Agent in the Treatment of Recurrent, Potentially Platinum-Sensitive Ovarian Cancer?Beth Israel Deaconess Medical Center, Boston, MA THE SURVIVAL OF patients with advanced epithelial ovarian cancer has clearly improved with the introduction of taxanes into first-line platinum-based chemotherapy.1 Unfortunately, most patients will relapse after achieving a complete clinical response to regimens such as paclitaxel plus carboplatin, and the vast majority of these patients are incurable. Nevertheless, there are now several agents capable of inducing multiple second and subsequent responses in the setting of relapsed disease, and we can now effectively palliate many patients in a manner that was not possible even a decade ago.2 Because palliation is the goal of second-line treatment, choosing the proper agent for use in the recurrent disease setting involves balancing the perceived need to obtain an objective response against the importance of maintaining an excellent quality of life. This is especially important because many patients with recurrent disease are asymptomatic and receive second-line cytotoxic chemotherapy for an increasing CA-125 level in the setting of relatively low-volume disease on computed tomography scan.3 The treatment-free interval (TFI), defined roughly as the period of time between the end of first-line chemotherapy and the start of second-line therapy, has been used as a guide to choosing a second-line agent for several years. As Markman et al4 have shown, a TFI of between 6 and 24 months predicts for a response rate of approximately 30% to second-line platinum, and a TFI of over 24 months predicts for platinum responses in the 60% range. Despite these reasonable response rates, two controversies have arisen regarding the optimal choice of chemotherapy in the setting of recurrent, potentially platinum-sensitive disease. The first involves whether patients are best served by treatment with single-agent platinum analogs, or whether there might be an advantage to the use of combination platinum-based regimens. To date, there is no good evidence to suggest that combination chemotherapy is better than single agents in the management of ovarian cancer patients with low-volume relapse. For instance, randomized studies have shown no survival advantage to the use of carboplatin plus epidoxorubicin compared with carboplatin alone (platinum-sensitive relapse),5 or to the use of paclitaxel plus epidoxorubicin compared with paclitaxel alone (platinum-resistant relapse).6 It is unfortunate that many of the available randomized comparisons are not sufficiently powered to draw definitive conclusions, although they suggest that such combinations generally yield equivalent overall survival at the expense of greater toxicity. Finally, phase II trials evaluating combinations such as paclitaxel plus carboplatin for second-line treatment of recurrent disease often show impressively high response rates and respectable progression-free survivals.7,8 Although at first glance this seems to provide meaningful information, such results are hardly surprising given the fact that these studies tend to include patients with marker-only relapse, thereby introducing an element of lead-time bias. For these reasons, the use of single-agent platinum remains the standard to which other regimens must be compared in the recurrent disease setting. A second controversy that has emerged over the years is whether newer, non–platinum-based drugs might have a role in the treatment of potentially platinum-sensitive disease (as opposed to the more traditional use of platinum in this setting). This is the topic of the article by Cantù et al9 in this issue of the Journal of Clinical Oncology, in which single-agent paclitaxel is compared with platinum-based chemotherapy with cyclophosphamide, doxorubicin, and cisplatin (CAP) in 97 ovarian cancer patients who recurred after a progression-free interval of greater than 12 months. The results of this trial show that the response rate was higher in the CAP-treated group (55% v 45%, CAP v paclitaxel respectively; P = .062). In addition, the median progression-free survival (PFS) and overall survival times were significantly improved through the use of CAP (15.7 v 9 months [PFS] and 34.7 v 25.8 months [overall survival], CAP v paclitaxel, respectively). The levels of significance for the PFS and overall survival differences were P = .038 and P = .043, respectively. Cross-over occurred in 23 CAP failures and 30 paclitaxel failures, with 22% of CAP failures subsequently responding to paclitaxel, and 47% of paclitaxel failures responding to CAP. Predictably, the CAP regimen was generally more toxic, with an increased incidence of grade 3 and 4 neutropenia. Despite the interesting question being asked in this study, several methodological problems exist that limit proper interpretation of the data. For instance, the small numbers of patients in this study make it more reasonable to consider this a randomized phase II trial, designed to explore the activity and feasibility of each regimen, as opposed to making a definitive statement regarding the superiority of one regimen over the other. In addition, it seems that a well-defined cross-over strategy was not a formal part of this trial, thus making it difficult to draw firm conclusions regarding the observed differences in survival between the two treatment arms. Also, we do not know whether the two treatment groups are balanced for use of first-line paclitaxel, a factor that might confound interpretation of the second-line response data. Finally, this study must be interpreted in the context of newer data showing equivalence of single-agent carboplatin to CAP in the first-line setting, as demonstrated by International Collaborative Ovarian Neoplasm Study 2.10 Had the authors chosen to compare carboplatin alone with paclitaxel, it is possible that the trends toward improved outcome with platinum would be maintained without the excessive morbidity associated with the CAP regimen.
