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Back to the Future: Multiagent Chemotherapy in Ovarian Cancer Revisited

Beth Israel Deaconess Medical Center, Boston, MA

IT IS INTERESTING to watch the paradigm shifts that have occurred over the past two decades of clinical investigation in epithelial ovarian cancer. With the recognition in the late 1970s that platinum compounds increased both response and survival in this disease, attempts were made to develop multiagent, platinum-based regimens containing potentially non–cross-resistant drugs with some degree of non-overlapping toxicities. This strategy of combining drugs with different mechanisms of action was designed to prevent emergence of drug-resistant clones and was spectacularly successful in the treatment of tuberculosis, Hodgkin's disease, non–Hodgkin's lymphomas, germ cell tumors, and certain types of leukemia.

During the 1980s, however, it was clear that more was not necessarily better. Well-designed randomized studies comparing platinum alone (or cyclophosphamide plus platinum) to more complicated regimens including doxorubicin and/or hexamethylmelamine and/or fluorouracil failed to demonstrate a convincing survival benefit for the multiagent regimen and yet predictably showed higher degrees of toxicity.^1,2 In the late 1980s, most of us were resigned to the fact that somehow the concept of multiagent chemotherapy, which worked so well in certain hematopoietic malignancies, did not seem to apply to many epithelial cancers, and a paradigm shift appeared to be necessary. Immunotherapy, gene transfer, antiangiogenesis agents, inhibitors of matrix metalloproteinases, and antagonists of signal transduction are now the household words of the 1990s, and with good reason. We will require more than one treatment modality to effectively cure most cancers.

Over the past few years, however, new classes of active agents have been developed that have forced us to revisit the multiagent chemotherapy concept in ovarian cancer. For example, taxanes such as paclitaxel and docetaxel, which are antitubulin agents that stabilize the tubulin polymer and result in mitotic arrest, have provided important options for patients with newly diagnosed as well as relapsed disease. The inclusion of taxanes in the first-line treatment of patients with advanced ovarian cancer is now widely recognized as a major advance that has produced increased response and survival.³ This observation alone has resurrected the concept of combination chemotherapy of epithelial cancers, has restored faith in the "hematopoietic" paradigm, and reminds us that our ideas are only as good as the tools that we have to implement them. However, taxanes are only the archetypal example of this phenomenon. Other agents with potentially non–cross-resistant mechanisms of action and proven activity in platinum-refractory ovarian cancer include topotecan (topoisomerase I inhibitor),⁴ gemcitabine (chain terminator and inhibitor of DNA repair),⁵ etoposide (topoisomerase II inhibitor),⁶ and liposomal doxorubicin.⁷ Many of these agents are interesting not only because of their potential for non–cross-resistance but also because of the significant degree of synergism they display with platinum compounds in vitro. In this regard, topotecan and gemcitabine have both been shown to dramatically potentiate the effects of platinum, perhaps by virtue of their ability to inhibit repair of platinum-DNA adducts.^5,8

In this issue of the Journal of Clinical Oncology, Herben et al⁹ describe the results of a phase I trial using the combination of paclitaxel, cisplatin, and topotecan as first-line therapy in patients with advanced epithelial ovarian cancer (most with suboptimally debulked stage III or stage IV disease). The drugs were administered in the sequence paclitaxel, cisplatin, and topotecan, with recognition of the fact that cytotoxic effects of the cisplatin/topotecan combination in preclinical studies are most impressive when topotecan follows cisplatin.⁸ Whether the mechanism of this effect involves topotecan-induced inhibition of DNA repair, or whether it reflects subtle alterations in topotecan renal clearance induced by cisplatin, is unclear. What is interesting from this report is the inability to achieve doses of topotecan that would be considered "optimal" for the treatment of relapsed disease in a single-agent fashion. Specifically, the recommended phase II doses with granulocyte colony-stimulating factor support are paclitaxel 110 mg/m² over 24 hours, day 1; cisplatin 75 mg/m², day 2; and topotecan at only 0.3 mg/m²/d for 5 days (days 2 to 6). The inability to achieve "therapeutic" doses of topotecan when this drug is combined with either paclitaxel or cisplatin has been noted previously¹⁰ and attests to the bone marrow–suppressive potential of this agent, especially with respect to the megakaryocyte lineage. The clinical response rate of 86.7% is encouraging but entirely expected on the basis of using therapy with a taxane/platinum combination.

