Duration of Therapy for Ovarian Cancer: How Long is Enough?
Presenter: David R. Spriggs, MD
Affiliation: MSKCC New York, NY
There are little scientific data available on the optimal duration of chemotherapy in the first-line treatment of ovarian cancer. As can be expected, there is even less information available on duration of treatment in recurrent disease, either in platinum-sensitive or platinum-refractory patients.
Furthermore, the ideal regimens of newer second line agents such as topotecan and liposomal doxirubicin (Doxil) are not yet established.
An important aspect in the management of relapsed ovarian cancer is the concept of tumor growth models, specifically the Norton-Simon model of Gompertzian growth. A basic principle of this model states that both growth and death rate of tumor cells is a function of tumor size. Specifically, the same dose of cytotoxic agent has less of an effect at higher tumor volumes. Furthermore, the size of tumor burden correlates directly with extent and timing of response; a "small tumor", (ie: 2 cm) treated with 6 cycles of chemotherapy will likely show an early and complete response(CR), in contrast to a "large tumor" (ie: 7 cm) which, even after 12 cycles of drug, might only show a late and partial response (PR). The consequences of this growth model are that recurrent ovarian cancer, which is usually associated with a greater tumor burden, likely requires extended treatment with longer follow-up in order to achieve maximal efficacy.
Issues of treatment duration require consideration not only of efficacy but long-term toxicity and patient tolerance as well. The cumulative neuro-, oto- and nephrotoxicities of cisplatin are well-known and leading to the gradual decrease in use of this agent. Carboplatin has associated myelosuppression and allergic complications with long-term use, whereas the use of taxanes can result in significant neurotoxicity. While the ICON 4 data, as presented earlier in this CME section, shows promising results with a taxane and platinum combination in relapsed disease, the tolerability of patients for platinum is certainly a limiting issue.
More recently, different second-line agents are emerging as potential treatment. A phase III international collaborative trial randomized relapsed patients previously treated with first-line platinum-based chemotherapy to receive either doxil (50 mg/m2 q 4wks) or topotecan (1.5 mg/m2 x 5d q 3wks). Primary endpoint was time to progression (TTP) while secondary endpoints included response rate (RR), duration of remission, survival and safety. In the absence of progressive disease, treatment was permitted to continue for up to one year, and even longer if the agents showed sustained clinical benefit. Overall survival thus far shows no statistically significant difference between the two arms, although toxicities did differ as expected. Myelotoxicity was 81% in the topotecan arm compared to 35% in the liposomal doxorubicin (Doxil) arm, whereas palmar-plantar-erythrodysesthesia (PPE) was 49% in the liposomal doxorubicin arm compared to only 1% with topotecan.
The real issue, however, is the feasibility of long-term use of these agents based on acceptable chronic toxicity. Topotecan has historical data showing acceptable patient tolerance with > 20-25 cycles. Liposomal doxorubicin-related PPE is generally well-managed with dose adjustments, and the cardiac toxicity is less than conventional doxorubicin. Evidence from several studies shows that liposomal doxorubicin is a feasible agent for long-term use, with the caveat that careful cardiac monitoring be performed during treatment.
In conclusion, extended treatment for relapsed patients offers theoretical advantages, and the use of taxane consolidation increases disease-free survival. Further study with the more novel chemotherapy agents mentioned here is also promising and warrants serious consideration.