51 Uveal melanoma

Background

Of all melanomas approximately 5% arise from the ocular and adnexal structures such as uvea, eyelids, conjunctiva and orbit.1 The majority (85%) of ocular melanoma are uveal in origin whereas primary orbital melanoma is very rare.1,2 Uveal melanoma is the most common primary intraocular malignant tumour.3

The diagnosis of uveal melanoma is made by clinical examination including slit lamp examination and indirect ophthalmoscopy, as well as ancillary studies such as fluorescein angiography and ultrasonography.4 The accuracy of clinical diagnosis among Collaborative Ocular Melanoma Study (COMS) participants was reported to be greater than 99%.5

Incidence

A rising incidence of cutaneous melanoma has been observed in recent years.1,6 With regards to uveal melanoma, there are only a few large population-based studies. Two studies from the United States have reported stability of incidence rate between 1950 and 1974 and between 1973 and 1997.3,7 The reported incidence rate of uveal melanoma has ranged from 5·3 to 10·9 cases per million because of variations in inclusion and diagnostic criteria, and methodology used in calculating the incidence rate.

Treatment options

The traditional form of treatment, enucleation, has been challenged in recent years and alternative methods of treatment including radiotherapy (plaque radiotherapy, proton beam radiotherapy, helium ion radiotherapy), local resection and transpupillary thermotherapy have been used more frequently to manage posterior uveal melanoma.4

Prognosis

Approximately 40% of patients with posterior uveal melanoma develop metastatic melanoma to the liver within 10 years after initial diagnosis and treatment.4,8 However, clinically evident metastatic disease at the time of initial presentation is uncommon, indicating early subclinical

metastasis in the majority of cases.8 Using conventional methods such as serum liver enzymes and liver scans, metastatic disease can be detected in only 1–2% of patients at the time of presentation.9 Systemic screening protocols using physical examinations, liver function tests, chest x rays and liver imaging studies every six months to one year have been proposed but the effectiveness of the screening protocols remains to be established.10

Question

Is plaque radiotherapy associated with improved survival as compared with enucleation for management of uveal melanoma?

The evidence

We found only a single randomised controlled trial that compared these techniques.

Comment

The Collaborative Ocular Melanoma Study (COMS) is an ongoing prospective study investigating patient survival after treatment of choroidal melanoma.11,12 The COMS consists of:

●a randomised trial of patients with medium choroidal melanoma treated with enucleation versus iodine-125 plaque irradiation

●a randomised trial of patients with large choroidal melanoma treated with enucleation only versus preenucleation external beam irradiation and enucleation

●a prospective observational study of patients with small choroidal melanoma.

Recently published initial results from the COMS indicate that for medium-sized melanomas, enucleation and iodine125 brachytherapy offer similar survival rates. During the 12-year accrual period 1317 patients were enrolled. A total of 660 were assigned randomly to enucleation and 657 to iodine-125 brachytherapy. The estimated five-year

cumulative mortality rates were 19% (95% CI 16–23%) for patients treated with enucleation and 18% (95% CI 15–21%) for patients treated with iodine-125 brachytherapy with a risk ratio of 0·93 (95% CI 0·76–1·14).

COMS is a landmark prospective randomised study enrolling a large cohort of patients. For medium-sized choroidal melanoma, iodine-125 brachytherapy can be offered to the patients without increasing the risk of mortality over the generally accepted standard therapy of enucleation. It is probable that these data can be equally extrapolated to other forms of plaque therapy such as ruthenium-106. Conversely, enucleation can also be recommended without fear of increasing mortality.

Question

Is proton beam radiotherapy, helium ion radiotherapy or local resection associated with improved survival as compared with enucleation for management of uveal melanoma?

The evidence

We did not find any randomised clinical trials comparing proton beam radiotherapy, helium ion radiotherapy or local

resection with enucleation for management of uveal melanoma.

Comment

Several retrospective studies have evaluated different modalities of treatment in the management of uveal melanoma. Zimmerman and associates in 1979 reported their observations on the rise in the mortality rate a few years after enucleation. On the basis of 2300 case studies the postoperative mortality rate increased from the estimated pre-enucleation rate of 1% per year to a peak of 8% during the second year after enucleation and then decreased monotonically. The authors postulated that the procedure of enucleation had a detrimental effect on the expected natural course of the disease.

Others have subsequently shown that the excessive mortality after enucleation for uveal melanoma is not related to the enucleation but to an active phase of tumour progression that led to the diagnosis. However, since then many retrospective studies have shown that survival in patients with uveal melanoma is independent of the method of local treatment such as plaque radiotherapy, proton beam irradiation20 or tumour resection (see Table 51.1).

Comparison of survival in patients treated with enucleation versus cobalt-60 plaque was performed on 237

patients with uveal melanoma. The eight-year survival estimates between the two groups was not statistically dissimilar (enucleation group 62%, plaque group 76%). In a larger study of 495 patients with uveal melanoma treated with enucleation and 556 patients treated with proton beam irradiation, the estimated five-year survival rate between the enucleation group and the proton beam group was similar (80% and 81% respectively). In a study of 731 cases that had been treated with helium ion and iodine-125 plaque radiotherapy, the estimated five-year survival rate was 76%, indicating similar survival to patients treated with enucleation.22

Implications for practice

For medium-sized choroidal melanoma, plaque radiotherapy can be offered to patients as an alternative to enucleation without compromising the overall patient survival.

Implications for research

Equal risk of metastasis with enucleation and plaque radiotherapy implies that the metastasis occurs prior to the diagnosis of uveal melanoma. Research into the role of prophylactic adjuvant systemic therapy to minimise the risk of metastasis should be considered.

References

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21.Augsburger JJ, Lauritzen K, Gamel JW et al. Matched group study of surgical resection versus cobalt-60 plaque radiotherapy for primary choroidal or ciliary body melanoma. Ophthalmic Surg 1990;21:682–8.

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23.Diener-West M, Hawkins BS, Markowitz JA, Schachat AP. A review of mortality from choroidal melanoma. Arch Ophthalmol 1992;110:245–50.

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