Two main issues are raised by this well-done study that are relevant to the design and analysis of future drug combinations in ovarian cancer. The first involves the best way to integrate new, potentially non–cross-resistant, bone marrow–suppressive drugs into the first-line management of this disease. Permutations of drug combinations are not limitless, so the options are fairly predictable and include (1) combination therapy such as that used in the study by Herben et al, accepting the need for a reduced dose of topotecan with granulocyte colony-stimulating factor support; (2) combination therapy with more standard doses of each drug as tolerated, with stem-cell support; and (3) alternating doublets (eg, alternating between topotecan/cisplatin, paclitaxel/carboplatin, and gemcitabine/cisplatin, not necessarily in that combination or order). Each of these approaches is currently being investigated in clinical trials, and each has its own merits and disadvantages. The approach described by Herben et al (option 1) is perhaps the most appealing from the standpoint of suppressing drug resistance, since the tumor is constantly exposed to each class of drugs with every cycle of treatment. It is also potentially more convenient, because it avoids the need for stem-cell support (option 2). However, proponents of option 2 have argued that the inability to achieve "therapeutic" levels of topotecan, for instance, when it is used in combination with paclitaxel and cisplatin, may negate the potential benefits of this approach and may necessitate the need for stem-cell support to permit full dosing. Although this view may eventually prove to be correct, it is presently a bias that is unsubstantiated by data. It is important to consider the possibility that the in vitro synergy between drugs like topotecan and platinum may translate into a significant therapeutic effect owing to potentiation of platinum's activity by low doses of a "chemosensitizer" like topotecan. In this regard, it is interesting to recognize that the significant bone marrow suppression observed in the study by Herben et al may already be telling us something about a possible synergistic phenomenon in vivo, despite the low doses of topotecan used. This may be one of the first examples of how a drug may be used as a chemosensitizer for DNA-damaging agents like platinum; the parallel to the successful use of drugs as radiosensitizers is obvious.^11,12 We should therefore put aside any preconceived notions of what is "therapeutic" until a new combination such as this is rigorously tested in a phase II trial with surrogate end points (see below), or until a proper randomized trial is performed. Because of the higher toxicities generally observed with triple-drug combinations, however, the alternating doublet approach has recently been popularized as a way to more safely incorporate new drugs into first-line treatment (option 3). One potential problem here involves an old premise suggested by the Goldie-Coldman hypothesis¹³: Each doublet must have equivalent activity, or you basically end up diluting the dose density of the effective regimen every time you alternate it with a doublet of lesser activity. Potentially "inferior" doublets immediately come to mind, including paclitaxel/topotecan (leading to decreased dose density of platinum, still the most active drug in the treatment of ovarian cancer) or topotecan/cisplatin (leading to decreased dose density of the taxane, the only other class of drugs that has been convincingly demonstrated to make a difference in this tumor). Another potential problem with the alternating doublet approach involves the common suggestion to treat with eight or more cycles of chemotherapy to achieve reasonable cumulative exposure to any one drug in the doublet regimen. Such a prolonged schedule of treatment with myelosuppressive agents may prove to be difficult for patients to tolerate, owing to increased bone marrow toxicity. Although these are theoretical concerns that make me wary of the alternating doublet approach, it is nevertheless an option that needs to be formally tested in ovarian cancer.

The second issue raised by the study of Herben et al is that of surrogate end points of activity. No matter which of the approaches outlined above is adopted, each will be highly active on the basis of clinical response, and we are left with the problem of deciding which combination deserves to be randomized against taxane/platinum chemotherapy. Here, at last, may be an important role for the second-look laparotomy, a procedure that has been forever in search of a widely accepted purpose. In the study by Herben et al, the three patients with suboptimal disease who underwent second-look laparotomy had achieved a pathologic complete response (PCR), an important first step toward long-term survival and an intriguing result given the expected PCR rate of 25% in this population.³ We do not know the rigor with which surgical exploration and biopsy were performed, we do not have long-term follow-up (expected relapse rate is at least 50%), and we do not know whether these results are purely reflective of chance alone. Nevertheless, the assessment of surgical response is still the most sensitive way of quantitating the activity of a novel regimen, and a sufficiently powered phase II study using PCR as the end point may enable us to eliminate regimens that may be no better than standard chemotherapy. An important caveat to the use of PCR as a surrogate end point is the fact that prolonged survival may also be associated with achievement of a microscopic residual disease state. For instance, it has been previously noted that the PCR rate in suboptimally debulked patients randomized to receive either paclitaxel/cisplatin or cyclophosphamide/cisplatin seems to be equivalent, although the fraction of patients achieving microscopic residual disease is higher in the paclitaxel-containing arm.³ Thus, some combination of PCR plus microscopic residual disease is perhaps more appropriate as a surrogate surgical end point for such a phase II study, in order to avoid prematurely discarding a potentially useful regimen.

It is heartening to realize that we now have many promising choices that did not exist even 5 years ago. Regardless of which biases are correct, and which surrogate markers of response are used, it is almost certain that one or more of these new combinations will be brought to randomized clinical trials in the next several years. We can only hope that some of these choices will prove to be better than standard therapy in the treatment of this devastating disease.

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