Commentary (Mannel): Modern Management of Recurrent Ovarian Carcinoma

In their article, Drs. Michener and Belinson make the case for treating recurrent ovarian cancer as a chronic disease, with limiting morbidity and providing palliation of symptoms their major goals. A review of recent literature would support their contention and management strategy. The cure rate for patients with recurrent ovarian cancer is < 5%, and the average patient in the United States receives more than five separate regimens of chemotherapy for recurrent disease. Previous attempts at aggressive treatment for recurrent disease have shown, at best, very modest benefit with significant expense and morbidity. What we are left with is a strategy of trying to determine which patients may benefit from aggressive salvage therapy and which are better managed with a chronic palliative attempt.

Serum Markers
One of the most frequently employed methods for detecting early recurrence is the use of serum markers. Asymptomatic elevations in CA-125 precede symptomatic or measurable disease by a median of 2 to 3 months. To date, it is not clear that having information that the tumor is recurrent by CA-125 results in any improvement in survival or quality of life. This question is being addressed by a European Organization for Research and Treatment of Cancer (EORTC) study randomizing patients to having CA-125 results made available (or not) for the management of ovarian cancer after front-line therapy. If there is any curative potential to salvage therapy, the early-intervention group should benefit from this information

Targeted Surgery
The other area the authors address, as a possible attempt at long-term control with an increase in progressionfree survival and overall survival, is targeted surgical intervention. Singleinstitution series have looked at variables such as initial stage of tumor, platinum-free interval, initial surgery, and location of recurrence. Some authors have reported being able to select patients who may benefit from surgery, but this strategy has never been addressed in a prospective randomized fashion, and the role of secondary cytoreductive surgery falls prey to the same criticisms that primary cytoreductive surgery does-selection bias, tumor biology, and chemosensitivity.

In an attempt to clarify this issue, the Gynecologic Oncology Group (GOG) will activate a trial in the near future, prospectively randomizing patients with recurrent platinumsensitive disease to secondary cytoreductive surgery vs no surgery. An important part of this protocol will be a quality-of-life survey to determine the functional morbidity associated with repeat surgery. Of note, case series have reported impressive results from surgical intervention for the rare patient with isolated liver, lung, or central nervous system metastasis as a site of recurrence.

Changing End Points
The authors express the concern that recurrent disease in general is not amenable to curative intent. Aggressive strategies such as secondary cytoreductive surgery, dose-intense chemotherapy, or biologic response modifiers need to be evaluated in a research setting. Outside such venues, it seems appropriate to follow the more conservative approach outlined.

More research needs to look at the role of reduced-dose, chronic chemotherapy as opposed to the strategy of high-dose multiagent therapy. Most research in recurrent disease is focused on identifying new agents or strategies that may have an impact on front-line therapy and, as such, are often highly toxic. End points such as response rate, progression-free survival, and overall survival are considered most important. If we are truly interested in treating recurrent ovarian cancer as a chronic disease, our end points may need to change. Tools measuring quality-of-life components, functional status, time spent in hospital, and toxicity such as neurotoxicity, fatigue, and other measures of daily living would need to be employed.

Time to progression or symptomatic recurrence may be a more valid end point than traditional response evaluation criteria in solid tumors. Such a strategy would require a reassignment of resources by the cooperative groups and the National Institutes of Health to focus on the long-term management of recurrent ovarian cancer. As mentioned above, this would include different study designs than the traditional phase II or III trials. Large cooperative groups have resisted putting resources into such a strategy, especially when the cure rate is so low and the demand for improved survival is so high. But we must remember that survivorship issues are relevant not only for those who are without evidence of recurrent disease. More energy should be applied toward developing meaningful research strategies that could help develop an outcomes-based approach to this chronic disease.