Commentary (Markman): The Management of Early Ovarian Cancer

The paper by Schilder et al is an outstanding review of the current status of the management of women with early-stage ovarian cancer. As the paper makes clear, despite the efforts of numerous cancer research groups around the world, an optimal treatment strategy for early-stage ovarian cancer has yet to be defined.

Several reasons can be advanced to explain our inability to make definitive statements regarding how women with early-stage ovarian cancer should be managed. First, a diagnosis of early-stage ovarian cancer is not common, accounting for no more than 25% to 35% of women with this malignancy. Second, the natural history of early-stage ovarian cancer is "relatively favorable," making it difficult to document that any therapeutic intervention is superior to surgery alone.

Third, as discussed by Schilder and his colleagues, optimal staging has not always been employed in reported treatment trials, making interpretation of the results of many studies problematic. Finally, treatment strategies for advanced ovarian cancer have evolved rapidly over the past 5 to 10 years, raising serious questions about the clinical relevance of any study of early-stage disease that does not include as part of its strategy a drug (or drugs) that have become "standard treatment" for more advanced ovarian cancer (eg, cisplatin [Platinol] plus paclitaxel [Taxol] combination chemotherapy) [1].

As noted by Schilder et al, the use of radiation (including both intraperitoneal radioactive phosphorus and whole abdominal radiotherapy) has fallen into disfavor in the United States as a method of treating early-stage ovarian cancer, despite the lack of definitive proof that chemotherapy is superior to radiation in this clinical setting. Again, several explanations can be proposed for this situation, including the potential toxicity of radiation to the bowel, the technical requirements for treating patients with radiation (compared with the intravenous administration of chemotherapy), potential bias among medical oncologists against radiation, and the lack of convincing data that even suggest the superiority of radiation over combination platinum-based chemotherapy.

With the availability of effective antiemetic agents, the demonstrated improvement in survival of ovarian cancer patients with advanced disease treated with a platinum-paclitaxel combination regimen (compared with cisplatin plus cyclophosphamide [Cytoxan, Neosar]) [1], and the clear ability to administer this treatment in the outpatient setting, it is difficult to argue that three (or even six) courses of such therapy will be associated with excessive toxicity. Thus, in the absence of a reason to consider intraperitoneal phosphorus or whole abdominal irradiation to be superior to combi- nation chemotherapy, there is little enthusiasm to further examine a role for radiation in early-stage ovarian cancer.

An important question, yet to be clearly answered, concerns whether early-stage ovarian cancer is simply disease that has been discovered earlier in its natural history (as opposed to the 70% of cases in which women present with advanced disease), or whether there are clinically relevant biological differences between "early-stage" and "late-stage" malignancy that have a great impact on defining the extent of disease at initial diagnosis. If early-stage ovarian cancers inherently are biologically less aggressive malignancies (thus contributing significantly to the superior survival rate), this will have important implications for the hypothesis that screening for ovarian cancer, to find "early-stage disease" among cancers destined to exhibit an aggressive course, will exert any meaningful impact on the natural history of these malignancies.

A retrospective analysis of the influence of age on survival of patients with early-stage ovarian cancer who underwent their initial staging laparotomy at the Memorial Sloan-Kettering Cancer Center provides provocative support for the idea that "early-stage ovarian cancer" is not simply disease that has been detected earlier [2]. All patients, regardless of age, underwent an extensive staging procedure performed by the same group of surgeons. Patients with tumors of low malignant potential were excluded from the analysis. Despite a small sample size (18 patients < 65 years old and 5 patients 65 and older), there was a striking difference in survival
(P = .016) in favor of the younger population with early (stage 1 or 2) disease. Whereas none of the 18 younger individuals had died of progressive cancer, two of five elderly patients with the same extent of disease at initial staging had expired due to recurrent or progressive cancer. Were there important biological differences between the elderly and younger women that accounted for these significant differences in survival?

Examination of other institutional and group experiences with ovarian cancer will be required to determine if these findings are reproducible. However, if confirmed, they do suggest that the biology of the tumor may play as important a role in the ultimate outcome of early-stage ovarian cancer as the specific therapeutic strategy employed in the management of this malignancy.

References:

1. McGuire WP, Hoskins WJ, Brady MF, et al: A phase III trial comparing cisplatin/Cytoxan and cisplatin/Taxol in advanced ovarian cancer (abstract). Proc Am Soc Clin Oncol 12:255, 1993.

2. Markman M, Lewis JL Jr, Saigo P, et al: Impact of age on survival of patients with ovarian cancer. Gynecol Oncol 49:236-239, 1993.