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ADJUVANT CHEMOTHERAPY IN EARLY OVARIAN CANCER

The Adjuvant ChemoTherapy in Ovarian Neoplasm (ACTION) trial is one of the largest randomized trials in early ovarian cancer patients together with the ICON 1 trial [1,2]. The results of the ACTION trial show that adjuvant platin-based chemotherapy delays disease recurrence in patients with early-stage ovarian cancer, of whom 297 of the 448 patients (66%) had undergone non-optimal surgical staging. No statistically difference was found for overall survival in the entire group of patients randomized in the ACTION trial, but was found when combining the results of the ACTION and ICON 1 trials. If we look at the patients in the observation arm who were optimally staged, both disease-free survival and overall survival were statistically better compared to the non- optimally staged patients in the same arm. The relatively poor prognosis of the non- optimally staged patients could be corrected by administrating adjuvant platinum- based chemotherapy. These results suggest that adjuvant chemotherapy in early-stage ovarian carcinoma may work predominantly by affecting microscopic metastases that remain unnoticed during the staging laparotomy. This hypothesis is supported by the finding that chemotherapy improved both overall and recurrence-free survival in the non-optimally staged patients and not in the optimally staged patients. The finding that adjuvant chemotherapy is effective in non-optimally staged patients might also explain the results of the ICON1 trial [2] and the combined ICON1/ACTION analysis [3], in which the majority of patients were most probably not optimally staged. Another finding in this study was the difference in the percentage of patients successfully treated for tumor recurrence between the optimally and non-optimally staged group. The optimally staged patients showed a higher salvage rate in the observation arm than in the chemotherapy arm, 75% versus 46%, respectively. In the non-optimally staged patients however the salvage rate was similar in both arms, 70% and 64%. In a study of the Italian Gruppo Interregionale Collaborative Oncology Group GICOG the same difference of effectiveness of chemotherapy was found in patients were a complete surgical staging was performed [4].

A second long-term follow-up analysis of the ACTION trial was performed after a median follow-up of 10.1 years, which substantiated the main conclusions that the benefit of adjuvant chemotherapy is most clear in the non-optimally staged patients and that the completeness of surgical staging is an independent prognosticator for both disease-free and overall survival [5].

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SURGICAL S TAGING

In the present study the completeness of surgical staging was found to be an independent prognostic factor by multivariate analysis. This is not a surprising finding because the completeness of surgical staging influences the likelihood of remaining residual disease. Optimal staging reduces the chances of metastases in the lymph nodes, omentum and peritoneum and incomplete surgical staging increases the possibility of hidden occult cancer in the peritoneal cavity. The prognostic value of the extent of surgical staging in early ovarian cancer has been found by others as well [6,7].

Although the particular staging steps were precisely mentioned in the protocol of the ACTION trial and strongly advised to carry out, only one-third of the patients entered in the study were optimally staged. In order to reduce this very low number we have tried to figure out what the reasons are why so many patients are not completely staged. One of the reasons may be that a substantial part of the patients with early ovarian cancer are diagnosed during a surgical procedure for acute abdominal pain or an ovarian mass and operated by a general gynecologist who does not have the surgical skills to perform an optimal surgical staging and has a lack of knowledge about the mechanisms of tumor spread in the abdominal cavity.

To perform a complete surgical staging surgical skills are needed and sufficient knowledge of the routes of metastases of ovarian cancer. In our study we have tried to differentiate between a lack of surgical skills for procedures involving morbidity on one hand or lack of sufficient knowledge of risk sites for ovarian cancer spread to carry out easy procedures without appreciable morbidity risk on the other. Pelvic and para-aortic lymph node sampling, procedures which carry a potential morbidity, were omitted in 78% and 52% respectively in the non-optimally staged group. In a previous Dutch study similar results were found [8], in 70% of the study population no lymph node sampling was done and also another study showed the same figure [9]. As we examine in the present study the easy procedures like taking blind biopsies of the paracolic gutters and from the pelvic side wall we found that it was omitted in 39% of the patients. Peritoneal washings were not done in 11% of the cases.

The role of lymph node sampling or lymphadenectomy on the prognosis in early ovarian cancer remains controversial. In a study of Baiocchi et al. [10] lymph node status was the most valuable prognostic factor in patients with disease limited to the ovary. A randomized study by Maggioni et al. [11] compared systemic pelvic and para-aortic lymphadenectomy to random sampling of lymph nodes in macroscopic early ovarian

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