“Recurrence within 6 Months of Platinum Therapy”: An Adequate Definition of “Platinum-Refractory” Ovarian Cancer?

Abstract

Listen

Translate article

Despite the activity of initial chemotherapy in advanced ovarian cancer, the majority of women with this malignancy will ultimately be candidates for a second-line chemotherapy strategy, due to either the presence of persistent or development of recurrent disease. Previously reported data have firmly established that individuals who have responded to a platinum-based chemotherapy regimen, and who experience a ‘‘treatment-free interval’’ following initial therapy, may respond again to treatment either with single-agent cisplatin or carboplatin or with a combination platinum-based regimen [1–5]. Unfortunately, a precise definition of the minimum required duration of the ‘‘treatment-free interval’’ to determine resistance, versus potential residual chemosensitivity to a platinum agent, has never been provided based on the results of well-designed controlled clinical trials. Therefore, it becomes quite relevant to ask which ovarian cancer patients should be considered platinum-resistant or potentially platinum-sensitive, either for entry into trials examining the activity of new chemotherapeutic agents in this malignancy or for selection of an appropriate secondline therapeutic strategy in standard oncologic practice. In the clinical trial setting, ovarian cancer researchers have recognized that objective responses observed to ‘‘new agents’’ in individuals with carefully defined platinum-resistant ovarian cancer suggest the opportunity for the drug to produce a clinically relevant cytotoxic effect against cancer cells which are either inherently resistant or develop resistance to cisplatin or carboplatin [6]. Further, such data would provide a strong rationale to explore the clinical utility of the ‘‘new agent’’ in combination with a platinum drug as initial chemotherapy of ovarian cancer. The history of the clinical development of paclitaxel provides support for this drug development strategy [7]. In clinical practice, physicians want to know if the cancer is unequivocally platinum-resistant when they seek to devise the optimal palliative second-line treatment strategy for an individual patient with ovarian cancer. How well does the current definition of ‘‘platinum-resistant ovarian cancer’’ satisfy the criteria for carefully documenting the absence of a clinically meaningful potential for a patient to respond to a platinum-agent in the second-line setting? In the opinion of this author, not well. Individuals who have actually progressed on an initial cisplatin or carboplatin-based chemotherapy regimen, or, in the absence of frank progression, have failed to achieve at least objective evidence of a response, reasonably can be considered to be resistant to platinum. However, the criteria employed by many investigators for ‘‘platinum-resistant disease’’ also includes ‘‘individuals who have recurred within 6 months of completion of platinum-based treatment’’ [8]. Thus, in many studies, patients who have experienced excellent responses (clinically or surgically defined) to platinum, but who demonstrate evidence of recurrent disease within 6 months following the end of chemotherapy are considered in the same category of ‘‘platinum-resistant ovarian cancer’’ as women actually progressing on initial chemotherapy. While it is certain that patients with documented disease progression following a relatively short treatment-free interval have a poor ultimate prognosis, what evidence exists to unequivocally state that individuals with previously highly sensitive cancer might not respond again in this setting if the same or a similar treatment program were employed? The realistic goal of standard (noninvestigational) therapy in this clinical setting is control and prevention of symptoms and maximization of quality of life. While a number of therapeutic alternatives might reasonably be employed in this difficult situation, the absolute exclusion of a platinum agent from consideration as a palliative option would appear to be inappropriate. The administration of even a single course of carboplatin or cisplatin in such patients would likely demonstrate if the individual is clinically ‘‘resistant’’ or ‘‘sensitive,’’ based on evidence of symptomatic benefit (e.g., decrease in pain, ascites), or the documentation of an objective anticancer effect (e.g., tumor shrinkage, decrease in CA-125). If a patient does not respond, then alternative regimens can be considered. As previously noted, the observation of objective responses in patients who progress or have failed to respond to platinumbased chemotherapy for ovarian cancer will be of considerable GYNECOLOGIC ONCOLOGY 69, 91–92 (1998) ARTICLE NO. GO984997