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Abstract
Aims To report on the use of multi-dose photodynamic therapy (PDT) in the treatment of posterior uveal melanoma.
Methods Prospective case series. 18 patients with posterior uveal melanoma were treated with a minimum of three sessions of PDT. Mean tumour thickness was 1.92 mm (median 1.75, range 0.5–4.4 mm) while the mean basal diameter was 7.1 mm (median 6.3, range 5.2–11 mm). Patients were assessed for visual acuity, complications, tumour status and systemic metastases.
Results In 16 cases, the tumour regressed with stable or improved vision in 15 patients (83%) over a mean follow-up period of 28 months (median 26.5, range 12–44 months). One patient developed an edge recurrence on two occasions ultimately requiring proton beam therapy while one patient showed no response to PDT before being successfully treated with proton beam therapy. Two patients developed scleritis requiring a short course of systemic steroids. No patient developed metastatic disease in the study period.
Conclusions Posterior uveal melanomas may be successfully treated with high dose PDT with retention of good vision in the majority of cases, at least in the short-term. Longer follow-up is required to see if these encouraging results are maintained.
- Choroid
- Neoplasia
- Treatment Lasers
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Introduction
A number of eye-preserving treatments are now routinely used in cases of posterior uveal melanoma including plaque brachytherapy (with a variety of isotopes),1 ,2 proton beam therapy3 and stereotactic radiosurgery.4 These offer excellent local control rates but often at the cost of significant impairment of vision from radiation retinopathy or optic neuropathy5 as well as a variety of anterior and posterior segment complications including dry eye, cataract, keratitis, scleritis and (occasionally) globe-threatening complications such as scleral melt or rubeosis.6 ,7 Similarly, transpupillary diode laser thermotherapy (TTT) has been used for small melanomas at the posterior pole; however, it has largely fallen out of favour as a solo treatment owing to the risk of late recurrence.8
Photodynamic therapy (PDT) using verteporfin as the photoactive agent was until the advent of intravitreal therapies, the mainstay of treatment for ‘wet’ macular degeneration.9 In ocular oncology, PDT has been used for some years in the treatment of circumscribed choroidal haemangioma10 but has also been used to good effect in a number of other neoplastic conditions including choroidal metastases,11 retinal capillary angiomas,12 ,13 vasoproliferative tumours14 and conjunctival squamous neoplasia.15 Various treatment protocols have been used for these conditions with some using the standard ‘treatment of age-related macular degeneration’ (TAP) protocol16 while others favour a bolus technique.17 In the treatment of uveal melanoma, PDT has had variable success with only a small number of cases in the published literature.18–22 These have mainly consisted of case reports; however, in the largest series to date, Campbell and Pejnovic reported tumour control in eight out of nine cases of posterior uveal melanoma treated with multiple sessions of PDT with minimal complications.23 An unpublished observation by this author with PDT in a single case of choroidal melanoma, which could not be treated by any other means, showed a favourable initial response, but relapsed 6 months later. This prompted the design of the current study to use a minimum of three consecutive PDT treatments, based on the regimen for TTT, in the hope of consolidating initial response and prevent recurrence.
Materials and methods
A total of 18 patients (10 men and eight women) were included in the study. All patients underwent detailed ophthalmic examination including Snellen visual acuity, slit-lamp examination and binocular indirect ophthalmoscopy, standardised A- and B-scan ultrasonography and colour fundus photography. A diagnosis of melanoma was made on the basis of clinical appearance, symptoms and ultrasonographic features. Patients were counselled of the various treatment options available which in our institution include ruthenium plaque brachytherapy, proton beam therapy, stereotactic radiosurgery or enucleation. In each case, the patient was reluctant to consider radiotherapy for a variety of reasons and after a full discussion of the risks and benefits elected to undergo treatment by means of PDT.
