Large series of conjunctival treated with no touch surgery and proton therapy are rare and visual outcomes are rarely documented in this situation. In this series of conjunctival melanomas, 92 patients were treated with conservative surgery and proton therapy targeting areas at risk for relapse on the ocular surface, conjunctival folds or tarsal conjunctiva. Two thirds of the patients also received cryotherapy perioperatively (to secure resection margins) or mitomycin postoperatively (to treat PAM, which is not included in the radiation fields). Eye preservation has been advocated since the 2000’s using an association of no touch surgery and cryotherapy of resection margins [8]. However, rates of relapses and related deaths [22], as well as local failure, remain substantial [23].
Attempts to reduce local relapse rates have used postoperative mitomycin and other topical chemotherapies [24]. Efficacy is however limited by the small penetration depth of these topical treatments and local relapse rates remain about 40–50% [24]. Radiation therapy (by brachytherapy or external beam modalities) also appears to decrease the risk of relapse [6, 10, 21, 25,26,27,28,29,30]. We here report 5-year and 10-year local failure incidences of 33.2 and 49.5% with proton therapy for conjunctival melanomas, which is consistent with the literature [2] [13, 27, 31]. Knowing the incidences of local failure, patients treated for conjunctival melanomas should have a tight follow-up schedule. Patients are asked to see their general ophthalmologist every 3 months for 2 years, every 6 months for 3 additional years, then annually. The patients are also asked to see their onco-ophthalmologist every 6 months during the first 2 years, and every year for 3 additional years.
Moreover, salvage conservative local treatment using proton therapy reirradiation was performed in 15% of the patients, i.e. in 56% of patients experiencing local failure. Thus, we were able to preserve eyes and vision in a half the patients with tumor relapse (similar to Shields’ [23]). It was so without compromising survival as deaths from conjunctival melanoma occurred in 4.4% of the patients.
Most local failures occurred out of the radiation field, and neither cryotherapy (of resection margins) nor mitomycin (covering the whole ocular surface, with PAM not included in radiation fields while invasive melanoma was) were protective factors for local failure. Out-of-field failures occurred in unirradiated ocular quadrants are consistent with the literature [26]. Enlarging radiation fields is however at risk of significantly increasing the probability of severe toxicity. Severe dry eye syndrome and limbal stem cell deficiency as a consequence of corneal vascularization are among these severe toxicities [21]. Thus, it may be worth reinforcing quality assurance of surgery to avoid tumor spread by strict compliance with the no touch technique, changes of instruments and not using conjunctival anesthesia but rather general anesthesia. Means to accurately define margins for proton therapy, such as dermoscopy [32] and impact of time between surgery and proton therapy might also be worth investigating. Finally, it might be preferred to limit the radiation fields to limit radiation-induced toxicities, with the idea that out-of-field failures may be retreated if necessary, as done in 56% of our patients.
In our series, most frequent toxicities were trophic toxicity by corneal/conjunctival/scleral thinning and madarosis, occurring in almost a fourth of the patients. Trophic toxicity was high in patients undergoing cryotherapy, which was abandoned after observation of these toxicities in the early years of the study. Despite cataracts in 23.9% and dry eye in 30.4% of the patients, 57% of them had stable or improved visual acuity despite treatment. Factors for visual deterioration were related to tumor extent. Finally, radiation therapy by either brachytherapy or proton therapy appears to not only reduce relapse rates but also to allow good visual acuity [26, 28, 29]. It is appropriate to treat extended forms of conjunctival melanomas either in depth (T2–3) or superficially (quadrants T1b-c) [21] and it can also treat ulcerative forms [30]. T3 tumors and complex tumor shapes including the conjunctival folds, caruncle or tarsal conjunctiva may not be easily treated with brachytherapy. In such cases, proton therapy is an appropriate technique [21]. As quality of initial surgery, i.e. a no touch surgery technique, is a major prognostic factor [22, 25, 33] [28], all patients underwent no touch surgery but in 47.2% of them, some form of surgery had been performed before referral and quality of first surgery could not be assessed [28]. There were 24% local relapses 5 years after first surgery at our institution and 39% when surgery was done before referral. Epithelioid type only was identified as a prognostic factor for progression-free survival. Distant metastasis rates and related-death rates were inferior in our series compared to others. While there are no clear explanations for this, it is noticeable that published series vary by the presence of precursor lesions. A majority of our patients had melanoma with PAM. These proportions are consistent with those of large series by Shields et al in which melanomas were associated with PAM (74%), from pre-existing nevus (7%), and de novo (19%) [23]. The presence of these conjunctival melanoma precursors is associated with different prognoses (de novo doing worse [23]. In our series, advanced T stage [16] was a more powerful poor prognosis factor. Other commonly found criteria, such as non-limbal location, were significant on bivariate analyses only [23, 34].
Visual outcomes were overall favorable and provide new data as we are not aware of large series of patients with melanomas and visual outcomes after proton therapy in other series.
This series has the drawbacks of retrospective monocentric series, but all patients underwent surgery and proton therapy. Like the no-touch technique, sampling and analyses of pathology specimen require expertise. In our experience, reports from outside institutions are very rarely informative with respect to thickness. Thickness may determine the need for sentinel node sampling, that was not performed systematically at our center. However, this issue remains debated and our regional failure rates were low despite long follow-up, suggesting that sentinel node sampling might not be systematically needed. Another limitation is the absence of BRAF staining [35, 36] and search for other biomarkers associated with prognosis [37] including immune markers [38]. Of note, we are currently conducting parallel multicentric immunostaining studies on operative samples. Furthermore, patients were variably treated with mutually exclusive cryotherapy or mitomycin depending on the period of treatment. However, these treatments had no effect on local failure or PFS in a series of patients homogenously treated with surgery and proton therapy.
