Ovarian survival after pelvic radiation: transposition until the age of 35 years

Premature ovarian insufficiency (POI) after high gonadotoxic therapy is one of the side effects of cancer treatment with high impact on quality of life. Due to the continued refinements in treatment regimens, the rates of complete remission and cure have been improved. Thereby, quality of life after cancer is becoming a very important issue in a large number of women [1]. For example in the Netherlands, around 350 new cases of fertile patients are diagnosed with cervical cancer every year [2]. Furthermore besides cervical cancer, patients with Hodgkin’s disease, rectal cancer and other malignancies who need pelvic irradiation are at high risk where a small dose of irradiation can already cause infertility and POI [3, 4].

Infertility, climacteric symptoms such as vasomotor hot flashes, urogenital and sexual dysfunction and emotional disturbances are the side effects of POI with high impact on quality of life [5, 6]. Especially, estrogen withdrawal in young women is associated with decreased bone mineral density and impaired lipid profile with increased risk of ischemic heart disease [7, 8]. Although hormone replacement therapy is highly effective in counteracting these risks, long-term studies equating endogenous and exogenous estrogens are lacking [9]. Moreover, hormone replacement therapy (HRT) in women with POI may raise certain serious adverse side effects [10]. Finally, the success of this therapy depends largely on the patient’s compliance of the prescribed protocol [11]. As it has been shown, a small number of women follow their HRT regularly [12].

In an attempt to protect the ovaries from pelvic irradiation and prevent POI, ovaries can be transposed outside the radiation field, also known as ovarian transposition (OT). This surgical technique has been performed since 1952, with varying rates of success [13]. The last 30 years, POI after transposition ranges from 33 to 100%, using various techniques and modes of follow-up [14‐28]. One reason of ovarian failure after OT may be the influence of scattered radiation therapy [29]. Moreover, it has been postulated that decreased blood flow to the ovaries, due to bending of the vessels as a result of the transposition, damage during surgery or as a side effect of the radiation therapy, increases the risk of POI. With regard to side effects of OT, the incidence of symptomatic ovarian cysts after OT is reported to range between 0 and 34% [15, 19, 22, 27]. In some of the reported cases, removal of the transposed ovary was necessary. More disturbingly, several studies have reported ovarian metastases in transposed ovaries [30, 31]. Thus, whether transposing the ovaries prior to radiation is a safe and effective procedure remains an ongoing issue.

We conducted a retrospective case–control study to evaluate the effectiveness and complications of ovarian transpositions prior to radiation therapy. Moreover, we evaluated the effect of age on ovarian survival after ovarian transposition.

From hospital databases of the Leiden University Medical Center, all patients were selected in whom ovarian transposition was performed between 1988 and 2010. From the same databases in which data were entered prospectively, women eligible for the control group were selected: pre-menopausal cervical cancer patients in whom the ovaries were not transposed prior to pelvic radiation.

The follow-up of 27 patients who underwent OT prior to pelvic radiation were reviewed (OT group). The majority of patients suffered from cervical squamous cell carcinoma. Other patients suffered from rectal adenocarcinoma (n = 3, stage 2, 3 and 3) or schwannoma (n = 1, grade II). Twenty-nine patients who suffered from cervical carcinoma and treated with pelvic radiation therapy (7 patients with adenocarcinoma, 22 patients with squamous cell carcinoma) in whom OT was not performed were included in the control group. In all women except one case (concomitant chemotherapy and pelvic radiation), surgery was the primary therapy. Characteristics, including details on adjuvant radiation therapy and concomitant chemotherapy of both cases and controls, are shown in Table 1.

In most patients, standard follow-up treatment was performed according to the Dutch national guidelines for cancer treatment. The follow-up, for example of cervical cancer patients consists of a 3-month interval in the first 2 years, 6-month interval at year 3 and 4 and a 1-year interval at year 5. Patients were seen earlier on request or when there were complaints.

Our data show that ovarian transposition (OT) prior to pelvic radiation results in a significant increase in ovarian survival after pelvic radiation: 5 years ovarian survival 60.3% after OT versus 0.0% without OT (p < 0.001) Published rates of POI and complications after OT prior to pelvic radiation differ greatly (ovarian survival between 33% and 100%), which results in an ongoing debate about the safety and effectiveness of the procedure [14‐28, 32]. However, most of the published data suffer from methodological flaws, since most studies are case series and non-comparative. Therefore, the results of effectiveness or disadvantages are not conclusive. The ovarian survival rates reported in this comparative study strongly support the advocates of ovarian transposition given its significant increase in ovarian survival after pelvic radiation and low complication rate.

