Despite the activity of initial chemotherapy in ovarian cancer, the majority of women presenting with advanced disease will ultimately experience disease recurrence and be required to consider second-line, or salvage, chemotherapy options. The well-written, informative article by Sabbatini and Spriggs provides a fairly comprehensive overview of important factors to consider when determining the most appropriate treatment options in this clinical setting.
Palliative Nature of Second-Line Therapy
Several points made by the authors should be emphasized. First, in general, second-line treatment of ovarian cancer must be considered palliative in intent. There is currently no reliable evidence that any therapeutic strategy has true curative potential in this clinical setting.
It is well recognized that patients may live for many years without evidence of clinical disease, only to have the malignancy become active and lead to their ultimate death. Thus, studies of second-line treatment options that report 3- or even 5-year follow-up cannot be taken as evidence of the curative potential of those regimens.
As a result, outside of the study setting, the toxicity of any potential salvage treatment program in ovarian cancer must be seriously considered. This is particularly relevant in patients with platinum- and paclitaxel(Drug information on paclitaxel) (Taxol)-resistant disease.
For the individual patient in this clinical setting, the treating physician should ask: Can I justify the use of drug "X," which results in a 10%, 20%, or 30% incidence of nadir fever, grade 3 thrombocytopenia (requiring platelet transfusions), anemia, neurotoxicity, and other toxic effects, in exchange for a reported objective response rate of 10% to 20% and a median response duration of only 4 to 6 months?
Rethinking the Definition of Platinum Resistance
Second, a comment should be made about the definition of "platinum-resistant disease" employed. The Gynecologic Oncology Group (GOG) and others have used a "6-month cut-off" to assign patients to a "resistant" or "sensitive" status. Thus, patients who have demonstrated a major response to platinum-based chemotherapy (eg, symptomatic shrinkage of tumor masses, decline in CA-125) but whose disease has recurred within 6 months following the completion of therapy are said to be "resistant" to further platinum treatment. What data exist to demonstrate that a patient who has shown significant evidence of an antineoplastic effect but who has not received a platinum agent for 5½, or even 4, months, cannot respond a second time to treatment with a platinum agent?
It is important to reemphasize that therapy in this specific clinical setting is entirely palliative in intent and that "maximizing quality of remaining life" must be considered the major legitimate goal of further antineoplastic therapy. With this objective in mind, what treatment would be more easily tolerated by the majority of patients than single-agent carboplatin(Drug information on carboplatin) (Paraplatin)? What evidence is there that patients who have experienced a symptomatic response to platinum therapy and who suffer a recurrence 4 or 5 months following the completion of therapy achieve a superior objective and subjective response to drug "X", as compared with a platinum agent or even single-agent paclitaxel?
Thus, it is reasonable to question the relevance of using the "standard criteria" for assessing platinum resistance--as utilized by the GOG and other groups for the expressed purpose of "determining eligibility for clinical trials"--for deciding how to treat individual patients in the nontrial setting.
Single-Agent vs Combination Therapy
Third, in view of the overall goals of salvage therapy, one must question the use of combination regimens, as opposed to single-agent therapy, outside of the study setting. Two (or more) drugs will be more toxic than one, and to date no data from controlled trials have demonstrated that a more "intensive" program, or the administration of a combination regimen in this setting, will result in an outcome superior to that achieved with single agents delivered at standard-dose levels.
Role of High-Dose Therapy in Platinum-Refractory Disease
Finally, while Drs. Sabbatini and Spriggs have appropriately concluded that "there is currently no place for dose-intensive therapy in ovarian cancer outside of the setting of a clinical trial," their statement regarding the use of high-dose therapy in platinum-refractory disease should be challenged. Here, they conclude that the result "has been disappointing, and only carefully selected patients entering high-priority clinical trials should receive high-dose treatment."
Considering the extensive body of data indicating the clinical futility of high-dose chemotherapy in refractory ovarian cancer, as well as the potential for severe toxicity, negative impact on quality of life, risk of death, and substantial costs associated with such an approach in this clinical setting, one wonders whether it is ever appropriate to consider this patient population for trials of high-dose chemotherapy.