The infusion protocol used was based on the TAP protocol, namely, an intravenous infusion of verteporfin (Visudyne, Novartis, UK) 6 mg/m2 given over 10 min, with treatment commencing 5 min following completion of the infusion.16 A Volk PDT lens (magnification 1.5×) was used to visualise the fundus and treatment was given for 166 s per spot resulting in an energy density of 100 J/cm2 as previously described for retinal capillary haemangiomas.13 Multiple overlapping laser spots were used to cover the surface of the tumour as necessary. As is usual following PDT, patients were advised to avoid exposure to sunlight or strong forms of artificial light for 48 h following treatment. All patients were assessed at 2- and 4-month intervals following treatment and provided there was no evidence of growth of the tumour underwent a further two sessions of treatment at those visits irrespective of the degree of regression of the melanoma. No postoperative drops were prescribed; however, patients were encouraged to take an oral non-steroidal anti-inflammatory (NSAID) such as ibuprofen 400 mg three times a day for 72 h following treatment.
Following completion of the course of treatment, patients were reviewed at 4–6-month intervals depending on the response.
Results
Patient demographics are shown in table 1. A total of 18 patients (10 men and eight women) were included in the study ranging in age from 24 to 75 years, with a mean follow-up of 25 months (median 28 months, range 10–42 months). Mean tumour thickness was 2.0 mm (median 1.75 mm, range 0.5–4.4 mm) while the mean maximum basal diameter was 7.45 mm (median 6.3 mm, range 4.0–11.0 mm). Features suggestive of a diagnosis of melanoma were the presence of lipofuscin (in 11 patients, 61%), subretinal fluid (all patients), symptoms (17 cases, 94%), low internal reflectivity on ultrasonography (16 cases, 89%) and absence of drusen (two cases, 11%). One patient (case 9) had previously undergone transpupillary thermotherapy 8 years earlier. In 16 cases, the tumour regressed (figure 1A–D) with a mean post-treatment thickness of 0.5 mm (median 0 mm, range 0–1.6 mm). Overall, vision improved or was stable in 15 cases and deteriorated in two cases with nine patients returning to acuity of 6/6 or better and 14 patients 6/12 or better. As might be expected, the risk of visual impairment both at presentation and following treatment correlated with the proximity of the tumour to the fovea (table 2). However, only one patient suffered a significant decrease in visual acuity (from 6/9 to 6/60) owing to a subfoveal location of the tumour. Subsequent ocular coherence tomography scanning showed this to be due to chorioretinal atrophy (figure 1E).
Patient and tumour characteristics
Final visual acuity results with respect to proximity of the tumour margin to the fovea
(A) Fundus photograph of case 4 at presentation. (B) B-scan ultrasound of the lesion in case 4 demonstrating acoustic hollowness. (C) Post-treatment fundus photograph of case 4 showing a flat scar. (D) Post-treatment B-scan ultrasound of case 4 demonstrating regression of the lesion. (E) Post-treatment ocular coherence tomography scan of patient 14. The arrow indicates an area of chorioretinal atrophy. (F) Fundal photograph of patient 5 showing recurrent amelanotic tumour at the edge of the otherwise flat treatment scar.
There were two cases of treatment failure. In the case of patient 5, the tumour showed an excellent initial response, regressing to a flat scar. Six months following treatment, he developed a small edge recurrence (figure 1F) which was again treated with three sessions of PDT and the tumour regressed once more, the patient retaining 6/5 vision in the treated eye. Unfortunately, he subsequently developed a second edge recurrence and was treated by means of proton beam therapy. The second failure was patient 17, a 46-year-old man who presented with a pigmented tumour measuring 8.9 mm in maximum basal diameter by 3 mm in thickness, adjacent to the optic disc. Proton beam was recommended; however, owing to his concern regarding possible visual loss he requested PDT and underwent three sessions of treatment with no response. The tumour subsequently enlarged resulting in a decrease in vision to 6/12 and he underwent proton beam therapy with a good result.