What are we to conclude from this study, and how should it shape our decision making with respect to the choice between a nonplatinum versus a platinum-containing regimen in the second-line treatment of potentially platinum-sensitive patients? To answer this question, it is useful to briefly review some of the available data that address the utility of nonplatinum-based regimens in the treatment of recurrent ovarian cancer, as outlined in Table 1. The three most extensively studied agents that are potentially non–cross-resistant to platinum are paclitaxel, topotecan, and liposomal doxorubicin, and each has been shown to induce responses in both platinum-sensitive and platinum-resistant patients.11-14 Although the response rates for platinum-resistant patients (TFI < 6 months) are generally quite low (Table 1), these agents exhibit substantial activity in patients who are potentially platinum-sensitive (TFI
Regardless of the appeal that this idea may have, the concept of prolonging the platinum-free interval through the interval use of a nonplatinum regimen raises several questions: (1) Despite response rates as high as 44% (Table 1), is second-line non–platinum-based therapy as active as second-line platinum in the patient with a prolonged TFI? The study reported by Cantù et al9 suggests that the answer to this question might be no, at least for the use of paclitaxel, although we are limited by the small size of the trial and lack of definitive conclusions. (2) Can artificially prolonging the platinum-free interval through the interval use of a nonplatinum drug actually preserve platinum sensitivity, or will it simply limit the utility of future platinum therapy by selecting for resistance? (3) Will the use of nonplatinum-based therapy provide patients with a superior quality of life compared with a generally well-tolerated drug such as single-agent carboplatin? Although the answers to these questions are not completely known, this information is critically important if we are to intelligently choose the best second-line agent in the recurrent disease setting. For instance, there is now compelling evidence to suggest that chemotherapy resistance is partly a result of defects in the apoptotic pathway, a process that mediates almost all forms of cell death in response to chemotherapy-induced injury.17-23 Thus it is reasonable to expect that almost any prior chemotherapy regimen will have a tendency to select for tumor cells that are more resistant to subsequent agents, by virtue of an impaired apoptotic response. We are all painfully aware of this clinical phenomenon in the daily practice of oncology, and it is nicely illustrated by the data in Table 1. The fact that patients who are resistant to platinum are generally resistant to liposomal doxorubicin, topotecan, or paclitaxel is an indication of clinical cross-resistance, and it implies the existence of an underlying mechanism of multidrug resistance that is shared by many classes of chemotherapeutic agents, regardless of their mechanism of action. There is no reason to assume that this process is unidirectional and would apply only to a specific sequence of drugs. Thus the use of topotecan or liposomal doxorubicin before platinum will indeed artificially prolong the platinum-free interval, but it is conceivable that it could also jeopardize subsequent response to platinum. This concern can only be satisfactorily addressed in a randomized trial setting. Despite the limitations of their trial, Cantù et al9 are to be commended for being the first to formally study the issue of nonplatinum versus platinum second-line therapy in a randomized fashion. More studies are obviously necessary to address this question further. Such studies should compare a nonplatinum drug with a regimen such as single-agent carboplatin, and a cross-over design should be a formal part of the trial. The idea is not to simply evaluate initial response to second-line therapy, but to determine how initial second-line choice affects subsequent response to the alternative agent, influences progression-free and overall survival, and impacts quality of life. The importance of assessing not only traditional measures of response (such as complete or partial response), but also assessing the ill-defined state of stable disease, cannot be underestimated in this kind of analysis. We have all treated patients who experience prolonged periods of disease stability with many of the agents listed in Table 1, and there is no doubt that such patients have derived significant palliative benefit despite not having been scored as responders by formal clinical trial definitions. Until data from such trials are available, we are left with the fact that platinum analogs are still the most active class of drugs for the treatment of epithelial ovarian cancer, and that single-agent carboplatin produces valuable palliative benefit with a reasonable toxicity profile in the majority of patients who recur after a TFI of greater than 6 months. REFERENCES
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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6 months), with response rates ranging from 20% to 44%. This observation has led to the interesting suggestion that it might be possible to prolong the platinum-free interval by using one of these alternate agents first, thereby saving platinum for later.
