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

Ovarian cancer is the deadliest of the gynecologic malignancies. Approximately threequarters of patients present with advanced- stage disease. With aggressive cytoreductive surgery followed by platinum-based chemotherapy, most patients will achieve remission. Despite this initially good response to treatment, most patients experience recurrence and ultimately die of their disease. Novel treatment strategies are needed. Molecularly targeted therapies offer the promise of improved efficacy with decreased toxicity. In this article, Drs. Stephanie Blank, Richard Chang, and Franco Muggia present an excellent summary of the current status of epidermal growth factor receptor (EGFR) inhibitors in the treatment of ovarian cancer. They describe the promise of these drugs as well as some of the questions regarding the best way to integrate them into therapy for ovarian cancer. Standards of Care
The treatment of ovarian cancer is multimodal. Surgery remains the foundation of treatment. The importance of comprehensive surgical staging for patients with apparent stage I disease and of optimal cytoreduction in patients with advanced-stage disease is well established. Selected patients with recurrent disease may benefit from secondary cytoreductive surgery. As the authors of this review suggest, there are several roles for chemotherapy in the treatment of ovarian cancer, including adjuvant therapy following primary surgery, consolidation therapy, and treatment of recurrent disease. The current standard of care for adjuvant chemotherapy is six to eight cycles of carboplatin and paclitaxel. Investigators have made many attempts to develop consolidation chemotherapy to decrease the rate of recurrence after initial therapy for ovarian cancer. Although one phase III study of consolidation paclitaxel demonstrated significant improvement in progression-free survival in the cohort of patients treated ed with 12 months of paclitaxel following completion of front-line chemotherapy, cumulative toxicity occurred and no overall survival advantage was observed, possibly due to relatively short posttreatment follow- up at the time this study was published.[ 1] As a result, the concept of consolidation therapy with paclitaxel has not been universally accepted. Once a patient experiences a recurrence, she will usually receive additional salvage chemotherapy. Selection of the specific agent(s) to be used as salvage therapy is driven by a number of factors including response to initial treatment, duration of the treatment-free interval, and clinical status of the patient. With a median survival of 2 to 3 years following recurrence, patients with advanced-stage ovarian cancer will spend much of this time in active therapy. The importance of developing treatments that minimize side effects and maximize quality of life is apparent but has only recently begun to be addressed in clinical trials.[2,3] EGFR Inhibitor Experience
EGFR inhibitors appear to be well tolerated. The most common side effects are dermatologic, primarily acneform rash. Tyrosine kinase inhibitors are also associated with diarrhea. Monoclonal antibodies also carry the risk of allergic reactions, anaphylaxis, and the development of human antimouse or other antibodies in a small number of patients (< 5%). Although preclinical data suggest that EGFR inhibitors are active against ovarian cancer cell lines in vitro, the results of phase I and II clinical trials have been disappointing, with few responses reported for single-agent therapy. When EGFR-directed agents have been combined with cytotoxic chemotherapy for patients with recurrent ovarian cancer, more encouraging activity has been observed, but it is unclear whether this response was significantly improved over what would have been achieved with chemotherapy alone. Therapeutic Challenges
The clinical development and evaluation of growth-factor-directed therapies represent a considerable challenge. First, these drugs may be cytostatic rather than cytotoxic. As established by the Gynecologic Oncology Group, end points emphasizing stable disease rather than clinical response may be more appropriate for agents such as these. If progressionfree survival is to be used as an end point, then the clinical, serologic, and radiographic parameters used to determine progression-free survival must be clearly defined at the beginning of the clinical trial. A randomized discontinuation design, in which patients with stable disease at 8 or 12 weeks of therapy are randomized to continue on active drug or placebo, is another way to capture the cytostatic effect of a new therapy. Secondly, receptor expression may be a useful predictor of response to therapy in some situations (eg, HER2/ neu and breast cancer) but not others (eg, HER2/neu and ovarian cancer[4] or EGFR and colorectal cancer).[5] Third, the interaction of targeted therapies and classical chemotherapy may be quite variable and depend upon the particular agent, target, disease, and setting. For example, in colorectal cancer, cetuximab (Erbitux) appears to modulate sensitivity to irinotecan (Camptosar) in patients whose tumors have progressed on this drug.[6] On the other hand, when used in patients with non-small-cell lung cancer, the addition of gefitinib (Iressa) to carboplatin/paclitaxel or cisplatin/ gemcitabine (Gemzar) provided no clinical advantage over chemotherapy alone.[7,8] And finally, clinical activity may result from a process that is entirely independent of the target or pathway against which the drug was designed. This makes patient selection and molecular monitoring even more of a daunting challenge. Mucinous Tumors
The authors discuss the "distinct biology" of mucinous ovarian cancers. Skirnisdottir and colleagues have shown that growth factor receptor expression patterns vary significantly among the histologic subtypes of ovarian cancer. In their study, HER2/neu receptors were associated with mucinous tumors, whereas serous tumors were associated with expression of both HER2/neu and EGFR. Clear cell and endometrioid tumors were unlikely to express either growth factor receptor.[ 9] Even within histologic subtypes, there is likely to be variation in the expression of these proteins. As noted above, expression or overexpression of a growth factor receptor may not be sufficient. It has recently been shown that gefitinib is most active in patients with specific gain-of-function mutations of the EGFR.[10] The importance of identifying the appropriate targets and including molecular correlates in studies of these agents cannot be overstated. Other Growth Factor Receptors
One must also consider that EGFR is not the only growth factor receptor pathway that is activated in ovarian cancer. Further, there is crosstalk between EGFR and other pathways and molecules including cyclooxygenase (COX)-2, vascular endothelial growth factor (VEGF) and its signaling pathway, and the PI3 kinase/mTOR pathway, to name a few. Inhibition of EGFR, by itself, may not be sufficient to inhibit the growth of some tumors because of compensatory upregulation of other growth factor receptors or increased activity of other molecules downstream of the target. The use of pan-tyrosine kinase inhibitors or multiple growth factor receptor inhibitors that target complementary pathways is currently being explored. This approach may result in increased toxicity, and quality-of-life issues will need to be addressed. Conclusions
The review of the status of EGFR inhibitors in the treatment of ovarian cancer by Blank, Chang, and Muggia introduces the reader to this very timely, important, and complex topic. There are many potential roles for these drugs in the treatment of ovarian cancer. Response rates and effect on quality of life will both be important factors in determining how best to integrate these agents into the treatment of ovarian cancer. Although several of these agents have been approved for use in other tumor types, the role of these drugs in the treatment of ovarian cancer remains unclear. In order to gain the greatest insight into the utility of EGFR inhibitors and other molecularly targeted agents, clinical trials will need to be designed not only to provide information on clinical response and tolerability, but also to incorporate correlative studies to help identify the mechanisms of sensitivity or resistance, as well as to identify subgroups of patients who are most likely to benefit from their use.

