Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003
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44.Wali R, Bissonnette M, Khare S, Aquino B, Niedziela S, Sitrin M, Brasitus T. Protein kinase C isoforms in the chemopreventive effects of a novel vitamin D3 analogue in rat colonic tumorigenesis. Gastroenterology 1996;111:118–126.
45.Millard SS, Koff A. Cyclin-dependent kinase inhibitors in restriction point control, genomic stability, and tumorigenesis. J Cell Biochem 1998;30/31:37–42.
46.Brugarolas JCC, Gordon JI, Beach D, Jacks T, Hannon CJ. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 1995;377:552–557.
47.Kondo Y, Kondo S, Liu JB, Haqqi T, Barnett GH, Barna BP. Involvement of p53 and waf1/cip1 in gamma-irradiation-induced apoptosis of retinoblastoma cells. Exp Cell Res 1997;251:51–56.
48.Elstner E, Linker-Israeli M, Umiel T, Le J, Grillier I, Said J, Shintau IP, Krajewski S, Reed JC, Binderup L, Koeffler HP. Combination of a potent 20-epi-vitamin D3 analogue (KH 1060) with 9-cis-retinoic acid irreversibly inhibits clonal growth, decreases bcl-2 expression, and induces apoptosis in HL-60 leukemic cells. Cancer Res 1996;56:3570– 3576.
49.Vandewalle B, Hornez L, Wattez N, Revillion F, Lefebvre J. Vitamin-D3 derivatives and breast-tumor cell growth: Effect on intracellular calcium and apoptosis. Int J Cancer 1995;61:806–811.
50.Skarosi S, Abraham C, Bissonnette M, Scaglione-Sewell B, Sitrin MD, Brastius TA. 1,25-dihydroxyvitamin D3 stimulates apoptosis in CaCo-2 cells. Gastroenterology 1997;112:A608.
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Therapy of Uveal Melanoma: Methods and Risk Factors Associated with Treatment
DAN S. GOMBOS
M. D. Anderson Hospital, Houston, Texas, U.S.A.
WILLIAM F. MIELER
Baylor College of Medicine, Houston, Texas, U.S.A.
I.INTRODUCTION
The past century has seen a dramatic shift in the management of uveal melanoma. A disease once universally treated by enucleation is now managed by a range of techniques that can often preserve the eye and varying degrees of vision. While some treatment approaches remain controversial, others are widely accepted. The primary goal of management is to prevent both local tumor growth and spread of tumor outside of the eye, thereby altering the natural course of the malignancy with its associated morbidity and mortality. Unlike the case in other ocular conditions, preservation of life is the most important factor here, with retention of the eye and vision a secondary goal.
Treatment for patients with uveal melanoma can be divided into five broad categories (Table 1): observation, photocoagulation therapy, radiotherapy, local excision, and organ resection (enucleation). The treatments represent a spectrum of approaches applicable for tumors of various size and intraocular location. The indications for certain techniques overlap with others. Some of the modalities discussed here have evolved over decades with proven efficacy, while others remain in their infancy with limited long-term data. The clinician is cautioned to assess each treatment option carefully and proceed with an individualized plan tailored to the
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Table 1 Treatment Options for a
Patient with a Uveal Melanoma
Observation
Laser therapies
Photocoagulation therapy
Transpupillary thermotherapy (TTT)
Photodynamic therapy (PDT)
Radiotherapy
Brachytherapy
Charged-particle radiation
Gamma knife
External-beam radiation therapy
Tumor resection techniques
Enucleation
specific needs of each patient. Detailed explanations of the risks and benefits will allow the patient to make an informed decision regarding the management option that suits him or her best.
II.OBSERVATION
As with most cancers, it is generally best to diagnose and treat uveal melanomas early in their natural course. Distinguishing small active melanomas from suspicious choroidal nevi, however, is an important consideration for the clinician before proceeding with therapy.
Small indeterminate lesions can remain stable for many years and often require no intervention. Some small tumors may transform and declare themselves as melanomas. When such a lesion presents itself, it is best to assess its risk for growth and malignant transformation. Such characteristics include tumor thickness greater than 2 mm, proximity to the optic nerve and the presence of symptoms, orange pigment, or subretinal fluid (Fig. 1). Small lesions that have dormant features can be followed closely with serial observation. Retinal drawings, fundus photographs, and echography should serve as a baseline for repeat assessment in 3 to 4 months. If the lesion remains stable, periodic review can be performed at greater intervals. Patients should be instructed to return for evaluation sooner if they develop any visual symptoms in the affected eye. Proceeding with therapy is reasonable if growth is documented (photographically or echographically) or the lesion demonstrates numerous risk factors [1].