PDT was generally well tolerated although several patients reported a moderate headache generally 2 days following treatment which settled with NSAIDs. Two patients, however (cases 7 and 11), developed a severe headache following the initial session of PDT thought to be due to scleritis which settled within a few days with a short course of systemic prednisolone. These patients who had relatively thick tumours at presentation had no further problems with subsequent sessions of PDT and interestingly showed a marked regression of their tumour after the first treatment suggesting that the scleritis was due to tumour necrosis. There were no cases of scleral thinning or extrascleral extension following treatment.
As is our current practice, all patients continue to undergo metastatic screening by means of 6-monthly abdominal ultrasonography and all patients remain systemically well with no evidence of metastatic disease to date.
Discussion
Over the last 15 years, a number of papers have reported the use of verteporfin PDT in the management of choroidal melanoma either as a primary treatment,18–20 ,23 an adjunct to radiotherapy21 or to salvage cases following failure of radiotherapy,22 with variable results. Tuncer et al21 reported a patient in whom a single session of PDT resulted in significant regression of a melanoma which had not shown any significant change following iodine plaque brachytherapy. In the paper by Barbazetto et al,22 four patients were treated with a single session of PDT using a laser fluence of 100 J/cm2. In each case, the tumour had recurred following brachytherapy and subsequent thermotherapy so it might be supposed that these tumours were peculiarly resistant to therapy. In two of their cases, the melanoma regressed or remained stable following PDT while two continued to grow necessitating enucleation. The most encouraging results so far were published by Campbell and Pejnovic who reported success in eight out of nine patients treated with PDT.23 In their series, patients received either 50 or 100 J/cm2 (although the exact protocol varied with time) and underwent repeat treatments until tumours were reduced to a flat scar or ceased to regress. In that series, none of their patients lost vision and three noted an improvement in acuity compared with the patients in the present study in whom six patients improved, nine were stable and three suffered a loss of vision. In comparison, proton beam therapy offers local control rates of up to 95% in some series3 but with a greater risk of significant visual loss in patients with tumours adjacent to the optic disc or fovea. In 1987, Seddon et al5 reported on visual acuity results in a large cohort of patients who had undergone proton beam therapy for melanomas within 3 mm of the optic nerve or fovea. In that group of 342 patients, 190 (43%) had a presenting visual acuity of 6/12 or better; however, at final follow-up, only 27.5% retained this level of vision and 50% had decreased to 6/48 (20/160) or worse.
In 2005, Wachtlin et al24 reported a series of four patients who underwent PDT immediately prior to enucleation. In two cases, the tumour was amelanotic and showed evidence of necrosis to approximately 2.5 mm depth; however, the two eyes harbouring pigmented tumours showed relatively little response suggesting that PDT may be less effective in cases of pigmented melanoma. This did not appear to be the case in the present series in which nine patients had amelanotic tumours and nine patients pigmented lesions. Of the two cases of treatment failure already described, one (case 5) was an amelanotic tumour while the tumour in case 17 was pigmented suggesting that tumour pigmentation need not necessarily be a contraindication to PDT.
In comparison with other forms of conservative therapy for uveal melanoma, PDT is relatively cheap (following an initial outlay for the laser itself), requires no general or regional anaesthesia, is performed as an outpatient procedure and may be repeated as required. Treatment is generally well tolerated although a small proportion may suffer a transient scleritis, occasionally necessitating treatment with systemic steroids.
The question remains as to which patients could be considered for PDT. Radiotherapy techniques such as proton beam therapy offer high rates of local control and globe retention but with the risk of significant visual loss in many cases.3 ,5 PDT seems to offer a better prospect of retention of good levels of vision but with a greater risk of local recurrence/primary failure and so could be considered for patients unsuitable or unwilling to undergo radiotherapy or in whom retention of vision is paramount.
Although the follow-up is relatively short, this study adds to the evidence that multi-dose PDT may be effective in the management of small posteriorly located uveal melanomas with retention of good vision in the majority of cases, at least in the short- to medium-term. Only time will tell whether PDT will suffer the same problem with late recurrences that has led to the demise of TTT as a primary monotherapy for uveal melanoma.
References
Footnotes
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Competing interests None.
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Funding None.
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Patient consent Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.