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Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, and the Dana Farber/Harvard Cancer Center, Boston, Massachusetts, USA
Key Words. Topotecan • Ovarian cancer • Bone marrow toxicity • Second-line therapy
Correspondence: Richard T. Penson, M.R.C.P., M.D., Massachusetts General Hospital, Yawkey-9066, 55 Fruit Street, Boston, Massachusetts 02114, USA. Telephone: 617-726-5867; Fax: 617-724-6898; e-mail: rpenson{at}partners.org
Received September 17, 2005; accepted for publication September 21, 2005.
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The manuscript by Armstrong et al. [1], reviewing the toxicity and efficacy of full-dose topotecan (Hycamtin®; GlaxoSmithKline, Philadelphia, http://www.gsk.com) delivered as second-line therapy in individuals with small cell lung cancer or ovarian cancer, will likely serve as both the most comprehensive and the final review of this active agent delivered at the U.S. Food and Drug Administration–approved dosage and schedule. The strength of the review is that it represents large, relatively homogeneous patient populations with prior platinum exposure and convincingly describes topotecan as an agent with activity that is comparable with those of all other approved drugs in this setting and a well-defined and relatively circumscribed set of toxicities. While the activity of topotecan in small cell carcinoma provides individuals with the hope for further palliation at the time of tumor recurrence, as discussed by Dr. Markman [2], the best use of this agent in the management of recurrent ovarian cancer is less clear because, in part, of a growing list of approved active agents, most notably liposomal doxorubicin (Doxil®; Alza Pharmaceuticals, Mountain View, CA, http://www.alza.com), gemcitabine (Gemzar®; Eli Lilly and Company, Indianapolis, http://www.lilly.com),and weekly paclitaxel (Taxol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com); a return to platinum; or a host of other agents such as vinorelbine (Navelbine®; GlaxoSmithKline), altretamine (Hexalen®; MGI Pharma Inc., Bloomington, MN, http://www.mgipharma.com), irinotecan (Camptosar®; Pfizer Pharmaceuticals, New York, http://www.pfizer.com), docetaxel (Taxotere®; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharmaus.com), etoposide (VePesid®; Bristol-Myers Squibb), and others.
Topotecan benefits from both the completion of randomized trials comparing it with other chemotherapeutic options in ovarian cancer and small cell lung cancer as well as a rich collection of phase II trials, particularly in both platinum-sensitive and platinum-resistant ovarian cancer. The limited spectrum of toxicities and the relative lack of cumulative toxicities are also notable advantages of the drug. Still, the widespread use of the drug is challenged by the risk for severe hematologic toxicity and fatigue. While oncologists may be quick to dismiss the cost of expensive growth factors for "paper" hematologic toxicities, the weakness of topotecan is that fatigue is an increasingly appreciated and clinically meaningful symptom. The toxicity profile has provoked the search for better schedules and the use of reduced doses including 3- and 4-sequential-day schedules as well as weekly schedules [3–5]. The safety of the agent and optimal dose for later lines of therapy is not defined, and there are challenges to extrapolating these data to clinical practice.
In 2005, an estimated 16,000 women will die from ovarian cancer. Advances in surgery along with carboplatin (Paraplatin®; Bristol-Myers Squibb) and paclitaxel therapy now offer excellent tumor cytoreduction, yet a cure remains elusive for the large proportion of ovarian cancer patients who present with advanced disease. Sadly, most patients experience tumor recurrence or progression within a few years of their initial presentation. The prevailing treatment paradigm for recurrent disease, particularly platinum-resistant disease, has been the sequential use of single agents with demonstrated activity in platinum-resistant, recurrent ovarian cancer, such as liposomal doxorubicin, topotecan, weekly paclitaxel, gemcitabine, and etoposide[6,7]. Integrating these agents into upfront chemotherapy was the premise for a recently completed international clinical trial by the Gynecologic Oncology Group (GOG-182), although early indications suggest that this strategy may not improve survival. The GOG 132 trial, which in the end compared the use of combination paclitaxel plus cisplatin with their sequential single-agent use, and the International Collaborative Ovarian Neoplasm (ICON II) trial suggest that as long as the agents are used, the sequence and schedule are less important [6–8]. Given that we may be asymptotically approaching the maximal survival benefit of chemotherapy, sequential treatment has become the focus of investigation. Paclitaxel and topotecan previously vied for use in the second-line setting, and now liposomal encapsulated doxorubicin hydrochloride is most commonly used because of the perception that it is associated with a superior quality of life [9].
Defining the "best" role for topotecan or any other agent in the palliative management of disease, particularly ovarian cancer, is difficult. The initial hope that topotecan may be more effective in platinum-refractory disease and the rhetoric around the concept of using topotecan to increase the platinum-free interval prompted investigation of topotecan as immediate consolidation after first-line therapy. Both studies reported to date have been negative [10, 11]. Answering a sequencing question is far harder than answering a consolidation question. Determining when and how agents are used and the best sequence to optimize quality of life is the challenge. We need new and creative clinical trial designs that will not compare a single drug with another single drug but rather planned sequences of therapies with an alternative sequence of the same therapies and with completely different sequences. For example, a trial that enrolled women at the time of the first recurrence of their ovarian cancer and compared treatment using drug A then drug B then drug C with an alternative sequence, such as drug B then drug A then drug C, or alternatively, different drugs, such as drug D then drug E then drug F, with end points of overall survival and quality of life, would address a real-life issue faced by oncologists but may be impossibly large or complex to accomplish.
What then should we conclude? More research would illuminate the utility of palliative chemotherapy. The GOG is enrolling patients into a randomized phase II study of topotecan, comparing the 5-day with the weekly schedules, and we are starting a study comparing oral with i.v. therapy, examining quality of life and utility. The most pressing need is to accept that palliative therapies are designed to palliate and improve symptoms, and hence, we must move away from end points of radiologic and marker response (computed tomography and cancer antigen-125) to a focus on "clinical benefit" and clinically more meaningful end points. The challenges are many, including designing studies that intelligently measure and monitor benefit over the natural history of the disease rather than a 3- or 4-month period of time. Trials of this design will be complex and will challenge the preexisting biases and dogma of patients, physicians, and clinical trialists and their statistical consultants, yet should be our lofty but ultimate aim.
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