Most tumors with documented growth should be treated. However in special circumstances, observation may be considered. Elderly monocular patients with small melanomas, who are at risk for visual loss with therapy are one such group. These cases require careful patient selection, informed consent, and close serial assessment.
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Figure 1 Photograph OD showing a juxtapapillary small uveal melanoma (2.2 mm thick) with orange pigmentation and subretinal fluid. The lesion grew within 6 months, eventually requiring 125I brachytherapy treatment.
III.LASER THERAPIES: PHOTOCOAGULATION, THERMOTHERAPY, AND PHOTODYNAMIC THERAPY
While various types of lasers have been employed in the treatment of uveal melanomas, the therapeutic principle is similar for most modalities; energy directed to the lesion is absorbed and converted to heat, which destroys the malignancy. The majority of lasers cause immediate cell death through coagulation of proteins, while newer approaches heat tumor cells causing tissue necrosis—so called thermotherapy. Generally these methods are indicated for small melanomas with documented growth or those lesions at high risk for future growth.
Meyer-Schwickerath, a pioneer in photocoagulation, was the first to treat a uveal melanoma with this approach in 1957. Since then a number of studies have suggested that laser photocoagulation can be used to treat small melanomas [2–6]. Some clinicians have limited this modality to tumors less than 2 mm in height, while others have treated lesions up to 3.5–4.0 mm [7,8]. Limited tissue penetration restricts its use for thicker lesions. Local tumor control is successful in approximately 85% of cases; however, studies with increased follow-up have demonstrated a propensity for late recurrences [9]. Melanomas in close proximity to the optic nerve or macula were initially selected for laser photocoagulation as an alternative to brachytherapy, but these cases now often seem prone to failure. Lesions posterior to the equator, in eyes that dilate well with clear media, are most amenable to photocoagulation; however, with the advent of indirect ophthalmoscopic delivery of laser, virtually any tumor is amenable. On occasion, when brachytherapy is not successful and a local tumor recurrence develops, tumors are treated with photocoagulation [10].
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A number of different lasers have been used to treat melanomas. While xenon arc photocoagulation was initially described, it has largely been replaced by argon and krypton lasers [7,9,11]. The general approach is to the treat the lesion with lowenergy, long-exposure burns in multiple stages. The melanoma is first surrounded with two to three rows of laser spots. At follow up, heavy white burns are applied to the tumor surface. Treatments continue at 3- to 5-week intervals until the lesion flattens and develops into a flat atrophic scar (Fig. 2A–C). Some tumors require multiple treatments until an acceptable response is achieved. Late recurrences, years following therapy, have been described so careful serial follow-up is mandatory if this method is selected (Fig. 3A,B) [4,5,12–15].
With the introduction of the 810-nm diode laser, a number of centers have abandoned traditional photocoagulation for laser-induced hyperthermia [16–20]. While indications for this modality continue to evolve, small pigmented tumors, less than 2–3 mm in height, that are not contiguous with or overhang the optic nerve seem to have the best response [17,18]. Local control in some studies is reported as high as 95%; however, reports with longer follow-up demonstrate failure rates up to 22% at 3 years [19–21]. Treatments are usually administered via a slit-lamp delivery system under retrobulbar anesthesia. Using a 2 to 3-mm spot size, the laser is applied to the lesion with an exposure up to 60 sec. A slight blanching of the tumor surface is the desired endpoint. Most clinicians advocate two to four treatment sessions until a flat scar is achieved, but others have demonstrated treatment effects years after only one session [22–24]. In one report, tumors requiring more than three treatments for tumor control were more likely ultimately to recur [21]. Amelanotic lesions tend to be resistant to this modality, as there is very limited laser energy uptake. As a result,
Figure 2 Photographs OS documenting xenon coagulation to a small uveal melanoma along the superotemporal arcade. (A) Initial treatment was placed around the margin of the tumor, followed by (B) treatment to the surface of the tumor, resulting in a (C) flat fibrotic scar.
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some centers administer compounds such as indocyanine green (ICG) prior to therapy of amelanotic tumors to increase laser uptake.
