We described our experience in the treatment of large UM with endoresection and adjuvant Ru-106 brachytherapy, both as primary or as salvage treatment after prior radiation therapy. The results of our series suggest that the use of this approach in selected UM patients may achieve good anatomical and functional outcomes, without significant treatment-related complications.
The internal resection of UM was performed for the first time in 1986 by Peyman and Cohen to treat tumors located in close proximity to the optic disc [32]. Subsequently, Lee et al. (1993) and Damato et al. (1998) reported their results in treating patients using the same procedure [7,33]. Initially this surgical technique was limited to posterior tumors for whom radiotherapy would be technically difficult, and was then extended to large posterior tumors for whom radiation would cause severe vision loss and enucleation would typically be recommended for [9,11,12,16]. In the literature, endoresection was more often described as a primary treatment in radiotherapy-naive patients, however, it was also used to treat patients with local recurrence following radiotherapy, when a large amount of necrotic tissue was expected (as is the case following gamma knife irradiation or proton beam irradiation of large tumors), in case of persistent large exudative retinal detachment following radiation, or in case of intractable vitreous hemorrhage and ghost cell glaucoma [7,8,12,17,34–38].
The results of our study are consistent with those of other experiences reported in the literature. The mean follow-up time in our series was 28.9 months. Thirteen out of fifteen patients (86.7%) were still alive and showed no evidence of local recurrence or distance metastasis at the last follow-up visit. In our study, no local recurrences were found after primary endoresection while a single case of recurrence was found after a salvage procedure. In this case, secondary enucleation was performed.
Reported rates of long-term local recurrence and enucleation after endoresection for UM are quite variable, ranging from 0% to as high as 23% [17]. Damato et al. reported no cases of recurrent disease in 41 primary endoresection surgeries, and one case after salvage endoresection [7]. Kertes et al. reported one local recurrence in 32 patients (3.1 %) with a mean follow-up time of 3.5 years [39]. Karkhaneh et al. detected one recurrence at the margins of the surgical coloboma and another new tumor focus in a study which included 20 patients (10%) with a mean follow-up time of 89.5 months [9]. Garcia Arumi et al. found local recurrence rates of 5.1% and 6% at 3 years and 5 years, respectively [12]. Susskind et al. reported 5- and 10-year actuarial rates of recurrence of 22.7% and 29.2%, respectively [31]. Caminal et al. found a 5-year recurrence rate of 12.2% [10]. Rice et al. found a recurrence rates of 18.2 % [40].
In our series, only one patient developed liver metastases and died as a consequence. The overall survival rate at the end of the follow-up was 93.3%. The patient who developed metastatic disease received endoresection as a salvage treatment after local recurrence occurred one year after Ru106-brachytherapy.
Despite the initial concerns about the risks of local or metastatic spread, the available data show that endoresection achieves survival outcomes comparable to those obtained with brachytherapy [17]. However, the technical complexity of this surgical procedure limits its use to a small number of specialized centers, especially in cases in which primary radiotherapy is deemed unsuitable.
The literature shows cancer-specific mortality rates ranging from 0% to 20%, albeit with variable follow-up outcomes [7,9–14,31,39–42]. Actuarial (Kaplan–Meier) survival rates at 5 years range from 90.9% to 100%, while at 10 years, survival rates range from 57.9% [28] to 97.6% [12,31]. These data are similar to those from the COMS study, in which 5-year overall and disease-specific mortality rates for medium-sized melanomas were 20% and 10%, respectively [43].
Only two retrospective studies have compared primary endoresection to brachytherapy for UM. Both studies found no significant differences in overall survival or disease-specific survival [10,40]. Rice et al. compared the outcomes of Iodine-125 brachytherapy (n = 148) and endoresection (n = 22) in the conservative treatment of medium sized choroidal melanoma (2.5–10 mm in height and up to 16 mm in the widest diameter) [40]. This study suggests that endoresection of selected tumors may achieve better visual outcomes than brachytherapy. Visual acuity of 6/18 or better was maintained in 41% of the endoresection group and 35% of the brachytherapy group. The likelihood of achieving a final visual acuity of better than 2/60 was 22% higher in the endoresection group (p = 0.034). Local recurrence rate was higher in the endoresection group than the brachytherapy group (18.2% vs. 14.9%), but was not statistically significant.
Caminal et al. compared primary endoresection to primary I-125 brachytherapy in a study in which cases were matched according to tumor height and postequatorial tumor location. No statistically significant differences between the two groups were observed in overall survival, metastasis-free survival, visual acuity, or eye retention [10].
UM surgical resection can be performed solely or in combination with preoperative or adjuvant radiotherapy. The use of an adjunctive ruthenium plaque has been initially suggested as a tool to improve local control, considering the possibility that tumor cells remain in the scleral bed or along the resection edges leading to tumor recurrence [7,44,45], and it is now generally accepted that adjuvant radiation after tumor resection can reduce the incidence of both recurrences and metastases [18].
A recent study conducted by Relimpio-López et al. evaluated the clinical outcomes of a combined approach (resection surgery and brachytherapy, conducted simultaneously or deferred) in management of anterior-located UM, affecting mainly the iris and ciliary body [45]. This experience included 26 patients treated with different combined techniques—exoresection followed by brachytherapy or endoscopy endoresection for ciliary body tumors— and showed them to be an effective and safe approach in selected patients, as long as strict follow-up is conducted after surgery.
