Fertility-sparing surgery in high-risk epithelial ovarian cancer: from the patients wishes to the precautionary principle
Fertility preservation is an important consideration for women with gynecologic malignancies, given the potentially severe psychological impact of infertility. Fertility-sparing surgery (FSS) of epithelial ovarian cancer (EOC) is an empirical treatment option initially proposed to young women presenting with an early-stage invasive tumor and a low risk of recurrence [1,2]. It is based on unilateral (salpingo-)oophorectomy and complete surgical staging and seems to be oncologically safe in patients with conventional histologic subtype and stage IA grade 1 or 2 disease . The recurrence rates reported in these subgroups were 7% in stage IA grade 1 and 11% in stages IA grade 2, so very close, or similar, to the rates observed after radical surgery [2-6]. Despite the importance of considering FSS for patients, however, many questions remain concerning its safety in stage I “high risk” patients (grade 3 and/or stage IC and/or clear cell tumor).
Risk of recurrence
Many studies have demonstrated that the risk of recurrence is increased in such cases compared to patients with grade 1 or 2 disease [2,7-9]. A very recent Chinese series demonstrated, in a cohort of 108 patients with stage I disease (52 treated conservatively), an increased risk in grade 3 or clear cell carcinoma (7). Moreover, in these patients, the risk of an ovarian recurrence in currently “debatable” indications for FSS is lower compared to extra-ovarian recurrences that occur more frequently and are less amenable to surgical cure when they arise in stage IA disease (a good indication for FSS), whereas isolated ovarian recurrences are more common and are also more curable [2,4]. As for grade 3 tumors, in an international multicenter study 95% of the recurrences were extra-ovarian (and only 22% of them were rendered disease free) . If the potential recurrences are less curable this could basically challenge the validity of these “debatable” indications. By running the risk of a potential recurrence (because the status of the patient is a borderline indication), we increase the risk of the patient developing an incurable lesion . One the other hand, we could also hypothesize that such extra-ovarian recurrences could be related to the natural history of disease, and the presence of “intermediate” or the “poorest” prognostic factors, and not to the preservation of the ovary itself.
The use of FSS in patients with stage IC disease should be analysed in light of the new FIGO staging system [4,10]. In fact, different clinical situations were previously mixed in this subgroup, which explains why the series reported in this context had different outcomes for patients treated conservatively for stage IC disease. The new 2014 FIGO staging system is therefore really helpful in differentiating potential differences in the prognosis between stages IC1, IC2 and IC3 disease . Recent series suggested that recurrence rate after FSS is acceptable (and seems to be similar to that observed with conventional treatment) for preoperatively ruptured stage IC1 tumors (half of these recurrences being then isolated on the remaining ovary). However, the recurrence rates are higher (23%) in stages IC2 + IC3 disease, thus bringing intoquestion the safety of this management in this situation .
The last question concerning the use of FSS is the case of clear-cell tumors [12,13]. Historically, these tumors had been considered high-grade lesions and thus ineligible for FSS. Yet, when we reviewed the different series published, 116 FSS procedures for clear-cell tumors had been reported (in a majority of cases for stage I disease). The recurrence rate was 17% (19 cases reported), so probably very close to the recurrence rate observed in patients treated radically . Among 19 relapsing patients, the time to the first recurrence was reported in 16 cases: two patients had relapsed within the 6 months after FSS, six between 6 and 12 months, seven between 12 and 24 months and only one after 24 months . This means that relapsing patients in this subgroup of clear-cell tumors had developed a recurrence very early, within the first 2 years after the initial treatment. Furthermore, 13 patients had an extra-ovarian recurrence and 11 had died or were alive with disease . This means that these patients have a high risk of an extra-ovarian and lethal relapse. These two facts had a pragmatic impact on the management of patients. Although this will not cast doubt on the potential validity of conservative management, as a recurrence may arise shortly and will then have a poor prognosis, we should not “authorize” the patient/couple to attempt a potential pregnancy before 2 years after FSS in clear-cell disease if we do not want to be faced with the diagnosis of a metastatic recurrence in a pregnant patient.
As mentioned above, it is finally unclear whether such recurrences are related to the natural history of the disease in these “high-risk patients” (grade 3 and/or stage IC grade 2 and/or stage IC3 disease) or to the use of fertility-sparing surgery itself. A recent series reported by Fruscio et al. suggested that the oncologic outcomes of grade 3 tumors are not related to the type of ovarian surgery (conservative or radical). However, the number of such patients is small (only 27 patients that is logical in these “limit indications” for FSS). With such small number of patients it is difficult to draw definitive conclusions when comparing recurrences rates between both populations (radical or conservative).
The management of patients with early EOC eligible for FSS should be multidisciplinary. The histological review of the ovarian tumor and surgical staging should be done by experienced teams. This conservative treatment can be safely performed in stage IA and IC grade 1 and 2 disease and stage IC1 according to the 2014 FIGO staging system. For patients with "less favourable" prognostic factors (grade 3, stage IC grade 2, clear-cell carcinoma or stage IC3 disease), the high rate of recurrence observed could be related to the natural history of the disease, whatever the type of surgery done (conservative or radical) or to the use of FSS itself. These patients should be then informed that radical surgery may not necessarily improve their oncological outcome. But these doubts are important regarding the information imparted to the patients in these different clinical situations, and finally also raise the question of the place of the application of the “precautionary principle” in this context, according to these uncertainties.
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