Disclosures:

Dr. Crispens has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. Dr. Rothenberg is a consultant for ImClone, OSI, and Eli Lilly; an advisory board member for ImClone and OSI; and receives research support from OSI and Eli Lilly.

References:

1. Markman M, Liu PY, Wilczynski S, et al: Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 21:2460- 2465, 2003.
2. Rothenberg ML, Liu PY, Wilczynski S, et al: Phase II trial of vinorelbine for relapsed ovarian cancer: A Southwest Oncology Group study. Gynecol Oncol 95:506-512, 2004.
3. Butler L, Bacon M, Carey M, et al: Determining the relationship between toxicity and quality of life in an ovarian cancer chemotherapy clinical trial. J Clin Oncol 22:2461- 2468, 2004
4. Bookman MA, Darcy KM, Clarke- Pearson D, et al: Evaluation of monoclonal humanized antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: A phase II trial of the Gynecologic Oncology Group. J Clin Oncol 21:283-290, 2003.
5. Saltz LB, Meropol NJ, Loehrer PJ Sr, et al: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201-1208, 2004.
6. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004.
7. Herbst RS, Giaccone G, Schiller J, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A Phase III trial: INTACT-2. J Clin Oncol 22:785-794, 2004.
8. Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A Phase III trial: INTACT-1. J Clin Oncol 22:777-784, 2004.
9. Skirnisdottir I, Sorbe B, Seidal T: The growth factor receptors HER-2/neu and EGFR, their relationship, and their effects on the prognosis in early stage (FIGO I-II) epithelial ovarian cancer. Int J Gynecol Cancer 11:119-129, 2001.
10. Lynch TJ, Bell DW, Sorella R, et al: Activating mutations in the epidermal growth factor receptor underlying the responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004.