Discussion

The SCC has a variable clinical presentation and evolution. Photophobia, red-eye, irritation, foreign body sensation and a white, painless, progressive growth on the surface of the eye are common presenting symptoms. Most tumours take place in the inter-palpebral fissure, especially on the nasal side.^{Reference Tunc, Char, Crawford and Miller13,Reference Waddell, Downing, Lucas and Newton14} They involve the conjunctiva and may expand onto the peripheral cornea, so visual acuteness is frequently normal in the early stages. It usually involves only one eye. The surface may be gelatinous, papillomatous or fibro-vascular. There is usually inflammation, leucoplakia and markedly dilated blood vessels, referred to as feeder vessels.

The therapeutic approach of this disease can be varied: surgery resection, topical chemotherapy (MMC or 5-FU), photodynamic treatment, immunomodulation with interferon^{Reference Cicinelli, Marchese and Bandello12} and radiotherapy (PBRT, EBRT or brachytherapy).

In our centre, we have treated 15 SCC patients with PBRT with a median follow-up of 48 months. Currently, 13 patients are alive (OS 86·6%) and 2 patients died from causes not related to the disease. We have seen a complete response in 13 out of 15 patients: only 2 patients had a local recurrence of disease (DFS 86·6%) and were treated later with surgery. In six patients the late side effects have regressed and one patient presented with severe late radio-induced toxicity that regressed after a few months: grade III conjunctivitis, red-eye syndrome and lacrimal duct stenosis (Figure 5). For the same patient, MRI images show a complete resolution of the disease (Figure 6). One patient presented with a lacrimal duct stenosis and had to undergo surgery to unblock the tear canal (Figure 7). One patient had severe eyelid perforation to the inner canthus of the eye.

Figure 5.

Patient with complete restitutio ad integrum, after grade III conjunctivitis, red-eye syndrome and lacrimal duct stenosis.

Figure 6.

MRI images show the complete resolution of the disease.

Figure 7.

Inner canthus fibrosis with lacrimal duct stenosis.

Surgical excision is the gold standard treatment according to current evidence. In the review by Cicinelli et al.,^{Reference Cicinelli, Marchese and Bandello12} authors describe how the surgical removal of a conjunctival lesion is performed as specified by Shields’ ‘no touch’ technique to prevent the potential risk of seeding and having large macroscopically tumour-free margins (at least 4 mm).

Ghicuni et al.^{Reference Gichuhi and Sagoo22} describe the adjuvant treatments to improve surgical radicality including cryotherapy, where 2–4 freeze–thaw cycles are used to erase residual tumour at the bed and clear margins. In addition, the topical application of cytotoxic drugs, such as 5-FU and Mitomycin C, can be applied to the tumour bed for about 2.5 min then washed out. Other agents include IFN-a2b drops, all-trans retinoic acid, anti-VEGF agents, Cyclosporin A and radiotherapy.

Several radiotherapy methods have been used for post-operative treatment or for local recurrence. Belaïd et al.^{Reference Belaïd, Nasr and Jmour17} treated 24 patients with post-operative radiation therapy. Eighteen patients were treated with kilovoltage radiation therapy (KVRT). The average delivered dose to the tumour bed was 64 Gy. Two patients were treated with Strontium 90 plaque brachytherapy (two fractions of 17 Gy). Four patients were treated with a combination of KVRT and Strontium 90 plaque brachytherapy. After a median follow-up of 110 months, 19 patients were alive and 17 patients with no evidence of local recurrence. Two patients had a local recurrence and were referred for surgery. Two patients were lost to follow-up. Three patients died without evidence of a relapse. They reported that the 5-year relapse-free survival rate was 90·9% and the 5-year OS was 86·4%. The reported toxicity was cataract in 15 patients, conjunctivitis in 17 patients, tearing of cornea in 13 patients and glaucoma in 2 patients.

Graufe et al.^{Reference Graue, Tena and Finger23} treated eight patients with local SCC recurrence with electron beams. Two patients were HIV positive. The dose range was from 50 to 60 Gy in 2·0- to 2·5-Gy daily fractions. After a mean 30·25 month of 5-FU, they found 75% local disease control. Only two patients developed a tumour recurrence. They reported side effects as mild-to-moderate erythema in seven patients and severe in one patient, one case of keratitis, a case of secondary of trichiasis and three patients with persistent madarosis as side effects.

In a major review, Finger discussed the role of EBRT with the intensity modulated method (IMRT) in the treatment of SCC.^{Reference Finger24} Modern radiotherapy techniques can be used to irradiate tumour, in cases not eligible for surgery, with better sparing of the surrounding healthy tissues, as accepted for other oncological indications.^{Reference Spatola, Militello and Tocco25,Reference Spatola, Tocco and Milazzotto26} The dose range used varied from 34 to 65 Gy, with an average dose of 50 Gy.^{Reference Finger24}

Although the literature on SCC is scarce and in many publications they are case reports, they have shown that SCC can be treated with radical PBRT with excellent results in terms of OS, disease-free survival and toxicity^{Reference Ramonas, Conway and Daftari15,Reference El-Assal, Salvi and Rundle16} and it can be a valid alternative to orbit exenteration or enucleation.

Ramonas et al.^{Reference Ramonas, Conway and Daftari15} treated a 91-year-old patient with a moderate-to-well-differentiated SCC of the conjunctiva with intraocular invasion with radical PBRT as an alternative to enucleation. Slit-lamp examination disclosed a highly vascularised conjunctival amelanotic mass arising from the limbus and extending onto the cornea from the 1 o’clock to 5:30 meridian in the right eye. Ultrasound biomicroscopy described and confirmed the invasion of the conjunctival lesion into the anterior chamber angle from the 1 o’clock to 5:30 position. The dose used for treatment was 32 Gy (8 Gy divided over four treatments on four consecutive days). After 9 months of follow-up, there was no sign of disease recovery and the regression was stable.

El-Assal et al.^{Reference El-Assal, Salvi and Rundle16} treated two elderly patients (73 and 83 years) with OSSN with radical PBRT after excisional biopsy. Four cycles of topical Mytomycin C were administered to one patient. The dispensed dose was 53·1 Gy in four fractions on four consecutive days for both patients. The patients remain recurrence free at follow-up.

In a French ocular oncologic centre, Caujolle et al.^{Reference Caujolle, Maschi, Chauvel, Herault and Gastaud18} treated 15 patients using PBRT either for recurrent or incompletely resected tumours with positive margins for conjunctival SCC. The doses delivered to the target volume varied from 40 to 60 Gy. After a median follow-up of 39·1 months, the tumour control rate was up to 86·8% with acceptable side effects.

In the present study, the data have shown PBRT to also be an effective and safe conservative treatment of SCC which can have a real and psychological advantage in terms of the patient quality of life. PBRT provides good disease control and patients demonstrated few side effects of treatment.

Due to the rarity of the disease, a limitation of this study is the small number of patients available to be treated to provide data for analysis for this study. Future studies need to include larger cohorts of patients so that there will be more data to evaluate the real advantage of proton therapy over other therapeutic methods.