Thermotherapy has been used as an adjunct to plaque brachytherapy. Socalled sandwich therapy has been described in the management of large choroidal melanomas treated with ruthenium plaques. Application of thermotherapy is used to lower the applied dose of radiation [22,25–26]. While tumor regression and survival are favorable with the approach, some studies demonstrate a significant loss of central vision. Thermotherapy has also been used as a salvage technique for eyes failing primary brachytherapy and photocoagulation.
Figure 2 Continued.
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Figure 3 Photographs showing (A) a stable laser treated small melanoma, which eventually regrew (B) two years following treatment, necessitating enucleation surgery.
Multiple complications have been described following laser therapies. They include vascular occlusions, neovascularization, macular wrinkling, edema, and exudation [13,15,17,18,20]. A serious concern includes the risk of extraocular tumor extension, a complication described with both photocoagulation and thermotherapy [12,21,27–33].
Reports have described the treatment of melanomas with photodynamic (PDT) or photoradiation therapy [34,35]. These approaches involve the administration of systemic agents (usually porphyrin derivatives) that are activated by light of a specific wavelength. The mechanism of action seems to involve vascular closure but may include a direct cytotoxic effect on tumor cells [36]. Small human trials have
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been published with short-term results [37]. While promising, this approach is not widely employed and requires further investigation.
IV. RADIOTHERAPY
Foster Moore is largely credited with the first use of local radiation to treat an intraocular tumor. His implantation of radon seeds into an ocular ‘‘sarcoma’’ is perhaps the first documented case of brachytherapy for a choroidal tumor [38]. Today ocular plaques are among the most widely used organ-sparing treatment options available for small and medium-sized uveal melanomas. Teletherapy in the form of charged particles is an alternate means of delivering targeted radiation and is available at selected centers in the United States and Europe.
A.Brachytherapy
Over the twentieth century, advances in the design and construction of plaques have led to their expanded use in treating uveal melanomas. Following Moore’s initial work, Stallard experimented with brachytherapy by suturing radioactive seeds to the sclera overlying intraocular tumors [39]. Later, to ensure uniform dosimetry, he constructed metallic carriers that housed the seeds and could be directly sutured to the eye. Though melanomas were initially felt to be radioresistant, Stallard found that melanomas regressed if treated at doses greater than previously used. Plaques offer a means of delivering high-dose radiation directly to the tumor with reduced side effects to adjacent structures [40].
Cobalt 60 initially became the standard radiation source due to its availability, long half-life, and consistent dosimetry [41–43]. Plaques could be constructed and reused over a period of years (Fig. 4). The difficulty of shielding cobalt and the unintentional radiation of adjacent ocular structures led to experimentation with alternative radioactive sources. Gold, strontium, iridium, and palladium plaques have all been described in the literature [44–46]. Each source varies in its availability, complexity of dosimetry planning, type of radiation emitted, and ability to be shielded [47]. The past decade has seen a gradual trend toward the use of two major isotopes, iodine 125 (125I) and ruthenium 106 (106RU). 125I is primarily used in North America and was the source selected for the COMS study [48]. It is an emitter of low-energy gamma x-rays and can be used to treat tumors of various heights, generally up to 10.0 mm in thickness [49]. It is readily available and easily shielded with a thin rim of gold (Fig. 5A,B) [50–52]. By constructing plaques with standard inserts [53], the COMS study was able to ensure uniform dosimetry for tumors treated in this trial. Ruthenium was introduced by Lommatzsch in the 1960s, and it gradually replaced cobalt in most European oncology centers [54–57]. Unlike iodine, ruthenium is a beta emitter and is coated on a silver carrier. Worldwide, these two sources are used in the majority of plaques constructed for the treatment of uveal melanomas.
Clinically, plaques are best suited for the management of medium size and actively growing small uveal melanomas. Dosimetry plans are based on the apical measurements of the tumor, desired apex dose, and dose rate of the emitting source. Tumors of greater height require treatment plans that deliver larger doses to the
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Figure 4 Photograph showing a 60Co radioactive plaque being placed over the base of a uveal melanoma.
underlying sclera. Doses of 70–120 cGy to the tumor apex are described in the literature, but most centers treat melanomas at doses of 80–100 cGy [38,43,54,58– 61]. The COMS study initially chose a dose of 100 cGy, but reassessment of the
Figure 5 Photograph (A) depicting a gold-plated plaque with a Silastic insert designed for use with the radioactive isotope125I. This plaque was utilized in the Collaborative Ocular Melanoma Study (COMS). (B) Photograph showing plaque sutured in place over the base of the uveal melanoma.