Commentary (Markman): Epidermal Growth Factor Receptor Inhibitors for the Treatment of Epithelial Ovarian Cancer

In this well-balanced overview, Dr. Blank and colleagues explore the current status of clinical investigation into a possible role for inhibiting the activity of epidermal growth factors as a management approach in patients with ovarian cancer. Knowledge of the natural history of this malignancy leads to consideration of several different drug development strategies, including (1) use of these drugs as single agents in the treatment of recurrent, persistent, or refractory disease; (2) exploration of combination therapy, added to a platinum- based cytotoxic regimen, as primary treatment or in patients with potentially platinum-sensitive recurrent disease (treatment-free interval > 6 months); or (c) use as a "maintenance" approach, following the attainment of a clinical (or surgical) complete response or an excellent partial remission. Evidence of 'Benefit'
While the simplest method with which to establish the clinical utility of one of these drugs-and to receive US Food and Drug Administration approval for a "defined indication"- would be to examine the agent administered alone in women with clearly defined "platinum-resistant" ovarian cancer, it must be remembered that failure of the drug to demonstrate convincing evidence of benefit in this specific setting should not be interpreted as showing that a particular drug is of no use in this malignancy. At least in theory, these agents may exert a critically important influence on the biology of the cancer through inhibition of tumor growth, rather than producing a direct cytotoxic effect on existing cancerous masses. As a result, although it may be observed, "shrinkage of measurable disease" may not be the optimal measure of what drugs can achieve in this clinical setting. Simply stated, if the objective response rate noted with such an agent in a phase II trial in platinum-refractory ovarian cancer is very low (eg, < 10%), this information (by itself) should not result in abandonment of alternative trial designs in this tumor type. Conversely, a "high objective response rate" seen in phase II studies when combining one of these growth factors with a platinum agent (generally carboplatin), either as primary chemotherapy (generally also with a taxane) or in platinum-sensitive recurrent disease (alone or with other cytotoxic agents), cannot be taken as evidence of any benefit from the added "biologic agent." This is due to the well-established fact that such chemotherapy, employed alone, may produce objective responses in 50% to 90% of patients (depending on specific characteristics of the treated population).[1,2] As a result, nonrandomized studies combining these (and other) biologic drugs with platinum-based chemotherapy in ovarian cancer must principally be viewed as toxicity trials, with a particular focus on the potential side effects associated with treating individuals for a longer duration (eg, four-plus cycles) than commonly achieved during phase I (or even phase II) studies in other common tumor types (such as non-smallcell lung cancer). Finally, while a "maintenance strategy" has great theoretical appeal with biologic agents that appear to retard tumor growth, it must be remembered that defining the benefits of such an approach require the conduct of a well-designed randomized phase III trial. Further, in the absence of specific data addressing the issue, the side-effect profile associated with very long-term use of these drugs (for example, when employed in "maintenance therapy") is unknown. Simply assuming this class of agents is nontoxic, with either short-term or longer-term use, is inappropriate, as recently documented with bevacizumab (Avastin), which has been associated with severe hypertension and arterial thrombotic events. Individual Patient Data
One possible approach to gaining preliminary data on the potential therapeutic benefits associated with inhibition of epidermal growth factors in ovarian cancer would be to explore the impact of such treatment on the natural history of an individual patient's disease. In a recent single-institution report, investigators suggested that a patient with ovarian cancer who attains a second remission following platinumbased chemotherapy almost always experiences a shorter second response, compared to the duration of the initial remission.[3] Thus, if a particular patient with recurrent ovarian cancer is treated with the same platinum-based program as employed for primary chemotherapy, then receives the epidermal growth factor inhibitor as a maintenance strategy, and the duration of the second remission is longer then the initial remission, this would be highly provocative evidence supporting the unique effect of the new agent in interfering with subsequent tumor growth. Ultimately, randomized phase III trials will be required to confirm or refute the benefits of the drug in this setting, but individual patient data may be interpreted appropriately as supportive of initiating such an investigation. Conclusions
As noted by Dr. Blank and her colleagues, there is increasing evidence that simply demonstrating a particular patient's cancer "overexpresses EGFR" on its cell surface may be insufficient data to predict a favorable clinical effect of that inhibitor of epidermal growth factor against the patient's disease. Therefore, it is clear that in the future it will be critically important for investigators to focus considerable effort on identifying the biologic or molecular features of a tumor that determine whether or not a cancer cell will be influenced by treatment with one of this class of novel antineoplastic agents.

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Markman M: Optimizing primary chemotherapy in ovarian cancer. Hematol Oncol Clin North Am 17:957-968, 2003.
2. Markman M, Bookman M: Second-line treatment of ovarian cancer. Oncologist 5:26- 35, 2000.
3. Markman M, Markman J, Webster K, et al: Duration of response to second-line platinum- based chemotherapy for ovarian cancer: Implications for patient management and clinical trial design. J Clin Oncol 22:3120-3125, 2004.