The main concern about endoresection technique is that surgical manipulation of the tumor with the vitreous cutter might theoretically result in systemic and local dissemination of tumor cells. However, as more data become available in the literature, this risk appears to be lower than originally believed and endoresection proves to be a safe procedure in terms of tumor control.
Circulating tumor cells in UM are more frequently detected in the metastatic stage compared to the early stage [46]. In the early stage, most patients in whom circulating tumor cells were detected had adverse prognostic risk factors (Class 2 status by gene expression profiling and monosomy 3) with increased risk of distant metastasis and worse clinical outcomes). The high detection rate of circulating tumor cells in UM patients suggests that the metastatic spread precedes initial diagnosis and treatment [47–49]. The rate of circulating tumor cells in UM does not appear to be influenced by the treatment modality. Suesskind et al. conducted a prospective study on 81 patients with UM demonstrating that no significant differences could be found in circulating melanoma cells among different treatment techniques, before and after treatment [50]. This study included 19 patients who underwent endoresection. None of the single therapeutic modalities included in the study (enucleation, endoresection, stereotactic radiotherapy, brachytherapy and transpupillary thermotherapy) was associated with changes in circulating melanoma cells values in the systemic circulation (all p > 0.20).
Overall, in our series the visual acuity was preserved and slightly increased at the last follow-up visit, with a mean BCVA of 20/40, while the preoperative BCVA was 20/50. Our final BCVA results appear to be significantly better than those reported in other endoresection studies [7–16]. For functional preservation purposes, in addition to the size of the tumor, a crucial aspect is its location. Regarding the dimensions, the mean tumor thickness was 7.14 mm, and the mean largest basal diameter was 11.2 mm, with most lesions in the “large” class of the COMS classification. On the other hand, regarding location, all the tumors included in our series were posterior to the equator, and in 60% of cases, the tumor was located in temporal sectors. In cases of endoresection for temporally located tumors, the macula and visual function are more likely to be affected [12]. In our case series, however, we observed an overall slight increase in mean BCVA, despite the localization of the tumors and the treatment received, which included adjuvant radiotherapy. In this regard, it should be noted that most of the patients had an exudative retinal detachment which was fixed with treatment, furthermore the increase in visual acuity may be also justified by the cataract extraction which was routinely performed in each case (all patients were phakic and six of them had cataracts).
Compared to others conservative approaches, endoresection surgery has the undoubted advantage to providing tumor tissue for chromosomal analysis and prognostic testing in all cases. In recent years, several studies have focused on the identification of prognostic factors for UM, highlighting the importance of cytogenetic and molecular genetic characteristics of the disease [51–54]. One of the most important chromosomal abnormalities associated with an increased risk of metastasis is the loss of a copy of chromosome 3 (monosomy 3), with a reduction of 5-year survival from approximately 100% to 50% [51,52]. Other abnormalities, such as 8q gain and 1p loss correlate, with poorer survival [51,53]. In our series, cytogenetic analysis was performed in all cases, and monosomy 3 was detected in 11 out of 15 (60%) patients. These data suggest a biologically aggressive disease in most cases, in a higher percentage than other experiences reported in the literature. Despite this, no higher recurrence and metastasis rates than other studies were observed.
The main complications of endoresection surgery include intraoperative bleeding, postoperative retinal detachment, commonly related to proliferative vitreoretinopathy, local tumor recurrence, and rarely fatal air embolism following fluid–air exchange [11,55]. In our series the treatment was very well tolerated without significant complications.
Previously, air was used to flatten the retina in this surgical procedure; however, this method was abandoned after the report of intraoperative and early postoperative death caused by air embolism [55,56]. It is known that air embolism can develop after endoresection for choroidal melanoma, despite avoiding air infusion [57,58]. Ruschen et al. hypothesized that a gas embolism was due to the entry of perfluorooctane into the bloodstream with the formation of gas bubbles in the pulmonary circulation, and the association with an increased vapor pressure of perfluorooctane [57]. In our case we always used perfluorodecalin, which has been reported to enter circulation during endoresection without systemic complications [58]. No significant complications associated with radiotherapy were observed in our series. It must be considered that brachytherapy was conducted with the lowest dose, sufficient to eliminate residual cells on the scleral bed, and with the vitreous chamber filled by silicon oil which appears to reduce the radiation-induced collateral damage on the healthy eye structures [59].
This study addresses some considerations that need to be taken into account. We are aware that this is a small retrospective series of 15 carefully selected UM patients, however, the results have been promising both in terms of disease control and functional preservation, confirming safety and efficacy data reported in the literature. The average follow-up time in our series was 28.9 months and the long-term risks of local recurrence and systemic spread remain uncertain, however, even the endoresection experiences in the literature in which the follow-up times were very long have not shown differences in terms of disease control for this procedure compared to other methods [12,17]. In any case, it will be interesting to observe the results in terms of disease control at a more extended follow-up in our series.
Our case studies also included two young patients (22 and 31 years at the time of treatment, case #1 and case #12) with a long life expectancy who underwent primary endoresection. These two patients presented large, posteriorly located lesions for which radiation treatment could have led to significant complications, and a non-negligible risk of secondary enucleation. We believe that the anatomical preservation of the eye in this case takes on particular importance, considering also the greater psychological distress of younger patients following eye removal [60]. These two young patients not only retained the eye, but also useful vision (BCVA 20/100 and 20/80 at the last follow-up visit), unchanged from baseline. This result appears to be extremely favorable, considering the size of the lesions and the localization, and we believe that it would have been difficult to obtain with other available treatment modalities.