Our results show that additional intra-vaginal radiation therapy and/or low dose chemotherapy (as part of chemoradiation therapy) has no significant impact on ovarian survival. Hence, these women should not be excluded from the option of OT. Unfortunately, due to small numbers it was not possible to compare patients after OT, receiving chemotherapy, EBRT and VBRT (n = 4), versus patients receiving EBRT and VBRT (without chemotherapy, n = 4). The PORTEC-2 trial showed the efficacy and reduced side effects of VBRT compared with external beam pelvic radiotherapy (EBRT) for patients with high–intermediate risk of endometrial cancer. Additionally, patients receiving VBRT only reported less bowel symptoms, which provided a better quality of life than after EBRT, contributing to the theory that VBRT delivers less scatter radiation that results in less impact on the surrounding tissue [33]. In contrast to our findings, Morice et all reported ovarian survival of 100% after OT, 90% after OT and brachytherapy and 60% after OT, brachytherapy and external radiation therapy [19]. Furthermore, ovarian survival after OT, external radiation therapy and brachytherapy has been described, respectively, in 33%; 80% and 100% [34‐36]. Yamamoto reported a 5 year ovarian survival rate of 38.5% after OTs and radiation therapy [16]. Furthermore, Beukers reported ovarian survival in 41% of patients after OT and radiation therapy, with a mean follow-up of 43 months [26]. Hence there is no evidence to supports not transposing ovaries in case of pelvic chemoradiation in combination with intra-vaginal brachytherapy.

In the literature, the age above 40 years has often been used as a cutoff point. In our cohort three women older than 40 years underwent OT, of whom two were lost to follow-up. Hence, it is uncertain whether OT of women above the age of 40 years is worthwhile. Additionally, the ovarian survival was statistically significant in all age groups (Fig. 3), although on having a close look into the age group of 35–40 years only two out of eight patients (25%) experienced ovarian survival until 74 months (Table 2).

Previous studies have shown a correlation between age and the dose of pelvic radiation and ovarian failure. Hamish et al. described ovarian failure at the age of 10 years after exposure to 18.4 Gy, but at the age of 30 years ovarian failure occurred after exposure to 14.3 Gy [4]. The effect of OT in women above 40 years of age is limited, because of reduced fertilization and a higher risk of premature ovarian failure despite OT [19]. In addition, progressively smaller doses of chemotherapy are required to produce ovarian failure with increasing age [37‐39]. In our opinion, to prevent POI, ovarian transposition should be discussed with all patients below the age of 35 years who need external radiation to the pelvis.

Despite OT, some women still suffer from ovarian failure after pelvic radiation. It has been shown that, due to scattered radiation, a substantial loss of ovarian function might still occur despite OT [21, 24, 40]. Furthermore, POI after OT and radiation therapy can be caused by migration of the ovaries back into the small pelvis after OT. Williams et al. reported ovarian failure which accounted in most patients of ovaries migrating back to the radiation area, as observed at repeat surgery [40]. An option for detecting the position of the ovaries is to attach a radio-opaque marker to the ovaries during transposition. The ovaries can be identified by imaging done for radiation planning and allows the radiotherapist to adjust the radiation field when necessary. Within our series, not all transposed ovaries were clipped by radio-opaque markers. Thus, in some cases it is unclear whether the ovary was still positioned outside the radiation field or had migrated back to the pelvis. In this context, we advise using radio-opaque markers to visualize the ovaries prior to and during radiation therapy. Finally, even in women after OT without radiation therapy, POI has been reported in up to 7% of women [15, 17, 18, 26]. Thus apart from damage due to radiation, multiple factors may contribute to failure of OT prior to radiation therapy.

Advocates of OT are supported by the data that POI has a high impact on the quality of life and may even cause more stress to the particular woman than suffering from cancer [25, 26]. Therefore, it is worthwhile to prevent POI and preserve ovarian function and/or fertility. However, complications due to OT should be weighted. The major adverse events related to OT are, however, rare: the occurrence of ovarian cysts, ovarian torsion and ovarian metastases on the transposed ovary [19, 20, 23]. In the presented series, adverse events were rare: an ovarian torsion was reported in the transposition group and was surgically removed. No ovarian metastases were reported in this study and surgical procedures were uneventful. In our opinion, OT is a safe procedure and should be offered to women below 40 years old whenever pelvic radiation is indicated.

In conclusion, our data show that ovarian transposition prior to pelvic radiation is effective, since both ovarian survival (p < 0.001) and time to POI (p < 0.01) are significantly better after OT prior to radiation therapy. Despite the low complication risk of ovarian transposition, we advise only ovarian transposition in women until the age of 35 years prior to pelvic radiation to prevent POI with its disadvantageous impact on the quality of life. In women aged 35–40 years, OT can be discussed when the procedure is executed during primary cancer surgery; however, the chances of long-term ovarian survival are limited.