Oncologic and visual outcomes after postoperative proton therapy of localized conjunctival melanomas

Conjunctival melanomas are rare but deadly tumors of the ocular surface. Substantial increase in incidence of conjunctival melanoma has been reported in the last decades with now up to 0.8 cases per million inhabitants [1, 2] in Caucasians. There is however some racial and ethnic variability [3]. Their changing incidence patterns coincide with those seen in cutaneous melanoma, suggesting a possible link to a sunlight-related etiology. Local recurrences are reported in up to 50% of patients at 10 years and metastatic disease may occur via both lymphatic channels to regional pre-auricular lymph nodes and parotid nodes [4] and hematogenously to distant metastatic sites [2, 5]. An eye-preserving strategy is advocated if intraocular and orbital structures are not involved [6]. In early local disease, the mainstay of treatment is the standard “no touch” surgical technique, which consists of removing the tumor with clear margins without touching the tumor [7, 8]. It may be associated with absolute alcohol corneal epitheliectomy in case of corneal involvement and cryotherapy of the cut conjunctival edge [9, 10]. Local relapses may be further minimized by adjuvant therapies [11], such as topical antimitotic agents (mitomycin C, 5-fluorouracil or interferon alpha-2b). However, topical drugs have limited penetration depth and limited efficacy in deeply invasive melanomas. Moreover, distant metastases and mortality are highly correlated with local conjunctival recurrence [5], suggesting that more aggressive local treatment should be necessary [10]. Adjuvant conjunctival radiotherapy can be performed using proton therapy, brachytherapy or electron beam radiation therapy [12‐15].

We evaluated the patterns of failure, progression-free survival and prognostic factors, toxicity and visual outcomes in patients with conjunctival melanomas referred to our tertiary-care institution and all treated with surgery and proton therapy.

After exclusion of seven patients who had surgery only or proton therapy only for comorbidities and age (N = 4) or unresectable disease (N = 3), the remaining 92 patients all underwent surgery and proton therapy. Patients and tumor characteristics are presented in Table 1. Patients had stage T2 to T3 conjunctival melanoma in 28.4% of cases and over two thirds of them had more than one quadrant involved. A majority of patients (65.2%) had conjunctival melanoma with PAM. Forty-two patients (47.2%) had their first surgery at our hospital. Adjuvant treatments other than proton therapy varied over time with cryotherapy performed systematically until 2009 and mitomycin delivered postoperatively after 2010 based on operative findings and histological reports: respectively 44 (47.8%) and 22 (23.9%) patients either received cryotherapy perioperatively or mitomycin postoperatively, the remaining 28.3% receiving surgery and proton therapy only. Among patients receiving mitomycin, 90.9% had PAM.

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, 25‐30]. 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.

The cumulative incidence of local failure after proton therapy following surgery at 5 years was 33.2%. Proton therapy allowed an efficient conservative ultimate treatment at relapse in about half the relapses. Outcomes compare favorably with the literature with visual preservation in most cases and manageable toxicities, requiring surgical intervention in limited numbers of patients.